Nutrition and Fitness - Mental Health, Aging

Nutrition and Fitness: Mental Health, Aging, and the Implementation of a Healthy Diet and Physical Activity Lifestyle Acknowledgement The publication of these proceedings is made possible by a grant from the Stavros S. Niarchos Foundation World Review of Nutrition and Dietetics Vol. 95 Series Editor Artemis P. Simopoulos The Center for Genetics, Nutrition and Health, Washington, D.C., USA Advisory Board Regina C. Casper USA Cuiqing Chang China Claudio Galli Italy Uri Goldbourt Israel C. Gopalan India Tomohito Hamazaki Japan Michel de Lorgeril France Victor A.Rogozkin Russia Leonard Storlien Sweden Ricardo Uauy-Dagach Chile Antonio Velázquez Mexico Mark L.Wahlqvist Australia Paul Walter Switzerland Bruce A.Watkins USA 5th International Conference on Nutrition and Fitness Athens, June 9–12, 2004 Nutrition and Fitness: Mental Health, Aging, and the Implementation of a Healthy Diet and Physical Activity Lifestyle Volume Editor Artemis P. Simopoulos The Center for Genetics, Nutrition and Health, Washington, D.C., USA 19 figures, 1 in color, and 26 tables, 2005 Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney June 9-12. Basel ISSN 0084–2230 ISBN 3–8055–7945–4 . Simopoulos. 6. without permission in writing from the publisher. or approval of the products or services advertised or of their effectiveness. aging.com Printed in Switzerland on acid-free paper by Reinhardt Druck.karger. . 4. aging. recording. or by any information storage and retrieval system. and the implementation of a healthy diet and physical activity lifestyle. p. This is particularly important when the recommended agent is a new and/or infrequently employed drug. ISSN 0084-2230 . Nutritionally induced diseases–Congresses. Series. Physical Fitness–Congresses. Aging–physiology–Congresses. options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The statements. 3. quality or safety. CH–4009 Basel (Switzerland) www. Box. Disclaimer. paper) 1.. This publication is listed in bibliographic services. methods. Health Behavior–Congresses. 95 [QP141] 612. [DNLM: 1. 1933. microcopying. – (World review of nutrition and dietetics. Physical fitness–Congresses. including photocopying. reproduced or utilized in any form or by any means electronic or mechanical. Diet. ISBN 3-8055-7945-4 (hard cover : alk.3 s–dc22 [612 2005013176 Bibliographic Indices. Mediterranean–Congresses. Includes bibliographical references and index. Nutrition–Congresses. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas. instructions or products referred to in the content or advertisements. QU 145 I60153nbc 2005] I. Title.Additional proceedings from the conference are published in volume 94 of this series Artemis P. 2. D. QP141. in view of ongoing research. No part of this publication may be translated into other languages. and the implementation of a healthy diet and physical activity lifestyle / volume editor. the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. cm. Nutrition and Health Washington. IV. 2004. Primary Prevention–Congresses.III. © Copyright 2005 by S. Title: Mental health. Artemis P.A1W59 vol. and the constant flow of information relating to drug therapy and drug reactions. 2. 7. Nutrition–Congresses. endorsement. 4. (USA) Library of Congress Cataloging-in-Publication Data International Conference on Nutrition and Fitness (5th : 2004 : Athens. v. P. Simopoulos The Center for Genetics. Simopoulos. All rights reserved. 5.O. 3. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. held in Athens. The appearance of advertisements in the book is not a warranty. Greece) Nutrition and fitness : mental health. Mental health–Nutritional aspects–Congresses. Health Promotion–Congresses. Artemis P. II.C. Drug Dosage. However. Karger AG. changes in government regulations. 95) Part 2 of the proceedings of the 5th International Conference on Nutrition and Fitness. If there is any deficiency in food or exercise the body will fall sick. . There must also be exercise. of which the effects must likewise be known. when proper attention is given to the season of the year. the age of the individual and the situation of his home. the changes of the winds. Positive health requires a knowledge of man’s primary constitution (which today we call genetics) and of the powers of various foods. The combination of these two things makes regimen. both those natural to them and those resulting from human skill (today’s processed food). But eating alone is not enough for health.Dedication The proceedings of the conference are dedicated to the concept of positive health as enunciated by the Hippocratic physicians (5th century BC). Olympian Ode 2004 Lee Pinkerson The Olympic games of Ancient Greece even more than athletic feats praise the spirit of life divine handed down from God through our ancestral line In body and soul. in heart and mind the ways of goodness they refined celebrated and known by all the Greek world unified in this concept. there’s no place for war Where the will to live burns bright they try with all their might awakening grace to join them and take flight every four years at the great Olympic games In the land of the wild olive branch the walnut and the honey bee embraced by a sea where the fish run free is a diet that is high in omega-3 The goats eat their fill of the plants on the hill so even the cheese has omega-3s The ancients had the nourishment they’d need to make them strong and make them smart fill the air with song and excel in the arts their world did dance in harmony . A CD recording of her singing and guitar performance was given to the conference program participants. Olympian Ode 2004 VII .com. they’re a way of life a torch to guide us past painful strife for possessions will not take us very far But the food we eat and the work we do the way we treat each other and the planet too will show how sweet we greet the daytime star every four years at the great Olympic games Lee Pinkerson wrote the lyrics and music for the Olympian song in February 2004 in honor of the 2004 Olympic Summer Games in Athens.And the walls would melt away when together they would play where race and class no longer separate every four years at the great Olympic games A millennium has come again the Olympics are back where they began let’s remember all they truly are More than a game. and for the Fifth International Conference on Nutrition and Fitness.leepinkerson. She can be reached from her website at http://www. .Commemorative 2004 Conference Medal Front Back Medal commemorating the 5th International Conference on Nutrition and Fitness. Greece. The medal is etched with the Olympic rings in honor of the 2004 Summer Olympic Games held in Athens. Berry.M.. A. Calif. (Jerusalem) IX . 1996 Keynote Address XXXIII Positive Health: Exploring Relevant Parameters Ferris. E.C. Osteoporosis.) Nutrition and Schizophrenia Peet. G. R.Contents XII Conference Organization XIV Preface XXV Declaration of Olympia on Nutrition and Fitness Ancient Olympia.E. Greece. Mood and Cognitive Function: The Influence of Nutrients and Physical Activity Casper. (Sheffield) Aging. M. (Stanford. (London) Mental Health 1 17 Psychiatric Disorders. May 28–29. and Physical Activity 29 Managing Obesity after Menopause: The Role of Physical Activity Dubnov. S. Mass.) Defining the Components of a Healthy Diet and Physical Activity for Health 80 What Is So Special about the Diet of Greece? The Scientific Evidence Simopoulos. Y. (Santiago) The Role of Government in Implementing a Healthy Diet and Physical Activity Lifestyle 140 Implications of Food Regulations for Novel Foods. (Columbia. Booth.C. Gillen. Patch.. L. S.J. D.. S. K. (Geneva) 52 Changes in Dietary Fatty Acids and Life Style as Major Factors for Rapidly Increasing Inflammatory Diseases and Elderly-Onset Diseases Okuyama.. The Evidence from Gene Transfer Studies Kang. (Washington. M.L.. Ichikawa. (Boston. M. (Wollongong) Contents X . Salen. J.. Australia. (Amherst.L...R. L.35 Osteoporosis: A Complex Disorder of Aging with Multiple Genetic and Environmental Determinants Ferrari. I. Leighton. (Grenoble) 115 The Nicotera Diet: The Reference Italian Mediterranean Diet Fidanza.C.. Safety and Labeling Lupien. (Nagoya) 62 Physical Activity for Health: An Overview Wahlqvist. Science and Practice Tapsell. F. D. Y. H. Fruttini. J. F. M. (Perugia) 122 Wine and Health: Evidence and Mechanisms Urquiaga. Fujii.. P. Combining Industry.W. Yamada.) 103 Dietary Prevention of Coronary Heart Disease: The Lyon Diet Heart Study and After de Lorgeril.X.P. A. Alberti.) 151 A New Look at Intersectoral Partnerships Supporting a Healthy Diet and Active Lifestyle: The Centre of Excellence in Functional Foods. A.. (Rome).S. Ito. Mass.) 93 Balance of Omega–6/Omega–3 Essential Fatty Acids Is Important for Health. (Melbourne) 73 Physical Inactivity Is a Disease Lees. F. C. Mo. 162 Why a Global Strategy on Diet. (Geneva) 167 Nutrition and Fitness Policies in the United States Lee.) 177 Author Index 178 Subject Index Contents XI . Physical Activity and Health? Waxman. Calif. A. P.R. (Stanford. Esq (USA) George P. Simopoulos. Organizing Committee Chair: Panos G. MD. PhD (Australia) Clyde Williams. MD (USA/Greece) Konstantinos N. Stewart Truswell. MD. MD (USA) Philip R. Pavlou Members: Elena Averoff Antonia Georgiopoulou XII . PhD (USA) Costas Parisis. PhD (Sweden) Bill Toomey (USA) A. Pavlou. MD. Lee. PhD (Greece) Konstantinos N. Wahlqvist. PhD (South Africa) Alexander Leaf. Casper. MD (USA/UK) Regina C. DSc (Greece) Executive Committee Frank W. PhD (Japan) José Ordovas. MD (Greece) Leonard Storlien.Conference Organization Conference Chair Artemis P. PhD (UK) Local Committees in Greece A. MD (USA) Conference Co-Chairs George P. DSs (Australia) Mark L. Chrousos. Stamatopoulos Co-chair: Leonidas N. Simopoulos. Stamatopoulos. MD. Seitanidis Secretaries: Evagelia Maglara Kalliopi – Anna Poulia Treasurer: Kostantinos N. PhD (Italy) Nikos Filaretos (Greece) C. Christakos. MD (Chile) Harumi Okuyama. Booth. PhD (China) Nicholas T. MD. MD (USA) Federico Leighton. MD. DSc (India) Sotiris Kitrilakis (Greece) Demetre Labadarios. DSc (Greece) Artemis P. Chrousos. Gopalan. MD. PhD. MD (USA/Greece) Raffaele De Caterina. Pavlou. MD (USA) Cuiqing Chang. PhD (USA) Peter Bourne. MD (USA) Eliot Sorel. MD (USA) Panos G. +1 202 462 5062 Fax +1 202 462 5241 E-Mail cgnh@bellatlantic. Suite 530 Washington. Rontoyannis Nikos Terzidis Nikos Yiannakouris B. Nutrition and Health 2001 S Street. Athens Hellenic Heart Foundation National Institute on Alcohol Abuse and Alcoholism. USA Onassis Cardiosurgery Center. DC 20009 (USA) Tel.net Major Sponsors The Center for Genetics. NIH.Maria Hassapidou Stavros Kavouras Sotiris Kitrilakis Saki Kypreou Konstantinos Natsis George P. N.. Scientific Committee Christos Aravanis Eleni Avlonitou Panos Behrakis Athina Bei Garifalia Emmanouil Dimitrios Hassiotis Nikos Katsilambros Denis Kokkinos Manousos Konstantoulakis Maria Liparaki Antonis Maillis Pantelis Nikolaou George P.W. Inc. Athens University of Thessaly XIII . Nutrition and Health Stavros S. Rontoyannis Yiannis Steriotis Pavlos Toutouzas Alexandros Tsopanakis Conference Organized by The Center for Genetics. Minami Nutrition/MorEPA/Barleans National Dairy Council (USA) Nutrilite Health Institute World Cancer Research Fund International/American Institute for Cancer Research Unilever In Co-Operation with Hellenic Association of Sports Medicine Hellenic Institute of Sports Research. Niarchos Foundation Conference Organization Under the Patronage of Food and Agriculture Organization of the United Nations International Union of Nutritional Sciences International Olympic Academy Committee for Athens 2004 Olympics Hellenic Ministry of Education Hellenic Ministry of Sports Conference Sponsors AstraZeneca Belovo California Walnut Commission/Walnut Marketing Board Harokopio University Hellenic American Union Hellenic Football Federation Mars. • Consider the psychosocial and other determinants of physical activity throughout the life cycle including intervention strategies. specifically. a former Olympic medalist and Vice President of the World Olympians Association. was entitled ‘Positive Health – Exploring Relevant Parameters’. • Determine the relationship of nutrition and fitness to chronic diseases. osteoporosis. mental health.Preface The Fifth International Conference on Nutrition and Fitness was held in Athens. This being the year when the Olympic Games were returned to the country of their origin. XIV . The goals and objectives of the conference were to: • Review and critique the latest scientific information on nutrition and fitness. the metabolic changes that occur with the type and amount of physical activity for the prevention and management of cardiovascular disease. diabetes and cancer. on June 9–12. from whom the elite athlete will be forthcoming. and emphasize healthy lifestyles consistent with proper nutrition and fitness. adaptation throughout the life cycle and the nutritional factors that contribute to fitness. the keynote address given by Elizabeth Ferris. throughout the life cycle. Greece. 2004. obesity. MD. the effect of the various dietary sources of energy on energy expenditure. • Stimulate national governments and the private sector to coordinate and thus maximize their efforts to develop programs that encourage proper nutrition and participation in sports activities by all. particularly. exercise and performance. taking into consideration genetic endowment. to achieve their potential in fitness and thus increase the pool of young athletes. and cancer. Both volumes begin with the Dedication to the concept of ‘Positive Health’. Volume 95 is entitled Nutrition and Fitness: Mental Health. The address sets the stage for the importance of physical activity in health and the deleterious effects of inactivity. cardiovascular disease. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. Asia. diabetes. the Metabolic Syndrome. Europe. syndrome X. and Cancer. Volume 94 is entitled Nutrition and Fitness: Obesity. This. discusses the role of physical activity or exercise on the occurrence of obesity. based on the individual and in the 21st Century proving it through molecular biology. It is expected that in the 21st Century scientific information will be developed that will deliver individualized genotype-based health care. The papers on obesity emphasize the severe burden of obesity worldwide and the need to have a classification system of obesity that relates to the specific population from whence the data were obtained that relate obesity to morbidity and mortality. specifically the function and effectiveness of exercise on weight reduction and a prescription for weight loss. and Cancer presents the papers on obesity. Cardiovascular Disease. in their paper on ‘Obesity in Preface XV . in her paper on ‘Exercise and Obesity in China’. the Metabolic Syndrome. The conference consisted of 10 sessions of oral presentations and 2 poster sessions in which 110 abstracts were presented.. clearly discuss the fact that these populations are at risk for the development of chronic diseases at lower body mass index (BMI) levels than Caucasians. Australia/New Zealand. the 1996 ‘Declaration of Olympia on Nutrition and Fitness’ and the Keynote Address entitled ‘Positive Health – Exploring Relevant Parameters’ by Elizabeth Ferris. through the establishment of regional committees. represents a complete circle returning and recognizing the Hippocratic concept of ‘positive health’ of 2500 years ago. Cardiovascular Disease. MD. and North and South America. the Commemorative Medal. Volume 94 entitled Nutrition and Fitness: Obesity. Scientists from 46 countries participated representing the continents of Africa. Cuiqing Chang. Kafatos et al. the Preface. China has developed guidelines and recommendations for the classification of obesity. the 2004 Olympian Ode by Lee Pinkerson. Kanazawa and his coworkers in their paper ‘Criteria and Classification of Obesity in Japan and Asia-Oceania Region’ presented by Shuji Inoue. The proceedings of the conference are presented in two volumes in this series. the Conference Organization. The Olympic spirit and the Olympic games celebrate achievement and the individual. Aging. of course. A conscious effort must be made to develop in all dimensions the environment in which the human genome finds its optimal expression.• Develop strategies for the distribution and implementation worldwide of the 1996 ‘Declaration of Olympia on Nutrition and Fitness’ for the New Millennium. Drs. As a result. and the boys fair worse than the girls. diabetes and cardiovascular disease. The program is one of the few programs in Europe to have reported positive results in terms of obesity and physical fitness in primary schools in Crete. emphasize the importance of body composition to evaluate health status in nutritional terms both at the population level and for the individual. in their paper on ‘Physical Activity and Body Composition’. in their paper ‘Epidemiology of Physical Activity from Adolescence to Young Adulthood’. Tatarani concluded that molecular and epidemiologic evidence from the studies in Pima Indians suggests that the abnormalities constituting the metabolic syndrome are the result of largely independent physiologic processes. clinical treatment and prevention strategies based on the ‘metabolic Preface XVI . businesses. Educational interventions in schools have great potential needed to tackle the urgent problems of dietary and lifestyle choices contributing to the blight of childhood obesity and its co-morbidities. The authors recommend multi-component intervention strategies at the societal and individual levels for weight control that include health professionals. The study failed to identify a single factor underlying the correlation structure of these variables. Aaron and coworkers. The results of this first national population-based study show that adolescent obesity is largely caused by lack of physical activity. Andreoli and De Lorenzo. Tataranni’s paper is on ‘Metabolic Syndrome: Is There a Pathophysiological Common Denominator? Lessons Learned from the Pima Indians. lipids and blood pressure may result from a single etiologic abnormality. schools.’ In addition to clinical physiologic and molecular studies. Therefore. The approach to its treatment includes lifestyle modification along with pharmacological therapy. in order to increase programs and opportunities for physical activity. as appropriate. body size. Labadarios. The paper on ‘Adolescent Obesity and Physical Activity’ by Hwalla's group describes the study carried out in Lebanon.Childhood: The Greek Experience’. a specific program in which the teacher uses ‘customized’ classroom materials that include a physical activity component and parental involvement. he carried out a factor analysis designed to statistically test the hypothesis that insulinemia. and health care organizations. presents the Greek experience. families. in his paper ‘Syndrome X: Clinical Aspects’ presents an overview of syndrome X and its relationship to obesity. provide a synthesis of the current knowledge about the epidemiology of physical activity during the transition from adolescence to young adulthood. inadequate nutrition and physical activity are related to an increase in risk factors and the need for health promotion programs. The etiology of the metabolic syndrome is not well understood. Pavlovic and colleagues indicate in their paper titled ‘Nutrition and Physical Activity of the Population in Serbia’ that for both children and adults. those with the metabolic syndrome. i. Common dietary components. Physical activity protects or reduces the risk for the development of cardiovascular disease by indirectly reducing a number of cardiovascular disease risk factors such as high blood pressure. Storlien and coworkers refer to thiazolidinediones. and also promoting direct anti-atherogenic vascular responses through the action of increased laminar shear on endothelial cells. the only really new class of anti-diabetic therapy introduced in the past few years. permitting or Preface XVII . thus enhancing both the health benefits and the likelihood of compliance. and are providing molecular explanations on how healthy or unhealthy lifestyles interact with our genes. While exercise training clearly moves muscle morphology and metabolism in a beneficial direction. as a prime example. obesity and diabetes. are potent gene regulators on many ‘pharmaceutical’ metabolic syndrome targets. Drs. The authors discuss their studies on the role of omega–3 fatty acids in modulating the immune system and suppressing vascular cell adhesion molecules. This class of drugs targets the nuclear hormone receptor PPAR␥ and the relationship between weight gain and PPAR␥2 polymorphism is highly dependent on the dietary polyunsaturated/saturated (P/S) ratio. greatly dependent upon understanding the individual’s genetic make up.’s paper on ‘Lifestyle-Gene-Drug Interactions in Relation to the Metabolic Syndrome’ emphasizes the fact that obesity drives the metabolic syndrome and the polygenic nature of disorders like obesity means that there will be a need for many approaches that will include lifestyle changes along with pharmaceutical support. Donati and Iacoviello’s paper on ‘Coronary Heart Disease. Recent advances resulting from studies of vascular biology using molecular biology techniques are revealing a previously unsuspected complexity of the vascular responses to nutrients and physical activity. such as fatty acids and simple sugars. Nutrition and Physical Activity’ discusses gene polymorphisms and their interactions with diet and physical activity as they affect lipids. Genetics. Therefore. hypercholesterolemia. hemostatic and vascular factors. De Caterina and Madonna in their paper ‘Role of Nutrients and Physical Activity in Gene Expression’ review the subject of how the rapid evolution of vascular and molecular biology in the last 20 years has completely transformed our understanding of the development of coronary heart disease.e. Storlien et al. it is necessary to understand how drug/diet interactions might act as a multiplier for the beneficial effects of exercise. There are strong indications that modulating muscle metabolism would be of enormous benefit in prevention and treatment of obesity. there is marked genetic heterogeneity in both compliance and response to exercise training in the needy population. Novel drugs are almost certain to interact strongly with dietary and other lifestyle variables.syndrome’ hypothesis may prove suboptimal compared with treatment of the individual components. Possible mechanisms include the lower cardiac output and peripheral vascular resistance at rest. This has serious implications in providing solid scientific background for preventive strategies that will focus on healthy nutrition. the reduction in blood catecholamine levels and plasma renin activity. All methods of dietary assessment are associated with measurement error. Rontoyannis’ paper ‘Physical Activity and Hypertension: An Overview’ focuses on the benefits of exercise in the control of blood pressure. Marangoni’s group. who already had one episode of heart attack. among others. In her paper ‘Measurement Error in the Assessment of Interaction between Dietary and Genetic Factors in Cohort Studies of Cancer. Only a few studies have reported data on the fatty acid composition of circulating lipids in confirmation of dietary intake. most likely due to the way in which dietary intake has been measured. The method has been validated. in addition to other medications. Rontoyannis emphasizes that walking may be the best and safest aerobic physical activity. does not require health personnel. There has been a lack of consistency in the data relating diet and cancer in cohort studies. less expensive than other methods. is rapid. The studies on the beneficial effects of the omega–3 fatty acids in both the primary and secondary prevention of coronary heart disease demand the development of methods to measure circulating fatty acids at the population level. even in the presence of unfavorable genes. Recent data on the prevention of fatal ventricular arrhythmia in humans indicate that cardiologists should prescribe 1 g of omega–3 fatty acids (EPA + DHA) to their patients. and provides valuable information on the impact of dietary habits. in their paper ‘A Method for the Direct Evaluation of the Fatty Acid Status in a Drop of Blood from a Fingertip in Humans: Application to Population Studies and Correlations with Biological Parameters’ discuss their method to determine fatty acids. The underlying mechanisms responsible for an exercise-induced reduction in blood pressure remain unclear. lifestyles and fatty acid supplementation on blood fatty acids. is applicable to population groups. the altered renal function leads to increased elimination of sodium resulting in a reduction of blood volume.inhibiting the expression of the phenotype. and the reduction in insulin levels and insulin resistance. on ‘Omega–3 Fatty Acids and Ventricular Arrhythmias’ presents a thorough review and new information on how omega–3 fatty acids decrease ventricular arrhythmia and sudden death. physical activity and life habits. This fact attenuates estimates of disease risk and reduces statistical power so that a relation between diet and disease may be obscured. Leaf showed that the effect of omega–3 fatty acids is to stabilize electrically every contractile cell in the heart. The next paper by Leaf and colleagues.’ Bingham points out that the effect of error on regression dilution and estimated sample size is compounded when Preface XVIII . and at any given submaximal levels of work. Physical activity is an important component of healthy lifestyles. Similar results were obtained by Tavani et al. in his paper ‘Cancer Risk Reduction by Physical Exercise’ reviews the evidence of the effect of physical activity on cancer development and concludes that there is enough evidence to recommend physical activity for life (long-term) for the prevention of certain cancers. In their studies. This could be due to the age of the indigenous population (the population is young) or to the level of physical activity. are compared with those from another assessed more accurate method.’ Bougnoux and colleagues clearly demonstrate the importance of dietary components in the etiology and development of breast cancer.070 women. usually a Food Frequency Questionnaire. and for the omega–6/omega–3 long chain fatty acids. dietary changes do not show a relationship with cancer. and the risk of selected neoplasms. Willer. In their paper ‘Fish. Volume 95 is part 2 of the proceedings. Traditionally repeat results from the method used in a cohort. the higher the estimated relative risk of breast cancer. they found alpha-linolenic acid and docosahexaenoic acid to be inversely related to the risk of breast cancer. especially of the gastrointestinal tract. These results support the view that measurement error might explain the lack of relationship between fat and breast cancer risk in previous prospective studies using data obtained by Food Frequency Questionnaires. ␻–3 Polyunsaturated Fat Intake and Cancer at Selected Sites’ they investigated the relation between fish consumption and omega–3 polyunsaturated fatty acids. Bingham therefore assessed dietary intake using both a food frequency questionnaire and a detailed seven day diary of food and drink in 13. Among the fatty acids. The higher the omega–6/omega–3 ratio. The hazard ratio for breast cancer for each quintile increase of energy adjusted fat was strongly associated with saturated fat intake measured using the food diary. Nutrition and Fitness: Mental Health. thus violating a critical requirement of this procedure. the omega–6/omega–3 ratio and omega–3 fatty acids have been Preface XIX . but not with saturated fat using the food frequency questionnaire. Aging. However. arachidonic acid.attempts are made to assess the interactions between dietary and genetic polymorphisms in assessing risk. errors between methods may be correlated so that results from the reference method are not independent of those derived from the test method. whereas they do in other chronic diseases such as obesity and diabetes. Muñoz Rivera and coworkers in their paper ‘Cancer Frequency in Poor Rural Communities Consuming a Very Limited Diet’ conclude that in Mexico. In the next paper ‘Omega–6/Omega–3 Polyunsaturated Fatty Acids Ratio and Breast Cancer. Nutrition and physical activity influence mental health. Their data show that consumption of even small amounts of fish decreases the risk of several cancers. where the trend was opposite for linoleic acid. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. Ferrari. Dubnov and Berry in their paper ‘Managing Obesity after Menopause: The Role of Physical Activity’ carried out a Medline and manual search for articles on overweight and obesity following menopause. Peet. the risks and methods of treatment emphasizing physical activity. Inflammation is now considered to be at the basis of many chronic diseases and conditions including aging. because overweight and obesity occurs in over 50% of that population. attention deficit disorders and dementia. Peet reviews the evidence that a low saturated fat and low sugar diet may be beneficial. atherosclerosis related diseases and pneumonia. particularly estrogen-deficient women and those with low calcium intake and genes associated with vertebral bone mass and size in adult men.studied in patients with depression. in his paper ‘Osteoporosis: A Complex Disorder of Aging with Multiple Genetic and Environmental Determinants’ reviews the genetic and environmental factors influencing bone turnover and bone density. but this has not been tested in controlled clinical trials. physical activity is a major mode of treatment and postmenopausal women should engage in physical activity daily. Mood and Cognitive Function: The Influence of Nutrients and Physical Activity’ reviews studies that have related variations in the amount of protein. and polyunsaturated fatty acids to mood changes. carbohydrates. Efficacy data on omega–3 fatty acids used as adjunct or in monotherapy in unipolar and bipolar depressive disorders are critically reviewed. which is brought about by excessive intake of linoleic Preface XX . Their results show that among postmenopausal women. Casper in her paper on ‘Psychiatric Disorders. bipolar disorders. suggests that genetic variation could emerge as an important variable mediating the effects between nutrition and mental disorders. in relation to mood and cognitive function. in their paper ‘Changes in Dietary Fatty Acids and Life Style as Major Factors for Rapidly Increasing Inflammatory Diseases and Elderly-Onset Diseases’ indicate that the major elderly-onset diseases in Japan are cancer. Casper also presents an evaluation of the literature that addresses the relationship between regular physical activity in the form of exercise. in particular the schizophreniform disorders. but also multigenic diseases. The usefulness of the gene variants or polymorphisms in predicting fracture risk and response to therapy remains to be demonstrated. amino acids. Increasing evidence that psychiatric disorders are not only multifactorial. Okuyama and coworkers. Evidence now exists that prenatal exposure to wartime famine may have had a bearing on the development of psychomorbidity. In addition to omega–3 fatty acid intervention studies. schizophrenia. Elevation of inflammatory tone is a likely major cause for these diseases. in his paper ‘Nutrition and Schizophrenia’ presents a critical review and evaluation of the literature on the role of dietary components on schizophrenia. worms and yeast. Whether any. This has been proven repeatedly in a variety of species including rats. or the growing burden of nutritional and metabolic disease. Mo. Diet and physical activity cannot be disassociated from each other. Changes in life style. Furthermore. omega–6) cascade. Reduced frequency of skin exposure to environmental changes (temperature. In experiments of nature. sustain and optimize movement. Because omega–6 and omega–3 fatty acids and their metabolites (eicosanoids. We must seek a unifying strategy for Preface XXI . mice. humans have been subjected to periods of non-volitional partial starvation. La. is an important factor in regulating the inflammatory tone and related diseases. However. not only the absolute amounts of omega–6 and omega–3 fatty acids. CR reduces metabolic rate and oxidative stress. or all of. fish. such as decreased physical activity and overnutrition in older populations lead to unfavorable energy balance.. Md. particularly the omega–6/omega–3 ratio. USA. improves insulin sensitivity and stress response. and at Washington University in St.. Caloric restriction (CR) is the only mechanism known to extend life span and retard age-related chronic diseases. sweating conditions) is a likely cause for enhanced skin and mucosal sensitivity to allergens in younger populations. These environmental factors could be modified by changing the life style. but also because of the profile of food components – macronutrients. the effects of prolonged CR on biomarkers of aging in nonobese humans are unknown. micronutrients and phytonutrients – which allow. not only because of energy need. at Tufts University in Boston. inflammatory mediators) are competitive at many steps of enzyme reactions and receptors. the results have been elusive. Therapeutic physical activity can reduce the problems of sarcopenia and frailty. and of senescence. USA) at the Pennington Biomedical Research Center in Baton Rouge. and alters neuroendocrine and sympathetic nervous system function. flies. Louis. besides choosing foods to keep a good omega–6/omega–3 fatty acid balance. Massachusetts. The absence of adequate information on the effects of good quality CR diets in non-obese humans reflects the difficulties involved in conducting long-term studies in an environment so conducive to overfeeding. In his paper ‘Physical Activity for Health: An Overview’ Wahlqvist states that preventive physical activity can address the burden of disease and longevity. but their balance. these changes provide the mechanism for life-span extension effect is presently unresolved..acid (LA. in almost all of these cases the diets have been of poor quality. Despite the enormous interest in uncovering longevity genes in humans. omega–6) and enhanced arachidonic acid (AA. The effects of physical activity in delaying aging are promising whereas the effects of caloric restriction in humans are now being systematically investigated in three major studies funded by the National Institutes of Health (Bethesda. Similar results have been observed in studies in India showing that the lower the ratio. traditional diets do not differ much or are similar in their composition relative to antioxidants.8:1 in the diet of the United States and 15:1 in the diet of Northern Europe. we must involve ourselves continuing as our own machines. coronary heart disease mortality. is the diet that is the closest to the diet on which humans evolved. Furthermore. there are exciting research data defining the type and frequency of genetic variation and how genetic differences influence dietary response and how diet. the lower the risk for total mortality. the ratio was balanced 1:1 whereas this ratio is 16. moving. essential fatty acids and a balanced omega–6/omega–3 ratio. but in the form of a Greco-Roman Temple rather than the Preface XXII . Lees and Booth in their paper ‘Physical Inactivity Is a Disease’ provide a concise review of the evidence of the importance of physical activity in the prevention of many diseases that affect modern humans.health advancement and for optimal health that is sustainable. What makes the diet of Crete different from the other Mediterranean diets is the balanced omega–6/omega–3 ratio of 1–2/1. nutrients and exercise influence gene expression. At the same time. In her paper ‘What Is So Special about the Diet of Greece? The Scientific Evidence.’ Simopoulos provides scientific evidence and emphasizes the importance to follow a diet consistent in composition to the diet upon which humans evolved. and their genes were programmed to respond. de Lorgeril and Salen in their paper ‘Dietary Prevention of Coronary Heart Disease: The Lyon Heart Study and After’ clearly show the fact that a modified diet of Crete with a ratio of 4:1 of linoleic to alphalinolenic acid decreased mortality risk by 70%. and integrated with the natural world. but 4:1 in Japan and 30:1 in India. balanced in the essential fatty acids and high in antioxidants. In order to accomplish that. socializing. and sudden death. There is now enough evidence to consider physical inactivity a disease. In his paper ‘Balance of Omega–6/Omega–3 Essential Fatty Acids Is Important for Health: The Evidence from Gene Transfer Studies’ Kang provides evidence at the molecular level of the importance of the balanced omega–6/omega–3 ratio. The latter is very important because during evolution. The Greek diet. In this respect. There is now enough evidence to define the components of a healthy diet as well as the components of physical activity at the population level. because epidemiologic studies provide robust evidence that physical inactivity is strongly associated with an enhanced risk of premature chronic diseases and death. thinking. Fidanza and coworkers in their paper ‘The Nicotera Diet: The Reference Italian Mediterranean Diet’ describe the Nicotera Diet as a model for the Italian population and present a food guide modeled after the Greek Column Food Guide. or help in the cure of some conditions. It will be necessary to develop a broad-based population approach that includes improving accessibility of nutrition information. The World Health Organization (WHO) has recognized the importance of nutrition and physical activity. The ‘Nutrition and Fitness Policies in the United States’ are discussed by Lee who reviews the programs and policies in the United States and the reasons for the difficulties in their implementation. Decreased cardiovascular disease and longevity are epidemiological parameters associated with wine consumption. at the World Health Assembly. In May 2004. Science and Practice’ outline the basis for the scientific program at the Centre of Excellence in Functional Foods. education. Australia is one of the first countries to establish a Centre of Excellence in Functional Foods. Lupien’s paper on ‘Implications of Food Regulations for Novel Foods: Safety and Labeling’ includes a concise description of the regulatory schemes in the European community. indicating how this may support the development of healthy diets and healthy lifestyles. New Zealand. the United States. Research at the center takes the form of strategic (government funded) and commercial (industry funded) projects. strengthening and sustaining broad-based community Preface XXIII . Japan and China. help prevent various non-communicable diseases. Functional foods are thought to be foods that improve bodily functions. member nations voted on WHO’s Global Strategy on Diet. Wine is an important component in the diets among the Mediterranean countries as well as in South America. Combining Industry. Over the last 15 years. new concepts have evolved about food’s functions. The paper provides examples of current functional food benefits and claims. and services. Australia.Pyramid Food Guide developed by the US Department of Agriculture and the US Department of Health and Human Services. Physical Activity and Health that appears in the paper by Amalia Waxman. Recent evidence suggests that longevity could also be the direct consequence of phenolics activating histone deacetylation. The need for adequate data is emphasized in order to substantiate claims and benefits to meet current and possible future regulatory requirements. Tapsell and coworkers in their paper ‘A New Look at Intersectoral Partnerships Supporting a Healthy Diet and Active Lifestyle: the Centre of Excellence in Functional Foods. There has been a wide range of research into the beneficial effects of foods and food ingredients. a gene expression regulatory mechanism proposed to explain the longevity associated with caloric restriction. Urquiaga and Leighton’s paper on ‘Wine and Health: Evidence and Mechanisms’ is an excellent review of the status of research on wine. beyond essential nutritional requirements for macronutrients and essential vitamins and minerals. Australia. programs and partnerships. food scientists and policy makers in government. dietitians. and working with the nation’s public and private elementary and secondary schools. nutritionists. geneticists. exercise physiologists. Similarly. private industry and international organizations. a population-based approach to physical activity is needed. Simopoulos. These proceedings should be of interest to physicians. MD Preface XXIV . Artemis P. both those natural to them and those resulting from human skill (today’s processed food). But eating alone is not enough for health. an international panel composed of members of the conference Executive Committee. The combination of these two things makes regimen. diet and physical activity. Greece. There must also be exercise. ‘Positive health requires a knowledge of man’s primary constitution (which today we call genetics) and of the powers of various foods. May 28–29. in Athens. it is important to reaffirm the concepts of positive health postulated by Hippocrates and to reassess their relevance to the Olympic ideal and the health of the world’s population. The Third International Conference on Nutrition and Fitness was held at the Olympic Athletic Center of Athens ‘Spyros Louis’. is based on the interaction of genetics. 1996 Background The International Conferences on Nutrition and Fitness are held in Greece every 4 years in the spring prior to the Olympic Games. Greece. 1996. met at the International Olympic Academy at Ancient Olympia to develop the ‘Declaration of Olympia on Nutrition and Fitness’ for 1996. XXV . If there is any deficiency in food or exercise the body will fall sick’ (480 BC). The concept of Positive Health. the changes of the winds. Following each conference.Declaration of Olympia on Nutrition and Fitness Ancient Olympia. May 24–27. the age of the individual and the situation of his home. Four hundred and eighty participants from 31 countries attended the conference. when proper attention is given to the season of the year. This international panel agreed that on the occasion of the 100th anniversary of the Olympic Games. The proceedings of the conferences are published in the scientific literature listed on pages XXXI–XXXII. a declaration is developed at a special meeting at the International Olympic Academy to update advice on nutrition and fitness for all. of which the effects must likewise be known. Following the conference. along with the session chairs. as enunciated by Hippocrates. and to this end put themselves into the hands of trainers who subjected them to a regimen. occupation. Each human being. Health was an excellence in its own right. The Concept of Positive Health may be represented by a triangle involving genetics. nutrition and physical activity that influence the spiritual. is exceptional in some way. Genetic variation is due to variants at a single locus. including the ability to handle environmental challenges. Nutrition and physical activity (exercise) are two of the most important environmental factors in maintaining health and well being. Training for war and athletic competition was of course well known among them. The details of the regimen practiced for health were an important part of Greek medicine. Physical Activity. sex. which they often conceived esthetically. that form the basis of human diversity. Those who had the means and the leisure applied themselves to maintaining positive health. 1. and Health The interaction between genetic and environmental factors influences human development and is the foundation for health and disease. 1). The interaction of genetics. time. Genetic Variation. Nutrition. Individuality is determined by genes. Genetic factors define susceptibility to disease and environmental factors determine which genetically susceptible individuals will be affected. the concept of positive health was important and occupied much of their thinking. developmental socio-economic status. geography. Among the Greeks. in being unique. and climate). mental and physical aspects of health (fig. constitutional factors (age. How extensively variable the human species is depends on the methods used for the determination of variability. or polymorphisms. nutrition and physical activity influences the spiritual. education. there is a Declaration of Olympia on Nutrition and Fitness XXVI . At the DNA level. the physical counterpart and condition of mental activation.Spiritual Genetics Nutrition Physical activity Physical Mental Fig. mental and physical aspects of health. Because of differences in gene frequency. Nutrients and physical activity influence gene expression. but obesity is rampant in many industrialized societies. but in affluent populations. to a lesser or greater degree. Diet The purpose of diet is to supply energy and nutrients required for optimal health. Energy intake must be balanced against physical activity. mainly by decreases in saturated and trans fatty acids. Micronutrients Adequate balanced micronutrient intake should be provided commensurate with emerging understanding of their need. In many conditions. excess fat promotes chronic degenerative diseases. including humans and practically all other organisms examined. an increased fat intake may be necessary to enhance energy availability and to insure absorption of fat soluble vitamins. Carbohydrate containing foods and soluble and insoluble fiber are needed for energy intake and normal bodily function. Instead. Changes in the nutritional environment and the type and degree of physical activity affect heritability of the variant phenotypes that are dependent. An average individual is heterozygous at about 10% of the loci. Macronutrients Fat is a concentrated energy source. Since the most extensive nutritional Declaration of Olympia on Nutrition and Fitness XXVII . dietary habits. Alleles that confer selective advantage in the heterozygous state are likely to have increased in prevalence because of positive selection acting on variants. proper diet and exercise have similar beneficial effects. there is much less. Protein intake should be adequate for normal growth and development and in adults for maintenance of body structures.great deal of variation. All populations need essential polyunsaturated fatty acids for mental and cardiovascular health. whereas at the level of protein diversity. universal dietary and physical activity recommendations are not appropriate. Genetic variation influences the response to diet. total fat intake should be reduced. on these environmental variables for their expression. but such increases should avoid adding saturated fats where practicable. In all animals. An omega–6:omega–3 fatty acid ratio of 4:1 or less appears desirable. knowledge of specific genes and response to exercise and diet should guide advice for health in the prevention and management of chronic diseases. Over 800 million humans are chronically energy deficient. In energy-deficient populations. and activity levels. and their effects may be additive. 30% of loci have polymorphic variants in the population. In such circumstances. increased levels of physical activity positively impact virtually all chronic diseases. improving body functions and protecting from illness. flexibility and body composition improve with increases in activity levels. Health-promoting physical activities aim at promoting growth. Because mechanization and industrialization have reduced occupational physical activity levels. Although low physical activity levels most frequently occur in more industrialized. Declaration of Olympia on Nutrition and Fitness XXVIII . coordination. special attention should be directed to correcting these deficiencies: 2 thousand million persons are anemic and 1 thousand million are at risk of iodine deficiency. even nontaxing physical activities such as walking. including aerobic capacity. Most populations would benefit from an increased intake of fruits and vegetables. and swimming can elicit improved health. Furthermore. muscular strength and endurance. and health workers should keep up-to-date with this new knowledge regarding both deficiencies and optimal requirements. Physical activity also has a well-known role in preventing and reducing obesity and also exerts a beneficial influence upon insulin metabolism. and some forms of cancer. 40 million children suffer vitamin A deficiency. Three of the most common chronic degenerative diseases of westernized nations (hypertension. peripheral artery disease. affluent nations. coronary heart disease. including. but not limited to stroke. In all three cases. e.influences throughout the world are related to inadequacies of micronutrients. Perhaps more importantly. bicycling. and outcome of these diseases. indices of human health also improve. Table 1 lists the types of physical activity. coronary heart disease. Understanding of micronutrient functions is currently increasing. Exercise prescription (regimen) as a means of treating or reversing various diseases should be considered as an essential therapeutic component. and noninsulin-dependent diabetes mellitus) are increasingly being recognized as diseases of insulin resistance. Sports training physical activities should include daily training programs in preparation for competition. the need for unitary ratios of calcium and magnesium in the diet. this behavior is becoming increasingly common in developing countries as well. gardening. For previously sedentary individuals. and reduce all causes of morbidity and mortality. osteoporosis.g. Physical Activity A wealth of scientific reports points to the inescapable conclusion that human fitness and health improve when sedentary individuals begin to exercise. A wide variety of fitness parameters. chronic obstructive pulmonary disease. a need exists to supplement with additional daily physical activities designed to improve health and fitness. physical activity clearly has been shown to reduce the severity. The variety of foods in the diets helps to maintain adequate micronutrient intake. and radio – at worksites. sports. undernutrition and malnutrition. and entertainment. The food and sports foods industry needs to be cognizant of the scientific evidence regarding optimal nutrition and physical activity levels. Leisure-recreational (exercise). Education about the beneficial physical and psychological effects of proper nutrition and physical activity in health and disease needs to be directed at all age groups – children. Education needs to address the detrimental effects of sedentary life-styles. breathing rate) All daily nonlabor minimum physical activities necessary for life maintenance Labor physical activities Industrial Agriculture Carpentry Homecare.g. etc. and in the community in order to reach everybody in the population. Education Education about nutrition and physical activity needs to be adapted to each country and to different populations and cultures. adults. in particular for children. low-to-moderate intensity of physical activities Walking Dancing Hiking Bowling Cycling Golf. Defining physical activity 1 2 3 Nonlabor daily physical activities Feeding Bodily functions (e. Education about opportunities to obtain proper nutrition and to carry out physical activity is important in view of findings that actual increases in elective physical activity depend on accessibility. Education should reach people through various channels – the mass media. There is a particular need for education of health professionals and health workers. Another means to achieve education would be through role models in the family. Another means of education would be the labelling of the nutritional composition of all foods sold. and educators. heart rate. television. Institutions such as schools can set examples for proper nutrition and physical activity. nutrition and sport scientists. and the elderly – since research has shown that awareness of the benefits of physical activity is correlated with actual physical activity. temperature regulation. etc. Declaration of Olympia on Nutrition and Fitness XXIX . print.Table 1. schools. osteoporosis. using large muscle groups rhythmically and repetitively. protein. (2) Every child and adult needs sufficient food and physical activity to express their genetic potential for growth. D. iodine. Special attention to adequate nutrition should be given to competitive athletes. essential fatty acids. dietary imbalance and a sedentary lifestyle. (7) Education regarding healthy nutrition and physical activity must begin early and continue throughout life. For sedentary populations. iron. mental and spiritual well-being. food consumption may need to be increased to meet their energy needs. potassium and zinc). (6) The attainment of metabolic fitness through energy balance. E and the B complex) and minerals (particularly calcium. particularly protective antioxidants and essential fatty acids. Nutrition and physical activity must be interwoven into the curriculum of school age children and of educators. Genes define opportunities for health and susceptibility to disease.Declaration (1) Nutrition and physical activity interact in harmony and are the two most important positive factors that contribute to metabolic fitness and health interacting with the genetic endowment of the individual. Metabolic fitness maintains and improves musculoskeletal function. physical activity must be increased. (5) The current level of physical activity should match more closely our genetic endowment. C. and inadequate opportunities for physical activity impair the attainment of overall health and musculoskeletal function. some cancers. (4) Nutrient intakes should match more closely human evolutionary heritage. mobility. For all ages and both genders the physical activity should be appropriately vigorous and of sufficient duration. (3) Balancing physical activity and good nutrition for fitness is best illustrated by the concept of energy intake and output. and intensity. and the activities of daily living into old age. good nutrition and physical activity reduces the risk of and forms the treatment framework for many modern lifestyle diseases such as diabetes mellitus. frequency. vitamins (particularly vitamins A. individual variation may need to be considered to achieve optimal health and to correct disorders associated with micronutrient deficiency. while environmental factors determine which susceptible individuals will develop illness. and cardiovascular disorders. Reestablishment of regular physical activity into everyday life on a daily basis is essential for physical. hypertension. nutritionists Declaration of Olympia on Nutrition and Fitness XXX . obesity. development. and health. The choice of foods should lead to a diverse diet high in fruits and vegetables and rich in essential nutrients. Therefore. Insufficient consumption of energy. for populations engaging in intense occupational and/or recreational physical activities. The ten points of the declaration have been printed in these languages. UK Gilman Grave. China Artemis P. MD (Cochairman). The copyright is held by the Executive Committee of the Conference. Boyd Eaton. Tanzania. Distribution of the Declaration The declaration has been published worldwide in newsletters. Basel. regular physical activity. William Clay. MD. (10) The ancient Greeks (Hellenes) attained a high level of civilization based on good nutrition. the community. (9) National governments and the private sector must coordinate their efforts to encourage good nutrition and physical activity throughout the life cycle and thus increase the pool of physically fit individuals who emulate the Olympic ideal. MD. USA References 1 2 Simopoulos AP (ed): Proceedings of the First International Conference on Nutrition and Fitness. stronger and fitter through regular physical activity and good nutrition.49(suppl):909–1124. Pavlou KN (eds): Volume I. Modern men. USA Catherine Siandwazi. Birrer. and children can emulate this Olympic ideal and become swifter. Proceedings of the Second International Conference on Nutrition and Fitness. 1993. and intellectual development. USA Peter G. World Rev Nutr Diet. Karger. Greece Regina Casper. Lee. Simopoulos AP. MD. Russian and Spanish. They strove for excellence in mind and body. ScD. and societal resources are necessary to reject unhealthy lifestyles and to embrace an active lifestyle and good nutrition. vol 71. Positive role models must be developed and prompted by society and the media. (8) Major personal behavioral changes supported by the family. women. S. USA (Secretary). MD Philip R. MD. The declaration was developed at Ancient Olympia. FAO. Bourne. May 28–29. USA USA. French. Pavlou. USA Richard B. UK Ji Di Chen. PhD. USA Konstantinos N.and other health professionals.1996 by the following persons: Alexander Leaf. Am J Clin Nutr 1989. MD. MD (Cochairman). Simopoulos. MD. United Nations USA Loren Cordain. It has been translated into the Olympic languages of Chinese. The Executive Committee wishes to encourage the translation and distribution of the declaration worldwide. Nutrition and Fitness for Athletes. magazines and journals. Declaration of Olympia on Nutrition and Fitness XXXI . Greek. World Rev Nutr Diet. Proceedings of the Second International Conference on Nutrition and Fitness. Nutrition and Fitness: Metabolic Studies in Health and Disease. Basel. World Rev Nutr Diet. Nutrition and Fitness: Diet. Nutrition and Fitness: Evolutionary Aspects. Policies and Programs. 1993. 1997. vol 72. World Rev Nutr Diet. vol 82. Genes. Proceedings of the Third International Conference on Nutrition and Fit ness. Pavlou KN (eds): Volume 2. vol 89. Basel. 2001. Nutrition and Fitness: Metabolic and Behavioral Aspects in Health and Disease. Simopoulos AP. Basel. Simopoulos AP. Nutrition and Fitness in Health and Disease. Pavlou KN (eds): Volume 1. Basel. Declaration of Olympia on Nutrition and Fitness XXXII . Simopoulos AP (ed): Volume I. Karger. Pavlou KN (eds): Volume II. vol 90. Proceedings of the Third International Conference on Nutrition and Fitness. Children. Karger. vol 81. World Rev Nutr Diet.3 4 5 6 7 Simopoulos AP (ed): Volume II. Karger. World Rev Nutr Diet. Karger. Simopoulos AP. 2001. Basel. Health. 1997. Physical Activity and Health. Karger. King’s College London. ‘Once an Olympian. I realised that I was more interested in health than disease and my professional career has followed a path of seeking out ways in which we can explore our capacities to create and maintain our own physical and mental health. There is a saying. a valuable asset to sport and to the Olympic Movement. London. that.000 Olympians from over 200 countries around the world. They form a unique resource. to recognise the contribution Olympians make and provide opportunities for former athletes to continue to play a part in the Olympic Movement. XXXIII . Without them there would be no Games. UK This year we are celebrating not only the Fifth International Conference on Nutrition and Fitness with its strong connections with Greece but also the return of the Olympic Games to the city where the modern Olympics was born over a century ago in 1896. So it was in 1995. the World Olympians Association was created of which I am a co-founder and Vice President. To me as an Olympian this conjunction of the Conference with the Athens 2004 Olympics is of special importance and augments the honour of being invited to open the conference. It is by Olympians’ efforts and talents that the Olympic Games come alive in the stadium. My involvement in sport influenced the choices I made as a doctor. As a medical student at the Middlesex Hospital Medical School at London University. the pool and the sports arenas. There are 100. always an Olympian’. with the support of the International Olympic Committee. – it was coined because of the unique experience competing in the Olympic Games has come to mean.Keynote Address Positive Health: Exploring Relevant Parameters Elizabeth Ferris Department of Nutrition and Dietetics. olives. right up to the present day. The ancient Greeks lived in a Mediterranean paradise awash with highly nutritious green.’ So much for his faith in the healing powers of doctors. John Dryden. The discipline to which they were subjected in childhood undermined their powers of endurance. he was expressing something that instinctively people through the ages have sensed must be true. In my address today I’d like to explore the parameters of positive health. ‘Oliver’. ‘Food. It was part and parcel of life for the ancient Greeks and when Hippocrates said. from the musical. The song. ‘Let food be thy medicine and medicine be thy food’. fish. food. Politics. starting with a little of the history of the Olympic Games to draw a connection between the aspirations of the ancient Greeks and the aims of the creators of the modern Olympics in 1896 that revived those aspirations and that. and. pointing out that it undermined their powers of endurance and scuppered young athletes’ ambitions of Olympic victory later on as adults1. yellow and red vegetables and fruit. pre-empted modern self-help devotees when he advised. The health benefits of physical exercise too have been widely proclaimed over the centuries. especially nutrition and physical fitness. glorious. The case for good food as a means of enjoying a long and healthy life is in no doubt. Using 1 ‘The disadvantages of excessive training in early years are amply proved by the list of Olympic victors. Book VIII] Keynote Address XXXIV .’ [Aristotle. ‘The wise for cure on exercise depend. The ancient Greeks had a thorough knowledge of high-level physical training and knew that you can have too much of a good thing.My participation at this conference in a way brings together my several identities – on the one hand as a former elite sportswoman and on the other as a doctor interested in preventive medicine and holistic health. He warned of the dangers of exposing young children to excessive training. The positive value to health of physical activity and nutrition is as old as civilization itself. God never made his work for man to mend. nuts. The 18th century English poet. based on Charles Dickens’ book.’ Aristotle agreed. says it all. Oliver Twist. wine. there’s nothing quite like it’. We may think overtraining is a modern phenomenon considering the enormous pressures professional athletes are under to perform well. With the warm climate and their love of sport it is little wonder that the concept of positive health through nutrition and physical fitness originated in Greece. remain an important objective of the Olympic Movement. not more than two or three of whom won a prize both as boys and as men. Hippocrates expressed his concern about its detrimental effects when he wrote: ‘Physical conditioning is at risk when exercise is at very high levels. of course. Food is far more than simply a means of staying alive. But two and half millennia ago. 2 The concept of a sound mind in a healthy body. Meanwhile. But the movement did not focus only on physical health. organised annual Olympic-style sporting festivals. and he organised his Olympian Games as nearly as possible to the ancient Olympics. He campaigned for physical education for children and petitioned Parliament to make it compulsory in all elementary schools [1]. Dr. the Greek Goddess of victory. and no doubt his own cash. as with so much in history. in particular in Victorian England on the playing fields of boy’s public schools. Before Coubertin was born. originated from the Roman satirist.130.this connection as a stepping stone.60–c. Brookes was also a Hellenist. The medals awarded to the winners bore the portrait of Nike. the idea that physical activity was essential to live a healthy life re-emerged. Like the ancient Greeks. Juvenal AD c. not only the moneyed classes. He called them the Wenlock Olympian Games. The concept that to be sound of mind you needed to take care of your physical health formed the basis for the physical education movement that grew up in the 19th century2. social and cultural principles as well. Brookes was a philanthropist who believed that everyone in the community. Accepted wisdom has it that the modern Olympics was the brain-child of a French aristocrat. William Penny Brookes. in a tiny town in England called Much Wenlock. it embodied moral. the story was rather more complex and interesting. he believed that sporting participation produced moral and intellectual benefits as well as contributing to physical health. a lover of all things from ancient Greece. Dr. was entitled to education and access to healthy leisure pursuits. a wealthy Greek called Zappas had made unsuccessful attempts to resurrect the ancient Games in Greece. I will touch on public health issues surrounding the global pandemic of obesity and its related serious health risks. The physical education movement provides a link between the ancient Greek cultural commitment to sport on the one hand and the creation of the modern Olympic Games here in Athens in 1896 on the other. in creating a re-enactment of the ancient Olympic Games in a field in rural Shropshire – and who competed in them? Dr. But. the classical poet of the Olympic Games. I will dip into recent scientific research that provides evidence in support of Hippocrates’ analysis of positive health. More than fourteen hundred years after the last ancient Olympic Games were held in the 4th century AD. Finally. from 1850 onwards. Keynote Address XXXV . Baron Pierre de Coubertin. with a quotation from Pindar. In tune with the ancient Greek approach. looking to the future. mens sana in corpore sano. an English country surgeon. I will suggest how our growing knowledge of the human genome is likely to impact on how we could maximize our potential for a healthy life. Why would a rural doctor spend his time and effort. P. Notwithstanding the ways in which elite sport has changed of late. now 82 years old but still alert and vigorous. especially children. he died in 1895 aged 87 having given his blessing to Coubertin’s international vision. the educational value of good example and respect for universal fundamental ethical principles. the Olympic Games have the capacity to inspire young people at the grass roots level to participate in sport and physical activities. I remember the overwhelming rush of young girls wanting to practice gymnastics after Olga Korbut entranced the world with her performance in Montreal in 1976. there are added bonuses in being involved in sport that I will come to a little later. in the Olympic Charter (in force as from 4 July 2003) under Fundamental Principles on p 9 defines Olympism as follows: ‘Olympism is a philosophy of life. will and mind. who was a young educationalist on a mission for the French government to research foreign systems of physical education.Dr. As history reveals. I maintain that this is just as true today as it was in 1896. Brookes. At the first modern Olympics in 1896. and drug-taking. And. there were no women because Baron De Coubertin thought the Games should remain ‘the exaltation of male sport’. values that today characterise what is called Olympism. it is not due to a Greek but to Dr. It is he who inaugurated them 40 years ago and it is still he. The two men shared a vision of recreating the Olympic Games in modern times. Coubertin wrote: ‘…if the Olympic Games that modern Greece has not yet been able to revive still survive today. After his meeting with Brookes. The important thing to recognise is that for Brookes and Coubertin the Olympic Games were a means by which universal physical education for all could be attained. exalting and combining in a balanced whole the qualities of body. Brookes’ Olympian Games had been in full swing for 40 years before Pierre de Coubertin. The two men shared a passionate commitment to physical recreation. W. not only for its health benefits but also for its moral and social value. The power to awaken such interest on a global scale is unique to the Olympic Games because of the extra dimension that the Olympics possesses compared with other international sporting events embodied in the philosophy of Olympism3. went to Much Wenlock in 1890 to meet Dr. The traditional attitude was that women Keynote Address XXXVI .’ 4 The story of the rise of women in the Olympic Games further illustrates my point. Coubertin was deeply impressed and immediately recognised a kindred spirit in the country doctor. due in part to professionalism and commercialism. Olympism seeks to create a way of life based on the joy found in effort. 3 The International Olympic Committee. Brookes and see his Games in action. to become more physically active4. 3]. who continues to organise and inspire them’ [2. Coubertin succeeded in this ambitious venture but sadly Brookes did not live to see the dream become a reality. Blending sport with culture and education. Their contribution to positive health lies in the potential to encourage people. Incidentally. recognised worldwide as icons of London. culture. tennis players and sailors took part in the second Games in 1900 and women have participated in every Olympic Games since. From a public health point of view. women are playing mixed table tennis matches in public. as the nation watched the coronation of Queen Elizabeth II in Westminster Abbey. and just a few months later. for us passengers. especially in developing countries. Morris’ seminal study [4] showed that conductors on the famous London red double-decker buses had significantly less coronary artery disease than the drivers of the buses. and health take precedence over concerns about sport. hundreds of women and girls turn up annually for a roundthe-houses run in Casablanca. women and girls are increasingly playing sport. There is still a long way to go but you have to admit that progress is being made when you see that in Afghanistan. more and more women have competed in the Olympics. the major cause of premature death in the world. in Athens 2004 the proportion of women to men will for the first time approach parity. Let’s fast forward to Britain in 1953. poverty. Women golfers. perhaps the most important fact is that physically active mothers are most likely to produce physically active children and physically active children are most likely to maintain the habit into their adult years. anyone hoping to take up this healthy job in future will be disappointed – these wonderful Red Routemasters. anyway. notwithstanding these social barriers and inequality. Fifty years ago. the year when. An opportunity for a little bit of exercise in the normal course of life itself will be were biologically unsuited to taking part in sport and. Of the 10. medical concerns turned to focus on non-communicable diseases. it was a male domain – a view that prevailed well into the 20th Century. Fleming’s discovery of penicillin and its development as an antibiotic by Lord Florey. The health benefits of being a conductor were attributed not unreasonably to the fact that they were much more physically active than sedentary drivers. The challenges women face in many countries relating to religion. where until recently women were hardly allowed to leave their homes.000 athletes women will make up approximately 41% and will compete in all but boxing and baseball. plus a mass vaccination programme saw the gradual demise of infectious diseases as a principal cause of death. Throughout the past 100 years. And yet. It didn’t take long for women to overturn the IOC’s entrenched view. Keynote Address XXXVII . are being phased out in favour of buses with just a driver whose only exercise is to press a button to open and close the doors automatically. Alas. news of the successful conquering of Mount Everest by the British expedition lead by Sir Edmund Hilary was celebrated. no more running and jumping on the platform at the back of moving buses – a game Londoners love to play. and in Morocco. arguably the most important sporting event of the 20th century was held when Roger Bannister conquered the four-minute mile. On the health front. education. A positive by-product of more women athletes in the Olympics is the growth of women’s sport around the world.I’d like to turn now to the immense contribution the scientific community has made to the issue of positive health. in particular coronary heart disease (CHD). it is the intensity of the exercise that matters [6]. The Chief Medical Officer in the UK just a few weeks ago.000 kcal or more per week.lost. that we used to take for granted. folate protects against a wide array of other serious diseases including cancer. outputting 2. and a new area of research has been identified – nutrigenomics. What about the effects of diet? Recent research has revealed that a nutritional substance – folic acid. Keynote Address XXXVIII . was diagnosed with terminal bone cancer and told she had just 6 months to live. The effect of folate research has been to open up new avenues of intervention with vitamins and other nutrients in disease prevention. In addition to the protective effect of exercise in coronary heart disease. completed an ‘Iron Man’ event and recently cycled 2. had a 39% lower risk of developing coronary heart disease and of death from the disease than their less active classmates [5]. In obesity. a young British mother who. Nutrigenomics fits very well with what Hippocrates knew instinctively when he spoke of the powerful effects of various foods and physical exercise on man’s primary constitution. and we know that exercise is beneficial. obesity related conditions and cancer5. dementia and birth defects [7]. No matter – perhaps we can make up for it by climbing the stairs in our office buildings – if we can find them! This remark may sound flippant. who had testicular cancer and went on after treatment to win the Tour de France six times. Lance Armstrong. Since then. The benefits of an active lifestyle were further confirmed in the 1980s by Paffenbarger and colleagues. It has many diverse biological properties expressed through a number of crucial gene pathways and has even been cited as the panacea of the 21st century. one of the B vitamins – gives considerable protection in heart disease by lowering homocysteine levels in the blood. physical activity has been shown to be significant in other serious diseases that are major causes of death in the modern world – diabetes. in an 5 An extraordinary story of bravery and endurance that raises important questions about the relationship of exercise to cancer is that of Jane Tomlinson. or that of the professional cycling phenomenon. Harvard alumni who took regular exercise. The amount and type of exercise recommended varies. are becoming less and less common for reasons over which we have little or no control. any increase in energy output is desirable. osteoporosis. In addition. but it is relevant to my theme because it highlights the fact that opportunities for activity in our everyday lives. where a healthy heart is concerned. the study of the links between nutrition and gene function. Jane has run three marathons.500 miles from Rome to Yorkshire in the North of England where she lives. We also now know. in 2000. where weight loss is the goal. No-one knows the role vigorous exercise has played in prolonging her life. Coronary heart disease is clearly a lifestyle disease with smoking and physical inactivity top of the list of risk factors. has alarming effects. This is hardly new: Plato was highly critical of those who were a nuisance to their doctors because of leading an ‘idle life’ and ‘filling our bodies with gases and fluids like a stagnant pool’ [11]. We now have evidence that exercise combined with a diet rich in nutrients. Young schoolchildren who went without breakfast missed out in more ways than one. For those of us who have those occasional ‘senior moments’. a little light running on the spot to stimulate a few new brain cells may help you to remember what on earth you’re doing there – if you can remember the original piece of research! In fact. an area associated with memory. our lifestyles have changed radically during the past 50 or more years. And they did equally badly when they had just a glucose drink. There are stem cells in the adult brain that produce new nerve cells in the dentate gyrus of the hippocampus. the children had powers of attention as poor as an adult who had had a slug or two of whisky or a tranquiliser. Three hours into school. like when you find yourself in the cupboard under the stairs and cannot for the life of you remember what you’ve gone there for. sugar and salt for the increases. it is claimed that 30 min of moderate exercise 5 times a week is enough to prolong life. Whilst this may seem like too little too late. The effects of nutrition on mental function and behaviour are equally interesting. produced a report entitled. this is a particularly productive line of research in support of physical activity in the aged. they showed an enormous improvement [10]. Fascinating research from the Salk Institute suggests that physical activity has a positive effect on brain plasticity. Young adult prisoners showed a remarkable reduction in antisocial behaviour when their diets were supplemented with vitamins. in particular. As obesity levels rocket. hardly a day goes by without another report of the growing pandemic of obesity across the globe. In our highly technologically developed modern world in which the need to extend ourselves physically in the normal course of our lives is diminishing day by day. the case for physical activity coupled with good food for a long and healthy life is made and is in no doubt. in particular folic acid. in young children. Population surveys show that the world is getting fatter and the incidence of Type 2 diabetes is increasing at an alarming rate.attempt to arouse the largely sedentary population to ‘get up and go’. With cereal for breakfast. Poor nutrition. on the other hand. And yet. Keynote Address XXXIX . With the scientific body of knowledge expanding. it seems reasonable to blame the modern diet high in fat. could help stave off symptoms of dementia and Alzheimer’s disease in increasingly ageing populations. and perhaps most disturbingly. We also know that exercise has positive effects on mood and feelings of mental well-being. however. Physical activity positively promotes this neurogenesis – in running mice at least [8]. minerals and essential fatty acids [9]. ‘Physical Activity and Health’ in which he recommended vacuuming and ironing as good examples of moderate exercise. The future of PE looks bleak. Perhaps the most alarming information to come to light concerning this growing problem is in a report of the International Council of Sport Science and Physical Education (ICSSPE) that states: ‘school physical education is in a perilous position in all continental regions of the world’ [17]. than they used to eat [12. Dinners were rather prolonged Keynote Address XL . even in China where until recently you would never see a fat person let alone an obese child [15]. According to a recently published account of what Olympic winners eat in ancient Greece: The main meal was dinner where the presence of family and friends and the consumption of wine were important elements. materials. fit and a bit fat than lazy and lean. the ancient Greeks got it right. In fact. For example. fewer fizzy drinks and less fat in food both at and away from home [18]. and is starved of funding. Children too benefit from this style of eating. children it appears are actually eating less today. especially in the media. organic farming is expanding in Europe to counter the use of additives and pesticides. and. The reasons are largely cultural: more car journeys with less walking. parental concerns about security and safety that restrict where and when children can play. alongside a popular anti-GM crops drive that has resulted in Monsanto cancelling its GM crop production programme in Europe. Along with TV watching goes snacking on high-density junk food and fizzy drinks that further contribute to the greater energy intake/lesser energy output problem [16]. good food and good eating initiatives are sprouting as public interest in nutrition grows especially in developed countries. Governments are giving out confusing mixed messages. in particular. in health terms. time and teachers. it is almost certainly better to be active. Children are getting fatter because they are much less active than they used to be and their energy intake in the food they eat is greater than the energy they expend in physical activity. On a more personal level. Children who eat meals with their family consume more fruit and vegetables. and savouring good. not more. On the one hand. is predominantly on what children eat because it’s obvious to see the outcome and it is easy to make value judgements about children who are fatter than we think they ought to be. It doesn’t make any sense. Again. they are advising children to do more exercise whilst on the other hand making it obvious that physical education is a Cinderella subject on the school curriculum deserving few resources. Another initiative is the slow food movement in Italy that has emerged as an antidote to the fast food culture in an attempt to replace it with old values of sitting down to meals with family and friends. PE has a low priority in school curricula.Counter-intuitively. 13]. The emphasis. wholesome nutritious food and wine. television watching and computer games are all cited as reasons for inactivity in children across the globe [14]. to flit.during which people were eating. is changing its image to provide more healthy salad and fruit options. It didn’t suit my personality and if the opportunity had not arisen to change to diving. He was hopeless at school sport – last in cross-country running. we need to change the terms we use. all words that exemplify what children do when they play – juxtaposed with the word ‘station’ which. under pressure from the media and the public. I am sure I would have given up. to flutter. The moral of his and my stories is 6 Montaigne said 500 years ago. to fly. ‘physical education’ is a rather dry phrase. ‘It should be noted that children at play are not playing about. drinking wine with water and discussing current issues. Perhaps a clue to how to appeal to children can be found in what youngsters like to do in their leisure time: they like to play computer games. from sport? But. a ball game. Sony had a brilliant idea when they called their equipment Play Station. gymnastics say. I started my sporting life as a swimmer but I became bored with the training. I heard a similar story from an Olympic swimming champion. their games should be seen as their most serious-minded activity. I remember that the welcome mid-morning interval between writing and arithmetic was called playtime. no eye-to-ball coordination. not all children are good at sport and many are alienated from participating especially when the emphasis is on competition and performance. McDonald’s. means standing still. Even children who show an aptitude for one sport. the opposite of motion. In the commercial world. accomplishment. we need to put play back into physical activity. and even applause for success – all the things an athlete gets. To me the title is an oxymoron. I suggest that. and the vitamin and supplement industry is booming as people self-administer these products in an attempt to bolster their well-being.’ Keynote Address XLI . may not show any talent for another. like soccer. (The term ‘symposium’ means ‘drinking together with others’) [19]. couldn’t run and so. if one can believe the stock quotes. the possibility of winning. a much more acrobatic sport. Perhaps. the leisure industry is profiting from increasing membership of gym and fitness centres although the percentage of people in the UK who regularly exercise hardly reaches double figures. we could go back to using the word ‘recreation’ – it has a more pleasurable ring about it. or hopes to get. to frisk. and play we did. to dart to and fro. loved it and made it to the very top winning 2 Olympic gold medals. But the word ‘play’ is evocative and enticing6. according to the OED. One day he fell through a plate glass window and severed a tendon in his calf. fortuitously. with respect to children at least. Why are computer games so beguiling to children? Is it because they provide positive feedback. enjoyment. Sony used the word ‘play’ – which according to the Oxford English Dictionary (OED) means to move about swiftly. In my early school days. took up swimming. shortened life spans and premature death in the current generation of physically inactive children for whom obesity and its concomitant problems are becoming the norm. The other group. almost as a side effect they were able to take more care of their health compared with those in the action group who only focussed on changing their diet and exercise. it seems. An alternative approach. Unless options are available to be tried and tested by the individual. the Pima action group. A possible clue may be gleaned from a fascinating study of the Pima Indians of Arizona [21]. walkways and playing fields. One group of subjects. had a mix of nutrition and physical activity active interventions. physical activity. Governments are considering what public health initiatives they can provide to help solve the problem. and by association. is associated with increased health risks [23. The study tested the efficacy of lifestyle interventions. for the rest of his or her life – and very possibly to the detriment of their health. Pima Indians suffer from high levels of obesity and diabetes. a child could be put off sport. All good ideas – but will they work? And will they work in time to defuse the ticking time bomb of poor health. is needed if public attitudes are to change. i.that if we had not had the good fortune each to find our own sporting niche neither of us would have won our Olympic medals. It’s possible to link the concepts of respect and self-esteem with autonomy [22].e. or the lack of it. I have touched on some complex issues in an attempt to suggest that the answers to the health problems we face do not lie in governments simply telling Keynote Address XLII . The cosmetic argument only carries weight with those vain enough to care. lack of autonomy. health warnings and clearer labelling on foods. Did this effect have something to do with building up the pride group’s self-esteem and respect for their Pima identity? I think so. received printed leaflets about activity and nutrition but in addition they engaged in regular discussions on Pima culture and history. a British Parliamentary Health Committee published a report [20] in which it recommended 80 measures including a ban on the promotion of sugary drinks and snacks in schools. curbs on advertising junk foods on television in particular during children’s programmes. the health argument has not exactly been able to inflame the public’s imagination. In 2004. Researchers have found that control at work. At the end of 12 months. the pride group was showing much more favourable results than the action group in terms of their health parameters – they had lost more weight and had more favourable blood glucose and insulin levels. It seemed that by boosting their pride in their Pima identity. The World Health Organisation recently presented its global strategy to improve public health through healthy eating and physical activity. the Pima pride group. and new building developments to feature cycle paths. The key question is how people can be enticed into changing their lifestyles to incorporate physical activity and good nutrition into their normal everyday lives. To date. 24]. 40 years later. when reaching for ways of dealing with chronic non-communicable diseases. in particular a child. The mystery was solved by Lodish and colleagues at the MIT when they discovered that Maentryanta and others in his family had a genetic mutation that accounted for the high levels of red blood cells [25]. The actual activity. In simple terms. It provided me with a full social life. the Finnish Olympic champion cross-country skier. researchers believe determines whether an individual grows more ‘fast twitch’ or ‘slow twitch’ muscles fibres [26]. For example. But it was the context in which I did it that provided the ground in which I grew up and thrived. He had 15% more red blood cells than normal and some were convinced he was blood doping although there was no evidence. can offer a rewarding lifestyle with healthy by-products. amongst the myriad of choices sport has to offer. I suggest that this is a very restricted view. O’Rahilly’s group at Cambridge together with other researchers have found a genetic connection between proneness to obesity and PPARy genotype [27].people to eat less and walk more. a sense of achievement and how to deal with failure as well as success. The underlying assumption has been that these are possibly the most important or even the only parameters in a person’s individual make-up relevant to health (and ill health). scientific studies and public health initiatives I‘ve highlighted show that. ‘Lucky old so-and-so – he can eat anything and stay thin’. I am still in touch with. before I reached the elite level. sport is an activity that. The gene. We’ve all said at some or other. which encodes for an enzyme – angiotensin-converting enzyme (ACE) –. Another study showed that a single gene – dubbed the ‘performance gene’ – may influence an athlete’s propensity to excel at either sprinting or long distance running. was a medical mystery. and physically fit and active adults have lower risks of heart disease. Eero Maentryanta. If. With respect to obesity. Moreover. Something has to ignite a person’s interest and that is why I have come back full circle to sport. their work shows that some people have a genetic propensity for obesity whilst others don’t. the experience of diving. a person. Active children are more likely to become active adults. This corresponds to our intuition. good friends who. good as that advice may be. was completely personal. diabetes and cancer. Keynote Address XLIII . Sport for me. Turning now to the future. genetic constraints and regulation influence individual potential to respond to exercise and dietary factors. teamwork. was a complete experience. My own view can be summarised as follows: (1) Genetic factors play at least as important a role as exercise and diet. travel. advice on what lifestyle changes an individual can make has tended to focus on just two variables – dietary habits and patterns of physical activity (with smoking as well in the case of CHD). can find something to illuminate their curiosity and suit them mentally as well as physically. in the broadest terms. She has to have an extraordinary genetic makeup. Elizabeth Ferris..n)/4 specified the exact relationship of all the relevant variables in a unique equation for each individual. (2) Future research will eventually lead to an awareness of the importance of other variables apart from diet and exercise. Look at Jim Fixx. Thank you all for your attention. and programmes of dietary and exercise interventions could be tailor-made to the individual. At the other end of the health spectrum is the Australian.. the changes of the winds. say. We are very fortunate to have leaders in these fields of research here at our meeting and I wish us to have a wonderful and stimulating conference. Evidence is all around us of very fit people who succumb to illness and die. 30 years on. B is diet. for instance. Dr. A is exercise. we would eventually end up with a detailed algorithm that would specify all the variables involved and relate them to each other in a quantifiable. who at 15 years of age was a multiple Olympic champion and the supreme swimmer in the world. This in turn will eventually expand our understanding. We know. a very fit man who died suddenly and prematurely from a heart attack.. New york. Gotham Books. In my ideal world. Statisticians are already grappling with producing such a mathematical equation. who started the jogging craze. where. How wonderful it would be if a formula such as 2(A+1/2B+2/3C⫺D. Keynote Address XLIV . she returned to swimming and qualified for the Australian Olympic trials. not only of the number of variables involved. the age of the individual and the situation of his home’ . It is possible that within a few years we may be able to characterise people according to their genotype. This year. ‘the season of the year. indeed. The future is exciting. D is hitherto unknown variable and n is all future relevant variables – along the lines that Hippocrates suggested. way.We can say something similar regarding the connection between fitness and health. at age 47. Shane Gould. that smokers vary in their risk of developing lung cancer and coronary heart disease. 2004. C is genotype. The human genome project has opened wide the potential for the kind of outcomes I am suggesting. but also how these variables relate to one another. These examples illustrate how an individual’s genotype may determine both potential for protection from developing disease as well as the risk of developing disease7. 2004 7 To see why diet and exercise cannot be the only variables that are relevant to health see: Campos P: The Obesity Myth: Why America's Obsession with Weight Is Hazardous to Your Health..and any number more. mathematical. May 17 1995. Marmot M: Job strain. Durnin JGVA: Physical activity levels – past and present. JAMA 2002. British Olympic Association. Keynote Address XLV . Totawa. Eves A. learning. London. Kriska AM. National Diet and Nutrition Survey: Young People aged 4–18 Years. JRSM 2004. decision latitude.322:313–314. Terkesidou L: The Golden Diet of the Ancient Olympic Winners. Paffenbarger RS. Sejnowski TJ. Morris JN. Plato: The Republic. Brit. London. p 109.ii:1053–1057.252:491–495. Norton. J Psychiatry 2002. No. job demands. Penguin Classics. Kozak D. minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. Sennett R: Respect in a World of Inequality. 1. Dietz WH: The obesity epidemic in young children.288:1994–2000. 1987. London. Rimm EB. Pincock C. 1994.97:254. Stansfield S: Contribution of job control and other risk factors to social variations in coronary hear disease. House of Commons Health Committee: Obesity: Third Report of Session 2003–2004. Pettitt DJ: Television watching and soft drink consumption.References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Anthony D: Minds. Marshak HH. 2001. Wing AL. 2003. pp 20–27. et al: Randomized clinical trial of lifestyle interventions in Pima Indians: A pilot study. BMJ 2001. Diabet Med 1998. 1992. Hammond SM. and the risk of coronary heart disease within the Whitehall II study. Kastaniotis Publishers. Hyde RT. Tanasescu M. Arch Fam Med 2000. pp 263–298. Field AE. Hanson AM. Humana Press. Arch Pediatr Adolesc Med 2003. ICSSPE Report. et al: Exercise type and intensity in relation to coronary heart disease in men. Lucock MD.181:22–28. et al: Family dinner and diet quality among older children and adolescents. Crowder MJ: Influence of supplementary vitamins. Bosma H. Venkat Narayan KM. Brunner E. van Praag H. Blix G. Richardson D. Yates Z: A differential role for folate in developmental disorders. in Massaro EJ (ed): Folate and Human Development. Cambridge University Press. Camargo CA Jr. 1111–1120. Appetite 2003.96:13427–13431. p 182. Marshall I: World-wide Survey of the State and Status of School Physical Education. JAMA 1984. vascular disease and other clinical conditions: The importance of folate status and genotype. and long-term potentiation in mice. Hails S: Breakfast reduces declines in attention and memory over the morning in schoolchildren. London. Hemingway H. Mullins S: British Olympians: William Penny Brookes and the Wenlock Games. Steinmetz CH: A natural history of athleticism and cardiovascular health. WOS 2nd MB. Giammatei J. In: La Revue Athlétique. Hardman K. 1986. Helm G. de Coubertin P: Les Jeux Olympiques à Much Wenclock. Wollitzer AO.57:147–153. Raffle PAB. Marmot MG. Hampson SE. British Olympic Association. J Epidemiol Commun Health 2003. New York. Proc Natl Acad Sci USA 1999. Christie BR. Kuper H. Cheng TO: Obesity in Chinese children. 2002. Heady JA. Bodies and Souls: A Trilogy of the British Olympic Heritage Network. Lancet 1953. Gage FH: Running enhances neurogenesis.12 (December 1890). Athens.41:329–331. Lancet 1997. Roberts CG.350:235–240.15:66F–72F. Pettitt DJ. Rockett HRH. in Norgan N (ed): Physical Activity and Health. Leitzmann MF. Publication Parliament UK. Gesch CB. 2000. The work was reported in Cell. Book 111. Frazier AL. Gilman MW. 2004. Part 111: Education. Wesnes KA. Hoskin M. Rifas-Shiman SL. ‘Whitehead finds answer to old puzzle’ – article from MIT Tech Talk.9:235–240. Stationery Office.157:882–886. Parks JW: Coronary heart disease and physical activity at work. Physical Education. Cambridge. 50:686–689.26 27 Montgomery H: Renin-angiotensin systems and human performance. Harding DJ. E-Mail elizabeth. O’Rahilly S. MBBS Department of Nutrition and Dietetics King’s College London. Browne PS. Chatterjee KVK. 30 November 2001.uk Keynote Address XLVI . Genes in Sport Conference. Franklin Wilkins Building 150 Stamford Street. Wareham NJ: Evidence for genenutrient interaction at the PPARy locus. Diabetes 2001.ac. London SE1 9NH (UK) Tel +44 1367 860313. Luan J. UCL School of Human Health and Performance.ferris@kcl. Elizabeth Ferris. 5]. Studies exploring possible relationships between nutritional factors and the incidence and course of psychiatric diseases are of recent origin. The heritability for psychiatric disorders [3] suggests that there is a significant environmental component in the pathogenesis of psychiatric disorders. Hereditary studies. increased an individual’s chance to react to stressful life events with depressive symptoms. Aging. yet modulated during development and throughout life by environmental factors. Assuming that psychiatric disorders have a genetic basis. For instance. research has increasingly focused on linking specific psychiatric disorders to specific genetic markers. USA Human mental function is genetically based. Stanford. As a result. [2] reported that a polymorphism in the 5-HTT gene. have revealed a significant environmental influence on gene expression [1]. vol 95. In normal populations nutritional factors and physical activity have been shown to have subtle effects on mood and cognitive ability [8]. is there a role for environmental factors? . and the Implementation of a Healthy Diet and Physical Activity Lifestyle. 7]. depressive disorder and suicidal behavior. For nutrition which powerfully impacts physical health and disease [4.Mental Health Simopoulos AP (ed): Nutrition and Fitness: Mental Health. however. Psychological factors are important environmental components which interact with genes or gene products to promote the expression of a phenotype. Basel. the mechanisms of the gene-environment interaction are under investigation [6. Caspi et al. Stanford University School of Medicine. 2005. Casper Department of Psychiatry and Behavioral Sciences. pp 1–16 Psychiatric Disorders. Calif. World Rev Nutr Diet. This chapter will address four questions: 1. Family and twin studies have shown that hereditary factors play an important role in the incidence and clinical expression of affective disorders and schizophrenia [1]. Mood and Cognitive Function: The Influence of Nutrients and Physical Activity Regina C. Karger.. in this case one or one or two copies of the short allele of the 5-HT T promoter. leaving a substantial portion to environmental factors [1]. What are the beneficial effects of the essential ␻–3 polyunsaturated fatty acids (␻–3-PUFAS) on human development and what is the evidence that malnutrition during prenatal life affects mental development? 3. leaves ⬎60% to environmental risk factors. A hereditary component for affective disorders is well documented [10]. In the late eighties. the maternal environment influences fetal developmental milestones. nevertheless. Genes instruct the development of the central nervous system (CNS). Another example of a gene/environment interaction would be the variant of the monoamineoxidase type A (MAOA) gene which has been linked to aggressive. infection or malnutrition may disrupt maturational processes. the risk of developing the condition is estimated to be no more than 46%. An example of a gene/nutritional environment interaction would be the APOE gene which has been linked to schizophrenia in Chinese and seems to confer vulnerability during times of malnutrition [6]. Early Development: Prenatal Growth and Diseases in Adult Life Aside from genetic factors. are there mental health benefits to physical exercise? Psychiatric Disorders are the Products of Genetic Regulation and Environmental Influences The genetic basis of human mental function and dysfunction is complex and due to the interaction of multiple genes. 13]. which. epidemiological studies began to point Casper 2 . the South Island Bipolar Study demonstrated an increased prevalence of bipolar and depressive disorders in relatives of bipolar patients [11]. Furthermore the recent discovery of the neuregulin gene which plays a central role in neural development and contributes to schizophrenia in both Icelandic and Scottish populations suggests the possibility of population based genetic variability [9].2. For schizophrenia. even if 100% genes are shared as would be the case for an individual with two schizophrenic parents. Lastly. at the same time environmental factors promote or in the case of hypoxia. impulsive and even violent behaviors in monkeys and humans. in altering the prevalence or the occurrence of psychiatric symptoms? 4. Recently. In the second part findings from placebo controlled studies and uncontrolled trials will be reviewed with the question in mind: do the data support a role for nutritional compounds. Maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems [12. specifically the ␻–3-PUFAS. to the conclusion that adults who had been born with normal, yet low birth weight have an increased susceptibility to diseases in adult life. Barker’s [14] analyses of birth and death certificates of people born in Hertfordshire, UK revealed that 2.3kg babies had double the rate of death from coronary heart disease, hypertension, stroke and type II diabetes, compared to 4.5-kg babies. These observations which were subsequently confirmed [15] generated the fetal origins hypothesis that proposes that the fetus adapts to a limited supply of nutrients, and in doing so, permanently alters its physiology and metabolism. The new set point appears to increase the risk of disease in later life. There is one report [16] which found a relationship between low weight gain in infancy and suicide in adult life. Observations that growth restriction during fetal life is associated with increased adrenocortical and adrenomedullary activity [17] and a higher prevalence of autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgSAb) [18] are important in view of the presence of similar endocrine abnormalities in major depressive disorders. Remarkably, an excess of protein may also modulate lifelong changes in the hypothalamic-pituitary-adrenal (HYPAC) axis. Herrick et al. [19] described hypercortisolemia in 28- to 30-year-old subjects whose mothers had been advised to consume 0.45 kg of red meat daily and avoid carbohydrates during pregnancy, an intriguing finding given the popularity of the Atkins diet. Another report [20] that described epigenetic metastability following excess intake of folic acid, vitamin B12, choline, and betaine leading to possible deleterious influences on the establishment of epigenetic gene regulation in humans deserves further study in view of current recommendations for large doses of folic acid in particular for patients taking antiepileptic drugs. Epidemiological studies of psychiatric disorders [21] have linked severe malnutrition during the first trimester to the risk of schizophrenia by analyzing the incidence of schizophrenia in birth cohorts born between January-February 1944 and November–December 1946 in Holland during the German occupation. Those conceived during the height of the Dutch famine and exposed to very low food rations during the first trimester (from February to April 1945) had an excess of neural tube defects [22] and double the relative risk for schizophrenia [21]. Brain imaging studies [23] have shown decreased intracranial volume and double the rate of brain abnormalities, in particular focal white matter hyperintensities in a subset of these patients compared to controls born during the Dutch hunger winter. As noted previously, Liu et al. [6] suggested that the epsilon-4 genotype of the APOE gene may be associated with the risk of malnutrition for schizophrenia. First trimester exposure to severe malnutrition during the Dutch hunger winter has also been reported to double the risk of schizoid personality disorders [24], schizophrenia spectrum disorders [25], and antisocial personality disorder [26]. Malnutrition during the second trimester appears to double the risk for affective disorders in adulthood [27]. Nutrients, Neurodevelopment and Psychiatric Disorder 3 Interaction between Nutrition, Growth and Development Animal Studies Bourre et al. [28] have documented during cerebral development in rodents a linear relationship between brain content of (␻–3) acids and the (␻–3) content of the diet up to 200 mg of ␣-linolenic acid levels per 100 g food intake, however DHA levels remained unaltered following ALA [28]. They observed that a diet low in (␻–3) acids affects learning in rodents. In rhesus monkeys, Connor et al. [29] showed more fatty acid lability when ␻–3-deficient monkeys were fed fish oil diets rich in DHA and other ␻–3 fatty acids. An earlier study [30] described that rhesus monkeys long term deficient in ␻–3 fatty acids displayed bouts of stereotyped behavior typical of monkeys raised in social isolation compared to monkeys fed a matched control diet abundant in ␻–3 fatty acids. Human Studies Fish oil supplements given from week 30 of the pregnancy extended the pregnancy duration on average 4 days in Danish women compared to women receiving olive oil supplements [31]. Low consumption of seafood has been associated with premature delivery [32]. Cheruku et al. [33] found that higher maternal DHA levels were associated with more mature infant sleep and wake states in newborns. Maternal supplementation with cod liver oil (total 1.2 g DHA ⫹0.8 g EPA) versus corn oil (4.7 g linoleic acid (LA) and 0.09 g ␣linolenic acid (ALA) from week 18 of pregnancy until 3 months after delivery increased children’s mental processing composite score significantly at 4 years of age. Intelligence correlated with head circumference at birth, but not with birth weight or gestational length [34]. Maternal supplementation with 2.8 g ALA did not prevent decreases in maternal DHA and AA concentrations, yet did increase EPA and DPA levels, with no difference in birth outcome [35]. Another study found similar visual, cognitive and language scores in breastfed and DHA- and DHA⫹AA-enriched formula-fed children at 39 months [36]. In a cross-sectional study phospholipid (DHA and AA) status at birth was not associated with cognitive development at 4 years of age [37] or with cognitive performance at 7 years [38]. Nutritional Factors in Affective Disorders Studies on the effects of amino acids, protein and carbohydrates on mood and the effects of caloric restriction on life span have been reviewed previously [8]. Casper 4 Polyunsaturated Fatty Acids (PUFAS) and Major Depressive Disorders (MDD) Phospholipids as components of membrane structure play a critical role in signal transduction via receptor mediated phospholipid derived second messengers such as prostaglandins or arachidonic acid. A role for the eicasonoids and immune activation in the pathophysiology of MDD [39, 40] is supported by findings that antidepressants of several classes decrease the production of pro-inflammatory cytokines such as interferon-gamma and tumor necrosis factor-␣, and increase that of interleukin-10, an anti-inflammatory cytokine [41]. Significant decreases of plasma polyunsaturated ␻–3 fatty acids are inversely associated with major depression [42], whereas increases in the ␻-6/␻-3 plasma ratio or red cell membrane phospholipids of patients with major depression correlate directly with the severity of depression. The comprehensive review by Hibbeln and Salem [43] makes it abundantly clear that testing of the therapeutic efficacy of PUFAS has underdone few double-blind trials, in fact most data derive from case reports, pilot studies, open trials, cross-sectional analyses and unpublished communications. Omega–3 Fatty Acids in Major Depressive Disorder (table 1) Placebo-controlled studies typically have included treatment resistant or partially improved patients who may not be representative and who are by definition difficult to treat. Four placebo-controlled studies have randomly assigned patients on antidepressant medication to receive ␻–3 fatty acids. Administration of 2 g EPA daily reduced depressive symptoms by week 3 in a 4-week study of Nemets et al. [44]. Peet and Horrobin [45] found that 1 g EPA daily, but not 2 or 4 g EPA ameliorated depression scores in mostly female medicated patients by week 4 on the Hamilton rating scale (HRS) and the Montgomery Asberg depression rating scale (MDRS) with the greatest improvement occurring at 12 weeks, when patients rated themselves as improved on the BDI. Marangell et al.’s 6-week [46] study failed to show benefit from 2 g DHA daily on the MDRS, even though the placebo group was more depressed at baseline. Su et al. [47] gave EPA/DHA 2:1, a total of 6.6 g daily after a placebo washout in a 12-week study and showed improvement in the HAMD score by 4 weeks with further symptom reduction by 12 weeks. Cross-sectional analyses [48] found elderly patients with MDD and with normal C-reactive protein levels to have lower ␻–3 plasma levels and higher ␻–6/␻–3 ratios. A population-based study of all males, 50–69 years old residing in southwestern Finland [49] found no evidence Nutrients, Neurodevelopment and Psychiatric Disorder 5 Table 1. Placebo-controlled treatment studies of ␻–3 fatty acids Author Major depressive disorders Nemets et al. [44] Peet and Horrobin [45], Marangell et al. [46] Su et al. [47] Type,dosage, duration Subjects, n Results Ethyl-EPA 2 g/day 4 weeks Ethyl-EPA 1,2 or 4 g/day 12 weeks DHA 2 g/day 6 weeks 20 70 EPA 4.4 g/day 8 weeks ⫹ DHA 2.2 g/day 28 ↓HRSD scores week 2 1 g/day ↓HRSD MADRS week 4 Response rates similar ⬃24–28% MADRS ↓HSRD scores week 4 & 8 Breast-feeding women with postnatal depressive disorder Llorente et al. [52] DHA 200 mg/day 36 101 No difference; only 14% of patients had MDD or depressive symptoms HRSD ⫽ Hamilton rating scale for depression; MADRS ⫽ Montgomery-Asberg depression rating scale; MDD ⫽ major depressive disorder. between fish consumption or overall ␻–3 dietary intake and depressed mood, MDD or suicide. Omega-3 Fatty Acids in Pregnancy and Postpartum Depressive Disorder Hibbeln [50] analyzed prevalence rates for postpartum depressive disorder (PPD) across countries and found an inverse relationship to seafood consumption. Higher DHA, but not AA or EPA, breast milk concentrations predicted a lower prevalence of PPD. Stronger evidence for a role of ␻–3 fatty acid deficiencies in postnatal MDD comes from a study by De Vriese et al. [51] who found lower ␻–3 PUFAS and lower ␻–3/␻–6 ratio in plasma lipids of women who developed postpartum depression compared to controls. Yet, a placebocontrolled study supplementing breast-feeding women with 200 mg DHA daily for 4 months postdelivery, even if it raised DHA lipid content, failed to influence measures of depression in a study by Llorente et al. [52]. This study was not a valid test, since too few (15%) women with MDD were included. In a small open label trial [53] which administered 2.96 g of fish oil (EPA/DHA ratio 1.3) during the last 4 weeks of pregnancy, 4/7 women experienced postpartum depression, not different from the relapse rate expected in untreated Casper 6 Placebo-controlled treatment studies of ␻–3 fatty acids in bipolar disorders Author Type. Omega–3 Fatty Acids in Schizophrenia (table 3) Schizophrenia is currently conceptualized as a neurodevelopmental disorder [1]. Nutrients. Remarkably. [57] who compared time to relapse over 4 months in 14 bipolar patients who received 6. Considering the high rates of breast-feeding among current mothers and the benefits from nursing.Table 2. 4 months 6 g EPA/placebo 4 months 6 g EPA/placebo 4 months 30 bipolar I and II. duration.4 g DHA or placebo. PPD merits further investigation in better designed placebo controlled studies which ought to include an infant assessment. infant monkeys fed a formula containing 1% DHA and 1% AA displayed better visual orienting and motor skills by day 7 and day 14 than breast-fed or standard formula-fed infant monkeys [54]. dosage Subjects.4 g DHA daily to that in 16 bipolar patients receiving olive oil placebo found more patients in the PUFA supplemented group to remain stable at 4 months than in the placebo group. [58] Keck et al. [57] 6. [58] women. only one report found some benefit from ␻–3 fatty acids in bipolar disorders.2 g EPA⫹3. These findings notwithstanding. increased rates of schizophrenia in urban versus rural settings and increased rates in dark-skinned migrants to colder climates [59]. Omega–3 Fatty Acids in Bipolar Disorder (table 2) Two studies have described either reduced erythrocyte membrane AA or DHA content in bipolar disorder patients [55] or an increased prevalence of bipolar I. Two studies by Keck et al. Neurodevelopment and Psychiatric Disorder 7 . disorder 59 bipolar depressed pts 62 bipolar rapid cycling Longer time to relapse No difference between groups No difference between groups Keck et al. Among the nutritional deficiencies low vitamin D has been hypothesized to underlie the relationships to excess of winter births. bipolar II bipolar spectrum disorder in countries with less than 50 lb seafood consumption per year [56].2 g EPA⫹ 3. n Results Stoll et al. [58] found no benefits from 6 g EPA added for 4 months to the medication regime of bipolar patients. Stoll et al. 12 weeks 3 g EPA 12 weeks EPA ⬎ DHA No difference 2 g improvement in clozapine patients ↓PANSS score ↓dyskinesia The rationale to use PUFAS in schizophrenia is based on Horrobin’s theory [60] of abnormal lipid metabolism in schizophrenia and on findings that schizophrenic patients as opposed to normal controls and depressed patients display a deficient flushing response to niacin subdermally suggesting reduced membrane arachidonic acid levels and reduced production of prostaglandin D2 (PGD2) in schizophrenia. reduced positive symptoms [64]. only. An open trial [62] found symptomatic improvement of negative symptoms in 20 schizophrenia patients following 6 weeks of 10 g EPA/DHA. [64] 14/12 Monotherapy Peet et al. Another analysis [65] in which 2 g EPA. but only 8/14 EPA treated patient required antipsychotic medication after 3 months. but not 1 or 4 g EPA were found to be better than placebo was based on 9 clozapine-treated patients. Noaghiul and Hibbeln [56] observed no relationship between seafood consumption and lifetime prevalence rates of schizophrenia. [61] a described lower than normal AA and DHA in drug naïve unmedicated compared to medicated schizophrenia patients and controls as well as modestly significant negative correlations between AA. 12 placebo-treated patients. In a monotherapy trial [64].ratio 1. as well as vitamins C and E) found clinical improvement in 33 patients [63]. Another uncontrolled study (180/120 mg EPA/DHA. In four out of five placebo-controlled add-on trials to standard antipsychotic medication EPA. dosage. [64] 45 Fenton et al. The strongest evidence for consistent improvement from Casper 8 . [62] Subjects. 4 g EPA/placebo.3. n 20 Arvindaksham et al. 6 weeks EPA 360 mg⫹ DHA 240 mg ⫹ vitamins C and E Improvement: AIMS and PANSS Sustained 4 months improvement 2 g EPA/placebo ↓PANSS score 2 g EPA vs. [67] 87 Peet and Horrobin [45] Emsley et al. but not DHA. 2 g DHA 3 months 3 g EPA/placebo 12 weeks 1. duration Outcome 10 g EPA/DHA ratio: 1. Polyunsaturated fatty acids in the treatment with schizophrenia: placebocontrolled studies of medicated patients Author Open-label trials Mellor et al. 2.Table 3.3. [66] 115 40 Type. [63] 33 Peet et al. Arvindakshan et al. 75]. EPA 320 mg EPA 1 g mineral 1 g ↓aggressive behavior stress-induced 26% reduction in disciplinary action ↓aggression scores DHA levels ⬎1 SD DHA food 3.Table 4. Impulsivity and Irritability (table 5) Although several uncontrolled studies [68–73] have reported reductions in aggressive behavior or hostility scores after administration of DHA or EPA. Fenton et al. Plasma Nutrients. year Number of subjects (age. A decreased risk for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) was found in individuals who used both vitamin C and vitamin E [76. criminal behavior Gesch et al. 355 NC 3–5 years Enrichment week 3 to 12 based on total PANSS scores and involuntary movement scores was presented by Emsley et al. years) Type. DHA supplements for 2 months in a placebo-controlled study [72] did not improve concentration or the behavior of children with attention deficit disorder.581 youths ADHD 20/20 children DHA 1. no firm conclusions can be drawn without more and better designed double blind controlled studies. hostility and/or aggression and ␻–3 fatty acids Authors. DHA 172.6 g/week ↓high hostility score ↑visual memory ↓errors commission ↓schizotypal. [70] Iribaren et al. [69] Zanarini et al. Neurodevelopment and Psychiatric Disorder 9 .19 students 3 months 231 male offenders ⬎18 years – 142 days BPD 20/10 women. ALA.and EPAtreated group in an older chronically ill population. Studies examining the relationship between irritability. dosage Outcome/results Hamazaki et al.6 g soybean oil LA. summarized in table 4. 77]. Mild Cognitive Impairment and Alzheimer’s Disease (table 5) Epidemiological studies. 8 weeks 3. suggest better cognitive function with long-term use of vitamin C and vitamin E [74. [71] Hirayam et al. [68] 22 vs. [72] Raine et al. [67] found no differences over the 12-week period between the placebo. [66] who in contrast to Peet and Horrobin [65] found a trend for patients on conventional antipsychotic drugs to fare better. [90] 83 children. dementia. [88] AD/other dementias versus NC ↓␻–3/␻–6 ratios phosphatidylcholine Tabet et al. dosage Outcome/results Fletcher et al. HR 0. ␻–3 PUFA and phospholipid levels were found to be reduced in AD and other dementias [78]. [74] 14. ↓antioxidant levels ↓oxidative enzyme levels Tully et al. [89] 81 AD/81 NC Intake vitamins C. A ↓vitamins C and E in severe AD Morris et al.54 Otsuka [87] 64AD/80 NC AD disliked fish and green vegetable EPA at 900 mg ↑cognitive function Conquer et al. NC MMSE: 19.968 (70–79) Nurses’ Health St.214 (75–84) Ascorbate levels upper quintile ↓mortality risk.9-year follow-up Grodstein et al. 25 CI vs.740 Vitamin C ⫽ ⬎500 mg/day ⫹Vitamin E combined incidence of AD Schaefer et al. [79] 815 (65–94 ) Fish once/week ↓60% AD 3. E. A. improves energy levels and reduces anxiety. C. [80] 148 AD/45 NC ↓EPA and DHA in AD vs. Long-term vitamin C and E users ↑cognitive status Rinaldi et al. [77] 200 AD/4. etc.Table 5. Four studies found a relationship between fish and PUFA intake and the incidence of AD [79–81]. [75] 63 AD. [81] 899 Upper quartile DHA 180 mg DHA daily fish twice/week ↓39% AD ↓47% dementia 9-year follow-up MMSE ⫽ Mini mental status examination. [86] 1. Physical Exercise and Emotional Health Clinical and experimental evidence from studies in elite athletes and in moderately depressed patient populations suggests that vigorous exercise of 30 min or more of moderate intensity physical activity on most.5 AD/ 28. 53 NC Vitamins E.9 NC Zandi et al. Case studies and case control studies of nutritional factors in aging. years) Type. tension and depressive Casper 10 . preferably all days. and AD Authors Number of subjects (age. Neurodevelopment and Psychiatric Disorder 11 . Physical activity and mental health theories regarding physiological and psychological changes Physical activity induces physiological changes Neurotransmitters – noradrenalin.increase vigor and reduce anxiety and tension Increases steroid reserves which counteracts stress Increases cerebral blood flow Increases alpha rhythm and hemispheric synchronization Lowers muscle action potential-reduces tension Increases body temperature – sedative effects Releases endorphins – analgesic properties Physical activity induces psychological changes Increases self-efficacy. the fact that at randomization 52% of women refused to be assigned to the lower exercise group limits the generalizability. and the sense of leaden paralysis and lethargy in severe depressive disorders reduce the possibility of exercise in these populations. hyperventilation. women at the higher end. The benefits of daily physical exercise in healthy and depressed populations have been reviewed previously by Casper [82]. Antenatal Exercise and Birth Weight Studies on the impact of exercise on birth outcome are of increasing importance considering that more young women now engage in strenuous exercise daily. increased heart rate) without an emotional disturbance helps desensitize Individuals to the physiological correlates of anxiety symptoms [82]. Another study begun at 34 weeks of pregnancy [84] found a bimodal relationship with exercise. dopamine.64. those who exercised ⬎ or ⫽ 5 times per week and women at the lower end. However.Table 6. respectively) to deliver babies with a low birth weight. In a prospective controlled study [83] that compared pregnant women who exercised ⬎5 times per week with women who exercised 3 times or less per week. self-esteem and self-sufficiency Induces a meditative. those who exercised ⬍or ⫽ 2 times per week were at increased risk (odds ratios 4. A much larger study using data from the National Maternal and Nutrients. Table 6 lists the physiological and psychological mechanisms which have been hypothesized to contribute to the improved wellbeing.61 and 2. relaxed state Distracts from daily stress and anxiety Repeatedly experiencing physical symptoms (sweating. serotonin. no statistically significant difference in the mean birth weight of babies born was found. The lack of motivation and interest. but also vitamins.47:210–220. References 1 2 3 4 5 6 7 8 Tsuang M: Schizophrenia: Genes and environment. Arch Gen Psychiatry 2004.301:386–389. improved sleep and/or reduced abnormal movements may account for the symptomatic improvements in MDD and schizophrenia. Biochim Biophys Acta 2003. 2001. Liu W. et al: Association of APOE gene with schizophrenia in Chinese: a possible risk factor in times of malnutrition. Karger. Barcelo-Coblijn G. No significant relationship between the duration of gestation and physical activity was observed. 2001. 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Campbell M: Activity patterns during pregnancy. Can J Appl Physiol 2003. CA 94305–5723 (USA) Tel. Mottola M. Breeze E. pp 115–143. Morris M. Conquer J. J Obstet Gynaecol Can 2003. MD Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine 401 Quarry Road.35:1305–1312. and cognitive impairment. Bell R.poster. Casper.40:70–73. Mellingen K.14:7–15. This has been taken to imply that the genetic predisposition to schizophrenia appeared at a very early stage of human evolution. 5]. or alternatively that there is some other powerful force affecting outcome. pp 17–28 Nutrition and Schizophrenia Malcolm Peet Doncaster and South Humber NHS Trust. mainly due to the negative symptoms. the latter explanation is preferred by Western commentators. 2]. usually together with ‘negative’ symptoms such as lack of drive and initiative. 4]. Aging. than in developed Western nations in Europe and North America [1. This must mean either that the more developed medical services in the West are positively damaging to the long-term outcome of schizophrenia. Not surprisingly. 2. vol 95. Sheffield. which is even stronger than all the benefits of modern treatments. Basel. blunted emotions and lack of judgement. These treatments are palliative but not curative so that most people who suffer from schizophrenia experience lasting disability. it is well established that the 2-year outcome of schizophrenia is substantially better in developing countries such as India and Nigeria. In particular. 2005. Whilst schizophrenia is of comparable incidence across modern cultures. but the nature of that powerful positive . It is characterised by so-called ‘positive’ symptoms such as delusions (false beliefs) and hallucinations (such as hearing voices). This distinction holds for a variety of outcome measures. UK Schizophrenia is a serious and disabling mental disorder which affects almost one percent of the population worldwide. Karger. including both social functioning and clinical measures such as relapse rates. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. Current treatment involves the use of antipsychotic medication and psychosocial interventions. there are marked differences between countries in the long-term outcome of schizophrenia. It is generally accepted that the incidence of schizophrenia is broadly similar throughout the world in all contemporary cultures [1. and that this genetic makeup may even be inherent to our humanity by promoting such attributes as language acquisition and creativity [3.Simopoulos AP (ed): Nutrition and Fitness: Mental Health. World Rev Nutr Diet. If this study had shown such a strong relationship with a purely social variable such as a measure of social cohesion. In order to investigate this further. and therefore that nutritional patterns which are good for the body as a whole will also be good for the functioning of the brain. but this approach has seldom been applied to the investigation of mental health problems. It was this study that provided the original basis for the well accepted better outcome of schizophrenia in developing countries which is quoted in every standard psychiatric textbook. it would have been regarded as a landmark study. appears to be an alien concept to most mental health researchers. The possible role of nutrition in determining the outcome of schizophrenia has been largely neglected until recently. However. and that the ratio of saturated to polyunsaturated fat predicted 99% of the variance in outcome. The rest of this article will explore evidence relating nutrition and schizophrenia. The researchers had noted that Scandinavian seamen who consume a diet high in saturated fat. Peet 18 .force in developing countries has not been identified. They found that more saturated fat and less polyunsaturated fat in the diet predicted a worse outcome of schizophrenia. The first such study was carried out more than 15 years ago [6]. However. Cross-National Ecological Studies Ecological studies have provided valuable insights into the aetiology of many diseases with a nutritional component such as cancers and diseases of the metabolic syndrome. appeared to have a high prevalence of schizophrenia [7]. and indeed direct personal observation of the management of the mentally ill in developing countries would suggest that this explanation is an example of Western mythology about the nature of society in those countries. the study was almost totally ignored. They correlated schizophrenia outcome data with information on dietary intake of fat from land animals and poultry (primarily saturated fat) relative to fat intake from fish and vegetable sources (primarily polyunsaturated fat). they used data on the international variations in outcome of schizophrenia which had been collected in a large World Health Organisation study [1]. The concept that the brain is an organ which evolved in the same biological environment as the rest of body. The usual explanation revolves around theories of greater social cohesion. This neglect appears to stem from the notion of a mind-body duality which somehow regards brain functioning as being separate from the rest of the body. Possible mechanisms by which nutrition may contribute to the neuropathology of schizophrenia will be outlined. support and acceptance for people with mental health problems in developing countries. because the relationship was with nutrition and this went against prevailing thought. there is no substantial evidence to support this. The reason for this was that nutritional intake of foodstuffs intercorrelate. Data for sugar consumption are taken from FAOSTAT and data for the relevant year [9]. but not all. 1. Relationship between national sugar consumption and the 2-year outcome of schizophrenia. We found strikingly similar predictors of poor two-year outcome of schizophrenia across both of the schizophrenia outcome studies and whether social or clinical variables were used as the primary outcome measure. We took nutritional data from the Food and Agriculture Organisation website [9]. and the other was a follow-up study also sponsored by the WHO. so that diets which are high in saturated fats are also high in sugar. measures dairy products meat and eggs were found to be associated with the worse outcome of schizophrenia and the consumption of pulses with a better outcome. Based on this pioneering work we have conducted a further ecological analysis [8]. although consumption of dairy products remained a significant predictor for one clinical variable (hospitalisation rate). A lower score indicates a better outcome. for example. On several. we examined the role of individual foodstuffs. On multiple regression analysis.Refined sugar consumption (kg per capita per year) 60 Denmark USA UK Czechoslovakia 50 USSR 40 30 Colombia 20 10 India Nigeria 0 100 200 300 400 Two-year total outcome for schizophrenia Fig. The correlation between outcome and sugar consumption is shown in figure 1. consumption of sugar was the dominant predictor across all social and clinical variables. which confirmed the earlier findings about schizophrenia outcome using new patient cohorts [2]. high sugar consumption was shown to relate to a poor schizophrenia outcome whichever outcome measure was used. This figure is based on the raw data published in [8]. On the straight correlations. The 2-year total outcome data for schizophrenia take into account a range of social and clinical variables and are derived from reference 1. Instead of examining dietary constituents. We used schizophrenia outcome data from two studies: one was the WHO study [1] used by Christensen and Christensen [6]. Nutrition and Schizophrenia 19 . For example. Some of these findings have been called into question on methodological grounds [14]. unexpectedly. [15] carried out a nutritional analysis of hospitalised schizophrenic patients. Historical Association between Diet and Schizophrenia At the beginning of the twentieth century it was widely believed that indigenous populations who lived by hunter gathering and substance agriculture. Whether this was present before prescription of clozapine and therefore may have contributed to the treatment resistance. Nevertheless. Clozapine is an antipsychotic drug with potentially life-threatening side effects (agranulocytosis). Stokes and Peet [unpubl. are reduced in cell membranes of patients who suffer from schizophrenia [10–13]. so it is reserved for the treatment of patients who have not responded to other antipsychotic agents.Case-Control Studies It has been shown repeatedly that cell membrane levels of polyunsaturated fatty acids. particularly clozapine [16].] carried out a further nutritional study on a separate group of schizophrenic patients in a rehabilitation unit. This examined dietary intake of all nutrients with regard to their ability to predict severity of schizophrenia symptoms. in the opposite direction. Further analysis showed that this was due to the confounding effect of background medication. Work in this area is of particular current interest because of concerns about the development of diabetes in patients treated with some of the newer antipsychotic drugs. or whether it is a consequence of taking clozapine. had less severe schizophrenic symptoms. The correlation between PUFA in the diet and severity of schizophrenic symptoms was found to be robust and independent of background medication. She found a significant correlation between severity of symptoms and dietary intake of ␻–3 fatty acids. the correlation with dietary intake of sugar was. Patients taking the antipsychotic drug clozapine were consuming twice as much sugar as those taking other antipsychotic drugs. This has normally been measured in erythrocytes. However. it appears that treatment-resistant schizophrenic patients taking clozapine have an exceptionally high consumption of sugar. It was found that severity of symptoms correlated with both polyunsaturated fatty acids (PUFA) and with sugar intake in the normal daily diet. Therefore. The correlation with polyunsaturated fatty acids were in the expected direction in that higher dietary intake of PUFA was associated with less severe schizophrenic symptoms. Those patients who had more ␻–3 fatty acids in their normal daily diet with no attempt at intervention. has yet to be determined. such studies formed the basis for investigating nutrition as a possible contributory factor to schizophrenia. Mellor et al. Peet 20 . some studies did not control for the effects of smoking and storage artefact. particularly docasahexaenoic acid DHA and arachidonic acid (AA). 24]. There is a substantial body of evidence to suggest that schizophrenia as we know it was relatively uncommon amongst indigenous populations and increased when indigenous peoples came into contact with Western culture. After the Second World War concepts of this kind were no longer acceptable. 18]. the number and variety of studies all pointing to low rates of mental illness cannot be ignored. as there is no evident time-lag. This belief was based on overtly racist concepts that the brains of these ‘primitive’ people were not sufficiently developed for them to experience the complex symptoms of mental illness. There is a close association between reported cases of insanity and the consumption of sugar by the general population for the period 1800 to 1914 [17]. the marked increase in insanity (as it was then called) had to be accommodated by the rapid construction of asylums during this period of time. At one time there was vigorous debate as to whether this was due to a true increase in incidence or a worse outcome [20. had lower levels of schizophrenia amongst Nutrition and Schizophrenia 21 . It was recognised that human beings all have the same capacity for brain functioning. this conceptual shift which was primarily driven by ideology may have caused important epidemiological information to be overlooked. This evidence has been summarised elsewhere [17. By their very nature. 21]. this explanation cannot possibly account for the massive need for increased provision for the insane which was driven by. At the same time as the mental health of the general population deteriorated. who ate a diet with much less saturated fat and sugar than ours. and was due to increased stigmatisation and lower tolerance of people who behaved unusually. It therefore appears that indigenous people. these studies were conducted decades ago and they can therefore be criticised because most of them do not conform to modern methodological principles. with the conclusion that the potential for mental illness is universal. If this relationship is causal this would imply a fairly immediate harmful effect of sugar on mental state. Whichever is true. Unfortunately. population consumption of both saturated fat and sugar showed massive increases [23. their diet was undergoing enormous change. Sociologists have argued that the reported increase in the rate of insanity was more apparent than real. There is also evidence that the prevalence of mental illness in Western nations increased markedly during the Industrial Revolution [19]. That said. Whilst there is some evidence that mental institutions were abused for the incarceration of people who behaved in a way that was perceived as socially deviant rather than being mentally ill. rather than being the driver for. the increased prevalence of mental illness in society. fuelled by the building of institutions to house them [22]. During this period.did not suffer from mental illness. This was reinforced by the WHO studies showing that the incidence (but not the outcome) of schizophrenia was similar across all contemporary cultures. including the shift to a Western diet. and therefore any increased risk of schizophrenia cannot be attributed to any specific nutrient. Avmore et al. more speech problems. Offspring of the mothers who were most exposed to famine during the first trimester of pregnancy showed a double relative risk of schizophrenia. More recent evidence suggests that breast-feeding may have a more subtle influence on the presentation of schizophrenia. Several studies have attempted to investigate the effect of breast-feeding on subsequent development of schizophrenia. and that there was a rise in the prevalence and perhaps incidence of schizophrenia during the Industrial Revolution which correlates with increased dietary intake of fat and sugar. Possible Mechanisms by which Diet Contributes to Neuropathology There is no doubt that genetic factors are important in the aetiology of schizophrenia although putative genetic markers have proved difficult to replicate. high sugar diet is associated with a poor two-year outcome of schizophrenia. and less social confidence as children. Because many of these abnormalities in childhood of people who eventually become schizophrenic. This nutritional deficiency was generalised. A polygenic inheritance is likely. In a large birth cohort [26] it was found that those who became schizophrenic later in life had delayed milestones of motor development. The importance of the environmental factors is demonstrated by the fact that concordance for schizophrenia in monozygotic twins is only around 50% [25]. there has been interest in the possible relationship between diet in pregnancy and infancy and subsequent development of schizophrenia. At age 15 both anxiety and lower IQ were independent predictors of future schizophrenia.their population. However. the data do indicate that nutritional factors during pregnancy can be a determinant of future schizophrenia in the offspring. are similar to those of children who are given feeds deficient in DHA as babies and infants. It is generally believed that schizophrenia is a disorder of neurodevelopment. An initial study reporting an excess of formula feeding relative to breast-feeding amongst people who subsequently developed schizophrenia [28] was refuted by a large cohort study which found no difference in rates of schizophrenia between people who had been breast-fed as infants and those who had received formula feeds [29]. Peet 22 . lower educational test scores. This is consistent with the ecological evidence suggesting that a high saturated fat. [27] examined the subsequent development of schizophrenia in children of mothers exposed during early pregnancy to the Dutch hunger winter of 1944/1945. Susser et al. [30] found that duration of breast-feeding was positively correlated with the age at onset of illness suggesting that prolonged breast-feeding might delay the onset of schizophrenia. solitary play preference. The possible influence of other dietary constituents including ␻–3 fatty acids has not yet been investigated. it is striking that the same dietary components which appear to be detrimental to the outcome of schizophrenia. A recent study showed reduced BDNF expression in the prefrontal cortex of patients with schizophrenia [42]. Schizophrenia typically presents in young adulthood. We have seen evidence to Nutrition and Schizophrenia 23 . This has led to an interest in the possible role of neurotrophins in the aetiology of schizophrenia. 45]. possibly due to apoptosis of neurones [33]. BDNF can also protect neurones against apoptosis [39]. Brain-derived neurotrophic factor (BDNF) is required to maintain dendrites [35]. In the light of all the evidence implicating BDNF in the pathogenesis of schizophrenia. Evidence from dietary surveys of schizophrenia patients suggests that their diet contains even more saturated fat and sugar than the general population [44. BDNF is also a modulator of neurotransmitters including gamma-amino butyric acid (GABA). 41]. which is regarded as important in the pathogenesis of schizophrenia [38]. it is of considerable interest that BDNF levels in rat brain have been shown to be significantly reduced by a diet which is high in saturated fat and sugar [43]. and the response of schizophrenia to the anti-psychotic drug clozapine [40. and expression in BDNF in the prefrontal cortex shows a significant increase during young adulthood at a time when the frontal cortex matures both structurally and functionally [36]. The feasibility of carrying out such studies depends upon the time point at which nutritional factors come into play. Earlier studies have shown a well replicated increase in the size of the cerebral ventricles which pre-dates the onset of overt schizophrenic symptoms [31. also modulate a neurotrophin which is currently of great interest in schizophrenia research. More recently. schizophrenic illness. the only way to directly test the validity of a nutritional hypotheses is through intervention studies. 32]. and plausible biological mechanisms exist by which nutrition could affect the onset and outcome of the schizophrenic process. There is continuing debate as to whether this abnormality is static or progressive.There is a great deal of evidence that schizophrenia is associated with significant neuropathology. However. Lack of brain BDNF has been shown in mice to result in reduced neuronal soma size and dendrite density in the prefrontal cortex [37]. there is evidence that neuronal cytoarchitecture is abnormal in the cerebral cortex of schizophrenic patients [34]. Intervention Studies There is epidemiological evidence of an association between nutrition and schizophrenia. This is similar to the changes in neuronal architecture which have been reported in brains from schizophrenia patients. Recent molecular genetic studies have shown an association between BDNF gene variants. However. An American study in which 3 g daily of ethyl EPA was added to existing medication found no significant benefit [48]. Three further studies have produced contrasting results. The first was a pilot study comparing DHA with eicosapentaenoic acid (EPA) added to existing medication for 3 months [46]. They also showed a considerable reduction in the severity of a movement disorder known as tardive dyskinesia. there is evidence that nutritional approaches may be beneficial even after the onset of the schizophrenic illness. such that more ␻–3 fatty acids in the normal daily diet was associated with less severe symptomatology [15]. This implies that nutritional interventions for people who have already developed schizophrenia may be of limited impact. found significant improvement in symptoms when 2 g daily of ethyl EPA was added to the antipsychotic drug clozapine. A subsequent UK study comparing 1. A recent study from Australia in patients with first episode schizophrenia showed that those treated with EPA required significantly lower dosages of antipsychotic medication [50]. This work was stimulated by initial findings. A study carried out in South Africa found significant improvement for both schizophrenic symptoms and tardive dyskinesia when 3 g daily of ethyl EPA was given together with already prescribed antipsychotic drugs [49]. This is a neurological abnormality which is found in up to 5% of patients with schizophrenia as part of the illness process. There have now been five double-blind placebo controlled trials of ␻–3 fatty acids in the treatment of schizophrenia.5 g of EPA. This led to a pilot study of fish oil which was given in addition to usual medical treatment to a group of schizophrenic patients who were still symptomatic despite being on the most appropriate available antipsychotic medication [15]. and that the neuropathology of schizophrenia is well established by the time overt symptoms become manifest. The finding from this study was that EPA was significantly more effective than placebo or DHA. Nevertheless. Several studies have also investigated EPA as a sole treatment for schizophrenia. and that DHA was no better than placebo. detailed earlier in this article that schizophrenic patients have reduced cell membranes levels of polyunsaturated fatty acids including DHA [10–13]. but which increases in frequency after prolonged treatment with the older antipsychotic drugs. it was reported that EPA brought Peet 24 . In one single case study. Most formal studies have focused upon treatment with omega-3 fatty acids. and that dietary intake of ␻–3 fatty acids appears to correlate with schizophrenic symptoms.suggest that malnutrition in pregnancy increases the likelihood of schizophrenia in offspring but breast-feeding may delay the onset of schizophrenia. These patients showed significant reduction in schizophrenic symptomatology after 6 weeks treatment with 10 g per day of concentrated fish oil which contained around 2 g per day of DHA and 1. but no significant benefit in the whole patient group [47]. 2 and 4 g of ethyl EPA as an adjunct to current medication. It may be EPA is effective only for certain subtypes of schizophrenia. but it appears that modern science is now offering support to such concepts. Nutrition and Schizophrenia 25 .about complete symptom remission accompanied by reversal of the pre-existing cerebral ventricular enlargement [51]. Routledge & Kegan Paul. A World Health Organisation ten-country study. Importantly. incidence and course in different cultures. However. Anker M. This was based on the philosophy that the body. low sugar diet in the management of schizophrenia. New York. functions at its best when in the biological environment provided by the nutrition on which we evolved. All patients given placebo required prescription of antipsychotic with the three months trial period whereas half of the patients treated with EPA did not require antipsychotic medication. where consumption of saturated fat and more particularly of sugar is less than in the UK and the USA [9]. it seems likely that EPA given without reference to the diet as a whole is not an effective strategy. Jablensky N. the EPA-treated patients had significantly less schizophrenia symptoms than those who were treated with placebo plus conventional antipsychotic drugs. for example by cutting out all processed foods. some practitioners have urged approaches which involve reduced consumption of saturated fat and sugar. A placebo-controlled study of EPA as a sole treatment for schizophrenia was conducted in India [46]. and in this case specifically the brain. Sartorius N.(monograph suppl 20):1–97. some clinicians have adopted this approach and have anecdotally reported success [52]. It is not clear why there is such variability in the results of studies of EPA treatment of schizophrenia. It is perhaps significant that the best results with EPA treatment have come from the studies in India and South Africa. 1979. Fasting is known to increase brain levels of BDNF in animals [54]. Ernberg G. A period of fasting often followed by a vegetarian diet was frequently used in the USSR to treat mental disorders. Korten A. This follows the principles of ‘orthomolecular’ psychiatry first put forward by Pauling [55]. and special units were set up for this purpose [53]. Bertelson A: Schizophrenia: Manifestations. Psychol Med 1992. 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Neurosci Lett 2003. Schizophr Res 2003. pp 452–462. Jovanovic JN. Collins P. Jones LB: Evidence for a decrease in basilar dendrites of pyramidal cells in schizophrenic medial prefrontal cortex.158:2071–2074. Peet M. and cell-surface stability. Am J Psychiatry 2000. Moss SJ: Brain-derived neurotrophic factor modulates fast synoptic inhibition by regulating GABA (A) receptor phosphorylation. 1444:2446–2453. S26 4TH (UK) Tel. and insulin resistance syndrome. Mattson MP: Reversal of behavioural and metabolic abnormalities. Pauling L: Orthomolecular psychiatry: Varying the concentrations of substances normally present in the human body may control mental disease. Jiang H. by dietary restriction in mice deficient in brain-derived neurotrophic factor. Guo Z. E-Mail malcolmpeet@yahoo. Malcolm Peet Doncaster and South Humber NHS Trust Swallownest Court Aughton Road Swallownest Sheffield. ⫹44 1114 2872570.com Peet 28 .54 55 Duan W. Endocrinology 2003. Ware M. Science 1968. Prof.160:265–271. Fax ⫹44 1114 2879147. Obesity: Prevalence. hypertension. and over 19 million American adult women are obese [6]. World Rev Nutr Diet. Almost one half of the women in the western world are overweight. Aging. This results in a natural net effect of weight gain . Berry Department of Human Nutrition and Metabolism. Yet the high and growing prevalence of obesity is mainly due to environmental effects influencing a genetic susceptibility [8]. Karger. Jerusalem. PA is paramount in managing obesity and combating weight gain. having a BMI of 25 or more [6. Causes and Consequences Almost one fifth of US adults are obese. Food and energy intake are higher than actually needed. Post-menopausal women. In some ways the development of obesity may be considered as a ‘normal’ response to an ‘abnormal’ environment. The causes of obesity are genetic and environmental. have an increased tendency for gaining weight and its associated metabolic syndrome [2]. deprived of the protective effects of endogenous estrogen together with negative environmental factors. Additionally. Braun School of Public Health. hyperlipidemia. Basel. 7]. diabetes. The health hazards associated with being overweight are numerous. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. including increased all-cause and cardiovascular mortality. 2005.Aging. cancer and more. Israel Obesity is an epidemic on a global scale [1]. posing a major threat to human health and well-being as well as consuming a large part of health care costs. The Hebrew University-Hadassah Medical School. including in the postmenopausal years [3–5]. Faculty of Medicine. pp 29–34 Managing Obesity after Menopause: The Role of Physical Activity Gal Dubnov. vol 95. while the mechanized surroundings produce a low level of PA. having a body mass index (BMI) of over 30. Elliot M. Osteoporosis and Physical Activity Simopoulos AP (ed): Nutrition and Fitness: Mental Health. A major cause for the weight gain is lack of sufficient physical activity (PA). and physical activity or physical fitness Mortality Obesity Intentional weight loss Physical activity/ physical fitness Overall Cardiovascular CAD events Metabolic syndrome Stroke Gallbladder disease Cancer ⇑ ⇑ ⇑ ⇑ ⇑ ⇑ ⇑ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ CAD ⫽ Coronary artery disease. The most common methods of weight reduction are lifestyle modification.Table 1. stroke. reflected by a closer association of mortality with the waist-hip ratio or waist circumference (markers of android adiposity) than with BMI (a more general measure of adiposity) [12. low back pain. 13]. Lifestyle Modifications for Intentional Weight Loss Most obesity complications are reduced with intentional weight loss. The metabolic syndrome includes type 2 diabetes mellitus. Estrogen has therefore an effect on the site of obesity. diabetes mellitus. pulmonary emboli. and depression. This weight gain is accompanied by changes in body composition and fat distribution toward a more android obesity [11]. 14]. obstructive sleep apnea. This later results in increased mortality. which is associated with the metabolic syndrome [2]. prescription and non-prescription medications. The risk for some common disease conditions that are influenced by weight gain. hypertension. hypertension and hyperlipidemia. A more comprehensive list will include increased mortality. gall bladder disease. HTN ⫽ hypertension. whatever the method used for the initial weight Dubnov/Berry 30 . several forms of cancer. heartburn. and its withdrawal after the menopause assists in bringing about the metabolic syndrome of overweight men. kidney stones. osteoarthritis. It should be noted that use of hormone replacement therapy has been shown to decrease the shift from gynoid to android fat deposition after menopause [11. throughout the years – both individually and globally. Some medical complications of obesity are presented in table 1. and gastric surgery for subjects with BMI over 38. weight loss. arthralgia. and lack of PA seems a major environmental contributor [10]. pseudotumor cerebri. coronary artery disease. Most importantly. Menopause is associated with weight gain [9]. Guides for the treatment of adult obesity are and proper food selection are available from the National Institute of Health. 28] and improve mood [29]. 27]. In meta-analyses assessing weight loss programs. several methods exist to assist in adherence [15]. a brisk walk of 3. only half reported doing any regular PA. It is therefore an important tool in weight loss and in the reversal of many obesity related comorbidities. fruits and vegetables. such as grains. 25]. Dieting only is not expected to maintain weight loss in the long term [19]. days of the week [30–32]. lifestyle habits may be effectively changed even in this age: you can teach an old dog new tricks. 23]. it has been shown that exercise is more of importance in long term weight maintenance [19]. The recommended 30 min may be accumulated through shorter bouts of activity along the day. In general. which lowers the metabolic rate and reduces energy expenditure. As discussed. The weight reduction program should include behavioral changes. while it Physical Activity and Postmenopausal Obesity 31 . lower the risk of fat and weight gain [24. as these carry a major role in the maintenance of the newly reduced body weight [20]. as shown in table 1: good fitness and engaging in PA lower mortality rates [22. future lifestyle modification is crucial in order to maintain the newly reduced weight. Thus. the American Obesity Association and the US Department of Agriculture [16–18]. lower the incidence of cancer [23. In a follow up after postmenopausal women who participated in a trial which encouraged increasing walking distance. Therefore.reduction. Physical Activity in Postmenopausal Weight Loss Among women aged 50–64. Food selection aimed for loss should allow a lower energy intake with a large enough bulk of food. those originally assigned to the walking group were still walking more than the control group –10 years after trial has ended [33].5 km a day is enough to exert most of the health benefits. offer some protection against the medical consequences of obesity and the metabolic syndrome [26. This is due to the concomitant reduction of muscle mass. insufficient PA is a major factor in postmenopausal weight gain. current nutritional recommendations for weight loss are simply adherence to the same guidelines that are established for all adults. This leads to a lower caloric output along the day. while only about one quarter report high intensity exercise [21]. preferably all. Exercise Prescription It is recommended for every adult to engage in 30 min of moderate-intensity PA on most. 1998.31(suppl 11):S564–567. Brzezinski A. Shapira N. with less decrease in the energy-utilizing fat free mass [34]. pp 105–126. and limited in fat and salt. Its role in weight management and the prevention of weight gain or regain along the years is fundamental. the health benefits of exercise alone may be similar to those achieved by weight loss in modulating the metabolic syndrome [35–37]. Berry EM: Managing obesity following the menopause: The role of physical activity. Dubnov G. Maturitas 2003. A suitable summary of this might be that ‘Fat and fit is better than lean and lazy’. for at least 30 min. World Health Organization. An important issue is that even if a person is unsuccessful at weight loss. With the aid of proper nutrition. References 1 2 3 4 5 World Health Organization: Obesity: Preventing and Managing the Global Epidemic. Increasing the amount of PA is expected to attenuate most of the obesity-associated medical situations. Behavioral changes aimed at supporting the decreased food intake and increased engagement in physical activities is of sound importance. The frequency of PA is 3–7 times a week. Astrup A: Physical activity and weight gain and fat distribution changes with menopause: Current evidence and research issues. The type of PA should include mainly aerobic exercises. Carr MC: The emergence of the metabolic syndrome with menopause. weight loss and its maintenance is achievable. jogging.88:2404–2411. Dubnov G. a simple calculation shows that a person has to walk about 100 Km in order to expend the energy equivalent to 1 kg of adipose tissue.44:89–101. a very important factor in weight loss maintenance. cycling and aerobic dancing. Israel. vegetables and grains. Report of a WHO Consultation on Obesity. Med Sci Sports Exerc 1999. Resistance training may be added. 2001. that is rich in fruit. weight loss by exercise preserves lean body mass [38]. such as walking. swimming. Conclusion Women in the postmenopausal years have an increased risk for weight gain and its associated morbidities. Berry EM: Weight control and the management of obesity after menopause: The role of physical activity. corresponding to brisk walking. ISAS International Seminars. split into up to three bouts.offered more fat loss. The intensity can be as low as 40% of maximal heart rate (MHR ⫽ 220 minus the age in years) for beginners. (eds): Nutrition in the Female Life Cycle. along with insufficient amount of PA. Dubnov/Berry 32 . in Lebenthal E. Additionally. Geneva. Further. J Clin Endocrinol Metabol 2003. This is mainly due to hormonal changes and an increase in central adiposity. Matthews K. Blair SN. Grady D. Shape Up America! and American Obesity Association. et al: Effects of hormone replacement therapy on weight. Bowman BA. et al: Recreational physical activity and ten-year weight change in a US national cohort. Vittinghoff E. Ann Intern Med 1999. Shlipak MG. Int J Obes Relat Metab Disord 1993. Obert KA. Am J Epidemiol 2003. Williamson DF. Totowa.analysis of the past 25 years of weight loss research using diet. NJ. et al: Genetic and environmental influences on total body and central abdominal fat: The effect of physical activity in female twins. Sherman SE. Hercberg S. Arch Intern Med 1990. Kohrt WM. Visser M. Beer. Brodney S: Effects of physical inactivity and obesity on morbidity and mortality: Current evidence and research issues.7:334–341. Berry EM: Physical activity and mood: The endocrine connection. D’Agostino RB. Solomon C. Science 1998. Kampert JB. Cobb JL. Kelly PJ. Madans J. JAMA 2001. Anda RF. Chiano MN.2002. Int J Obes Relat Metab Disord 1997. Wu FB. National Institutes of Health: The practical guide to identification. Pelissier C. Daling JR. 1990.5. Barrett-Connor E: Association of total and central obesity with mortality in postmenopausal women with coronary heart disease. ed 5. body composition. Hum Reprod 2003. Constantini NW (eds): Sports Endocrinology. Resnick HE.54:424–430.21: 941–947. et al: Associations of general and abdominal obesity with multiple health outcomes in older women. Roux C: Changes in body composition during post-menopausal hormone therapy: A 2 year prospective study. Wing RR. et al: Physical activity and mortality in women in the Framingham Heart Study. evaluation.term weight losses. Arabi A. and food intake in early postmenopausal women: A prospective study. Blair SN. 2000.6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Mokdad AH. Physical Activity and Postmenopausal Obesity 33 . US Department of Agriculture: US Department of Health and Human Services. et al: Prevalence and correlates of recreational physical activity in women aged 50–64 years.134:96–105. et al: Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. Stanford JL.org. Koceja DM. Dietary Guidelines for Americans. Arch Intern Med 2000. Also available at http:// www. Miller WC. Garnero P. Wing R. Benhamou CL. Wurtman J. fat distribution.shapeup. Libbey. JAMA 1996. Reubinoff BE. J Gerontol 1992. 2000. Hamilton EJ: A meta. et al: Obesity and other health determinants across Europe: The EURALIM project. Shape Up America! and American Obesity Association: Guidance for treatment of adult obesity. Morabia A. Peters JC: Environmental contributions to the obesity epidemic. et al: Physical activity and risk for cardiovascular events in diabetic women. Berry EM: Strategies to improve patient compliance in the management of obesity. Hill JO. Am Heart J 1994. 1996.17:279–286. Holloszy JO: Exercise training improves fat distribution patterns in 60 to 70 year old men and women. Ulrich C. et al: The continuing epidemics of obesity and diabetes in the United States. Fertil Steril 1995. et al: Physical activity and cancer etiology: associations and mechanisms. Klem ML.158:1161–1170. Ann Intern Med 2001. Kohl HW. in Warren MP. Bethesda. Folsom AR. et al: Behavioral strategies of individuals who have maintained long. Kanaya AM. Stampfer MJ. exercise or diet plus exercise intervention.130: 873–882. in Oomura Y (eds): Progress in Obesity Research. National Institutes of Health. Anderson KE. Kushi LH. Menopause 1998. Med Sci Sports Exerc 1999. accessed 10.286:1195–200.280: 1371–1374. J Epidemiol Community Health 2000. Porcher R.276: 205–210.18: 1747–1752. McGuire MT. et al: Weight gain at the time of menopause. Humana Press.151:97–103. Dubnov G. 2000. Slate S. Cancer Causes Control 1998. McTiernan A.Borst S. London.64:963–8. Ford ES.128:879–884. Washington. US Department of Agriculture.160:2117–2128. Rojanski L.31:s646–s662.47:M99–M105. Samaras K. Obes Res 1999. Kuller L.5:95–101. McTiernan A. and treatment of overweight and obesity in adults.9:487–509. pp 421–431. Kohl HW 3rd.in press. and all-cause mortality in women. National Institutes of Health: Physical activity and cardiovascular health. et al: Physical activity and public health – a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine.net Dubnov/Berry 34 . Pereira MA. Blair SN: The relation of body mass index. Cheng YJ. MD Department of Human Nutrition and Metabolism Faculty of Medicine. Int J Obes Relat Metab Disord 1994. Ballor DL.184 kJ) through diet or exercise: which is better for men with obesity? Public Health Rev 2005.10:417–23. et al: A randomized walking trial of postmenopausal women. Blair SN. Am J Epidemiol 2002. Gibbons LW: Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and allcause mortality in men and women. Macera CA. The Hebrew University-Hadassah Medical School POB 12272. Obes Res 2002. cardiorespiratory fitness. Day RD. Pate RR. Med Sci Sports Exerc 1998. 91120 Jerusalem (Israel) Tel. Berry EM: Energy deficit of 1. Karni Y.30 31 32 33 34 35 36 37 38 American College of Sports Medicine Position Stand on the recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness. Cai J. Stevens J. Fax ⫹972 2 643 1105 E-Mail [email protected]. JAMA 1995. JAMA 1996.273:402–407. Kaplanski Y. Barlow CE. NIH Consens Statement 1995. Poehlman ET: Exercise training enhances fat. Paffenbarger RS Jr. ⫹972 2 675 8298. Arch Intern Med 1998.18:35–40. Pratt M.158:1695–1701. and flexibility in adults.huji. Kampert JB.30:975–991.000 kcal/day (4. Magazanik A. Braun L. Blair SN.ac.13:1–33. Elliot M.free mass preservation during dietinduced weight loss: A meta-analytical finding. Barlow CE. Farrell SW. Evenson KR. Kriska AM. gal-d@bezeqint. Thomas R: Fitness and fatness as predictors of mortality from all causes and from cardiovascular disease in men and women in the lipid research clinics study.276:205–210. Berry.156:832–841. Simopoulos AP (ed): Nutrition and Fitness: Mental Health. the lifetime risk of suffering an osteoporosis-related fracture approaches 50% in women and 20% in men [3.5–2. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. 6]. and at least doubles for each SD decrease of BMD relative to peak [5. Osteoporosis is less common in males than females [12] and men have a three times lower risk of fractures compared to women because they reach higher peak bone mass.e. Aging. Osteoporosis is diagnosed by dual-energy X-ray absorptiometry (DXA) when bone mineral density (BMD. However. ⬍⫺2. Ferrari Division of Bone Diseases. This disease represents a major public health concern that will only increase in importance as life expectancy increases and the population ages. so-called peak bone mass. Osteoporosis results from a failure to acquire optimal peak bone mass during growth [7]. Department of Rehabilitation and Geriatrics.0%/year). 11]. Karger. 4]. Geneva.5 SDs from the mean bone density in young adults (i. osteoporosis has been recognized as a ‘global problem’ by the World Health Organization (WHO) [2]. hypogonadism affects only about 30% of aging males [14] and men have a shorter life expectancy compared to women. pp 35–51 Osteoporosis: A Complex Disorder of Aging with Multiple Genetic and Environmental Determinants Serge L. World Rev Nutr Diet. but bone loss continues in older persons [10. 2005. which reflects a larger bone size rather than a greater bone mineral density within bone [13]. Switzerland Determinants of Osteoporosis and Fracture Risk Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture [1]. and/or to maintain bone mass in later years. 9]. fracture risk increases continuously as BMD decreases [3]. Basel. Specifically. vol 95. Women experience a more rapid phase of bone loss after the menopause (0. due mainly to estrogen deficiency [8.5 T-score). Moreover. Accordingly. g/cm2) is below ⫺2. Geneva University Hospital. . 20]. Multiple endogenous. Twins and parentsoffspring studies have shown that heritability. such as hip geometry. 22]. 18]. intervention trials using calcium supplements and/or dairy food products have proven beneficial to improve bone mass gain in children. However. calcium. diabetes.Table 1. can predict fracture risk at least as well as cardiovascular risk factors can predict the risk of coronary heart disease. environmental and life style factors concur to the occurrence of osteoporosis and related fractures (table 1).e. 19. they remain relatively insensitive to identify all individuals who will eventually have a fracture [6. bone specific alkaline phosphatase) and resorption (collagen degradation products. NSAIDS) Chronic disease (malabsorption. osteoporosis is also determined by ‘bone quality’ traits. such as pyridinoline and C-terminal cross-linking of type I collagen. femur cortical thickness and trabecular connectivity in the vertebrae. CTx) [16]. i. Risk factors for osteoporosis Age Low body weight (BMI ⬍18) Early menopause (⬍45 years) Hypogonadism Family history of osteoporosis/fracture Low physical activity Low calcium intake (⬍500 mg/day) Smoking Excessive alcohol intake Medications (corticosteroids. which represents the architecture of the skeleton. and its turnover rate [15]. The latter can be evaluated indirectly by a series of serum and urine biochemical markers that reflect bone formation (osteocalcin. vitamin D and protein supplements all improve bone mass and/or fracture risk in the elderly [23–26]. the properties of the bone material (collagen type 1 and mineral). hyperthyroidism) In addition to bone density. In turn. the most important determinant of bone mass remains the genetic constitution. Although BMD (by DXA). bone turnover markers and prevalent fractures. Ferrari 36 . primary hyperparathyroidism. Heritability of Bone Mass and Strength Both women and men with a family history of osteoporosis have significantly decreased BMD compared other subjects [27–30]. anti-epileptic drugs. particularly those with a poor calcium intake [21. CRF. RA. the additive effects of genes. These markers are commonly used to evaluate osteoporosis risk in addition to BMD [17. Moreover. alone and in combination. Fracture is a very complex phenotype.Fig. soft tissue padding. Genome Screens for Bone Mass in Humans Genome-wide screening approaches search for loci flanked by DNA microsatellite markers that co-segregate with the phenotype of interest in a population of related individuals. in addition to bone quantity and quality-related factors (above). 40].0. The pedigrees so far investigated are families with a proband characterized by an extreme skeletal phenotype (high or low bone mass [36–38]). respectively) and those identified in more than one study are shown in bold. QTLs for bone geometry and size at the spine and femur [41.0 and ⬎3. The latter factors likely explain why additive genetic factors appear to contribute only about 30% to the population-based variance in the liability for fracture [35]. 44]. genetic contribution to the rate of bone turnover and bone loss after menopause has been less precisely evaluated. These studies have started to map a large number of QTLs for BMD [41. as well as nuclear families and sibships from the population at large [39. have been identified. 1. 1). In addition. and might actually be smaller (40–60%) [33]. In contrast. and exogenous factors present in the living environment. Quantitative Trait Loci (QTLs) for bone mineral density (BMD) in Caucasians were identified by genome-wide screening approaches in five separate studies (see text for details). etc. explains 60–80% of the population variance for peak bone mass.8–3. and the influence of these genetic factors is expressed well before puberty [31. as well as for bone ultrasound properties [45]. Adapted from Ferrari [147]. 43. 42] (fig. protective responses. dozens of genes with relatively small additive effects and a few genes with rather large effects might be involved [46–50]. which. Although the actual number of genes contributing to bone strength is currently unknown. also depends on other endogenous factors such as the propensity to fall [34]. QTLs with suggestive or evidence of linkage are indicated (LOD scores 1. 32]. Osteoporosis 37 . [42. The VDR gene. It is now clear that genetic variants may influence bone mass at specific skeletal sites. 68–72]. using polymorphic candidate genes coding for bone structural molecules. 75]. Vitamin D Receptor Gene (VDR) Polymorphisms The vitamin D receptor (VDR) mediates the effects of calcitriol [1. In addition. 0. found that 23 of 67 studies reported a significant association between VDR genotypes and BMD at lumbar spine. The latter studies and those involving interleukin-6 (IL-6) and the recently discovered LDL-receptor-related protein 5 (LRP5) gene polymorphisms are summarized below. [53] first reported that VDR 3⬘-UTR Bsm1 alleles (B frequency. estrogen receptor-␣ (ESR1) and type I collagen A1 chain (Col1A1) have recently been meta-analyzed. A Fok1 variant in the VDR first start codon (ATG). carries multiple polymorphisms [52]. such as dietary calcium intake. Ferrari 38 .and post-menopausal women far exceeded the number of false positive results expected under the null hypothesis (alpha ⫽ 5%) [76]. respectively) were associated with BMD in adult women and postmenopausal bone loss. cytokines involved in bone remodeling. and others noted a vanishing influence of VDR genotypes on bone mass with advancing age [63. However. Despite an apparent predominance of negative studies.25(OH)2 D3] on the intestinal absorption of calcium and phosphate and on bone mineralization.Population-Based Association Studies Hundreds of association analyses have been reported with BMD. BMD and bone loss. Gong et al. and estrogen-deficient or -replete females. 74]. Subsequently. bone and/or body size in children [62.4 and 0. etc. some investigators failed to find such association [73. Among them. looked at the association between VDR alleles. and interact with environmental factors. selectively affect males or females. young or old adults. In the first analysis. Two recent meta-analysis [76. with discordant results [55–67]. several studies suggested that VDR alleles might be associated with bone mass. (f frequency. bone turnover markers. growth factors and/or their receptors implicated in bone and mineral metabolism. and sometimes fracture. such as the vertebrae or hip. the authors calculated that the number of positive studies in pre. association studies with the vitamin D receptor (VDR). 63. 51]. hormones. mostly pre.4 among both Caucasians and Asians) was later reported to be also associated with BMD in postmenopausal women [54]. Morrison et al. 0. 77] eventually support some significant association of VDR polymorphisms with bone mass in women. numerous population-based studies including hundreds to thousands of subjects. whose nine exons and multiple promoters span over more than 80kb.and post-menopausal women.1 among Caucasians and Asians. whereas 22 of 51 studies reported a significant association with femoral neck BMD. 3) [83].More recently. Risk was greater for women who were older. For instance. both before and after stratification for calcium intake and other variables [84].e. we failed to observe a significant effect of calcium supplements. However. In contrast.3 years) study in elderly postmenopausal women (n ⫽ 193. In contrast. the BB genotype was associated with a more than twofold increased risk of hip (but not forearm) fracture compared with the bb genotype. 79–81]. In summary.704 community-dwelling women aged 65 years and older.028) lower spine BMD in BB compared to Bb/bb (i. and either association or interaction with VDR genotypes [unpubl. Others found that VDR 3⬘-UTR genotypes were similarly distributed among 105 rachitic children from Nigeria (calcium intake. VDR Taq1 TT homozygotes (same as bb) had a significantly lower rate of bone loss at both the femoral neck and lumbar spine compared to tt (same as BB). including 9. Moreover. whereas the Fok1 ff genotype was significantly under-represented among cases [78]. a meta-analysis of VDR association studies published between 1994 and 2001 found 13 eligible studies in post-menopausal women. BMD gain in response to calcium was significantly increased at several skeletal sites among BB and Bb. leaner. failed to demonstrate a difference in VDR alleles distribution among 530 cases with a hip. under usual dietary calcium intakes. Two large cohort studies have examined the association between VDR genotypes and fracture risk. a long-term follow-up (6. p ⫽ 0. leading to an estimated 2. or less physically active or who had a calcium intake below 1078 mg/d (odds ratio. 4. the VDR allele B could be associated with a modest deficit of bone mass growth in infancy and with an even more modest increase of bone loss after the menopause.e. a dominant effect of the B allele). vertebral or other fracture. it remains uncertain whether VDR genotypes contribute significantly to fracture Osteoporosis 39 . i.011. 200 mg/d) and 94 healthy controls. but not in bb girls [63]. In contrast. in 235 pre-pubertal boys. These differences were no more detectable in those with the highest calcium intake [82]. this analysis did not confirm association in premenopausal women nor at the femoral neck [77].43%/year. A significant interaction between VDR-3⬘ genotypes and calcium intake on BMD and BMD changes has also been observed in postmenopausal women [65. In the Nurses Health Study (mean age 60 years). women with the BB and Bb genotypes had a significantly greater bone loss at lumbar spine compared to bb (–0. data]. mean age. a recessive effect of the B allele) [77]. the Study of Osteoporotic Fractures (SOF). Epidemiological observations and prospective intervention studies suggest an interaction between dietary calcium intake and VDR polymorphisms on their association with bone mass in both children and aging subjects. in 9 eligible cohort studies.4% (p ⫽ 0. and controls. In a cohort of 144 pre-pubertal girls receiving calcium supplements (850 mg/day) compared to placebo [21]. 69 years) reported that among those with low calcium intake (below 456 mg/day). A meta-analysis of the association between ESR1 genotypes and BMD including more than five thousand women from 22 eligible studies (n ⫽ 11 in Caucasians and n ⫽ 11 in Asians). were subsequently analyzed in association with bone mass. Estrogen Receptors Gene (ESR1 and ESR2) Polymorphisms Estradiol plays a major role in the acquisition and maintenance of peak bone mass in both females [86. It will therefore be interesting to investigate potential interactions between ESR1 and ESR2 alleles on bone mass. but since the XbaI and PvuII sites are in strong linkage disequilibrium. although only three studies were available before menopause. with contrasting results [64. 87] and males [8. suggesting that ESR1genotypes might influence peak bone mass acquisition. concluded that homozygotes for the XbaI XX genotype have a modestly but significantly higher BMD (⫹1–2%) at lumbar spine or hip compared to xx [102]. ESR1 gene polymorphisms.47–0.93] in XX vs. In this meta-analysis. as well as in men and women from the Framingham Osteoporosis Study [105]. Genotypes identified by PvuII and XbaI restriction enzymes in the first intron of the estrogen receptor (ER) alpha gene (ESR1) were originally found to be significantly associated with BMD in postmenopausal [90] and younger pre-menopausal [91] Asian women. some authors reported an interaction between ESR1 polymorphisms and hormone replacement therapy (HRT) [94. which is coded by a separate gene (ESR2). calcium-dosing trials stratifying the cohort by VDR genotypes. 92]. this possibility needs to be investigated in prospective. 101] as well as a gene-by-gene interaction between ESR1 and VDR alleles [64. associations were recently described between ESR2 CA repeat polymorphisms and BMD in postmenopausal Japanese women [104]. xx) [102]. including PvuII. differences between genotypes tended to be up to five time greater in pre. 89]. Most interestingly. 92–100]. differences in fracture risk were disproportionately high compared to the small differences of bone mass observed between genotypes (odds ratio. There is recent evidence that estrogen receptor-␤. 85]. No differences were found between PvuII genotypes. XbaI and a TA repeat polymorphism in the promoter region. this may explain why some authors found an association with P/p alleles. Ferrari 40 . Accordingly. Interestingly. plays a distinct role in the regulation of bone mass [103].compared to post-menopausal women.risk in the elderly.66 [95% CI. Since it has been suggested that calcium supplementation could be associated with a better bone mass response in carriers of the VDR allele B [31. bone loss and/or fractures in Caucasian women. 0. 88. 0. suggesting that ESR1genotypes might influence bone quality above and beyond BMD. another large meta-analysis looking at hundreds of genetic association studies across various complex disorders and polymorphic genes confirmed a significant association of COL1A1 Sp1 alleles with fracture risk (OR. Collagen type 1 is a major structural molecule of the bone matrix (and is also found in skin and tendons). 0. mostly in older subjects. The s allele was first associated with lower lumbar spine BMD and a higher prevalence of vertebral fractures in postmenopausal women [107].2 SD decrease compared to S) but a more prominent association with fracture risk (OR 1.4 among Caucasians) and. and bone loss. Of note. in 434 healthy white American postmenopausal women (mean age. Taken together with the functional data mentioned above.06 among Caucasians) in the IL-6 gene promoter are associated with IL-6 activity in vitro and in vivo [116. where two collagen I␣1 chains associate with one collagen 1␣2 chain to form the triple helix of collagen. 117].9 in Ss and ss compared to SS genotypes. A common –174G⬎C polymorphism (frequency of C.1 in Asians [106]). a rare –572G⬎C polymorphism (frequency of C. the COL1A1 s variant was recently shown to produce too much collagen 1␣1 molecules compared to the S allele in vitro. resulting in a rare s variant (frequency. A second large population-based study confirmed an allele-dosage effect of the s allele on decreasing BMD. causing bone to be less resistant to mechanical stress [109].1–0. as well as on increasing the incidence of vertebral fractures during a 4-year observation period [108]. bone loss. or markers of bone resorption [110–112]. these results indeed suggest that COL1A1 Sp1 polymorphisms may affect some ‘bone quality’ component which is poorly reflected by BMD alone. – the bone resorbing cell –. and the agerelated decrease in BMD was more prominent among IL-6 ⫺174 GG and GC Osteoporosis 41 . 0. bone resorption was significantly lower among ⫺174CC (and ⫺572GG) compared to the other genotypes. Most importantly. particularly following estrogen deficiency [114. 72 years). In this case as well.15 in Caucasians. a meta-analysis of published data concluded to a modest effect of the s allele on BMD (equivalent to 0.6) [113]. Interleukin-6 Gene Promoter Polymorphisms Interleukin-6 (IL-6) is a pleiotropic cytokine playing a central role in the activation of osteoclasts. COL1A1 polymorphisms have also sometimes failed to show association with BMD.1–0. In turn. bone turnover.5 and 1. respectively) [109].Collagen 1␣1 Chain Gene (Col1A1) Polymorphisms Another widely investigated candidate gene for osteoporosis that carries a functional polymorphism in its regulatory region is the collagen type 1␣1 gene (COL1A1). A G⬎T polymorphism in the binding site for the transcription factor Sp1 was described. fractures. 0. Despite this good evidence for functionality and association with bone fragility. 1. to a lesser extent. ⬍⬍0. 115]. ultrasound properties of bone. 8%. Subsequently.574 unrelated men and women (mean age 60 years) with cross-sectional bone mineral density measurements at the hip. two studies reported an association of IL-6 polymorphisms with peak bone mass. past 15 years since menopause. and intermediate with GC. the latter study failed to detect a lower rate of bone resorption or bone loss associated with the ⫺174CC genotype in 234 postmenopausal women (mean age. 120] and in families of osteoporotic probands [121. age. significant p values were found for an interaction between IL-6 ⫺174 genotypes and years since menopause. In contrast. bone mineral density was significantly lower with genotype ⫺174 GG compared to CC. namely years since menopause. whereas no linkage was found in young. These observations suggested that IL-6 genetic variation might specifically contribute to the population variance in bone mass in the elderly. Thus. This cohort comprises 1. estrogen status and dietary calcium. estrogen status. Loss-of-function mutations in LRP5 are responsible for osteoporosis pseudoglioma (OPPG). no significant association with bone mineral density was observed in either women (n ⫽ 819) or men (n ⫽ 755). and alcohol. the interaction between IL-6 promoter polymorphisms and factors known to affect bone turnover. dietary calcium and vitamin D intake in women. in models that considered only the main effects of IL-6 polymorphisms. 118]. physical activity. in case of estrogen-deficiency or insufficient calcium intake (⬍940 mg/day). 64 years). BMD differences at the hip between IL-6 ⫺174 CC and GG were as high as 16. In women with both estrogendeficiency and poor calcium intake. Moreover. these data indicate that the influence of IL-6 gene variants on bone mass may depend on gender. It is currently unknown whether IL-6 polymorphisms directly contribute to fracture risk and it would be particularly interesting to investigate whether they could modulate the skeletal response to selective estrogen receptor modulators (SERMS) [127]. an Ferrari 42 . [125]. smoking. Several lines of evidence point to LRP5 as a candidate gene for osteoporosis. healthy sister pairs [123]. Consistent with the study of Garnero et al. dietary calcium and vitamin D intake. estrogen status. one in young adult males [124] and the other in pre-menopausal females [125]. In summary. Several studies have identified the IL-6 gene locus (7p21) to be linked to BMD in postmenopausal women [119.1%) [117. LDL-Receptor Related Protein 5 Gene (LRP5) Polymorphisms: A Novel Genetic Susceptibility Factor for Male Osteoporosis LRP5 is a member of the low-density lipoprotein (LDL) receptor-related family coding for a transmembrane co-receptor for Wnt signaling [128]. 122]. was examined in the Offspring Cohort of the Framingham Heart Study [126].genotypes (⫺9 to ⫺10% over 10 years) compared to CC (⫺5 to ⫺6. However. Moreover. and by a clear heritable component [30. in that the favorable effects of physical activity on BMD would be more prominent among carriers of the 18T allele.4037 C⬎T. In keeping with the previous association study. A population-based study of five LRP5 polymorphisms with allele frequencies ⬎2% found that a missense substitution in exon 9 (c. LRP5 polymorphisms could be a first identified genetic factor for gender-related differences in bone size and a specific susceptibility factor for spine osteoporosis in men.4 years. genome-wide screens in humans (and Osteoporosis 43 . 1) [134–136]. spontaneous fractures and blindness [129]. Accordingly. but not females. Hence. 1-year changes in lumbar spine bone mass and size in pre-pubertal boys were also significantly associated with these LRP5 variants [137]. Meanwhile.autosomal-recessive disorder characterized by low bone mass. 140]. the LRP5 locus (fig.A1330V) alleles were significantly associated with bone mass and projected area of vertebrae at the lumbar spine in adult males. whereas LRP5 gain-of-function mutations result in high bone mass and sclerosing bone dysplasias [130–132]. p. data]. Summary and Perspectives Thirty years have elapsed since the first published evidence of a high heritability for bone mineral density (BMD) in twins [141].V667M) and haplotypes based on exon 9 and exon 18 (c. mice with targeted disruption of LRP5 have a deficit in bone formation and sustain fractures [133]. Moreover. p.2047G⬎A. Consistent with the presence of a QTL for stature at 11q12–13 [138] [139]. Most importantly. and 10 years since vitamin D receptor (VDR)-3⬘UTR alleles were the first described gene variants associated with BMD in humans [53]. the exon 9 variant was also significantly associated with stature in both genders. LRP5 polymorphisms were investigated in 80 European-Caucasian men with idiopathic osteoporosis and 88 controls (mean age: 50. Moreover. a QTL for bone mineral density in the general population was mapped at 11q12–13. exon 9 A and exon 18 T alleles were twice more common in cases than controls. accounting for up to 15% of the population variance for these traits in men [137]. This rather uncommon form of osteoporosis affects middle-aged men and is characterized by low peak bone mass and an increased incidence of vertebral fractures in absence of secondary causes. range 23–70). and the odds for idiopathic male osteoporosis and fractures among carriers of the 9A-18T haplotype were greater than 2 [unpubl. suggesting that LRP5 polymorphisms could contribute to the risk of spine osteoporosis in men by influencing vertebral bone growth during childhood. ongoing analyses of LRP5 polymorphisms in the Framingham Osteoporosis Study suggest an interaction with physical activity in men. we should be aware that the strength of the association may depend on gender. Guidelines for population screening as applied to genetic susceptibility to disease have recently been published [145]. age. Lancet 1993. Stylianos Antonarakis. Genant HK. et al: Interim report and recommendations of the World Health Organization Task-Force for Osteoporosis. 1). References 1 2 3 4 5 Osteoporosis prevention. evaluate the positive and negative predictive values of gene markers with respect to osteoporosis and fracture risk. although not discussed in this review [41]) have taught us where to look for specific genes (fig. population-based association analyses are required to ultimately demonstrate the implication of gene variants to any complex disease [144]. Black DM. USA) for their financial support. and interactions with a number of life style and environmental risk factors for osteoporosis (table 1). Rather than looking disdainfully at the ‘genetic revolution of medicine’ [146]. Osteoporos Int 1999.359: 1761–1767.341:72–75. ethnicity.359:1929–1936. Most importantly. diagnosis. and Prof. Prof. René Rizzoli. Departments of Geriatrics and Rehabilitation. Poor G. 143]. John Eisman (Sydney). David Karasik and the Framingham Osteoporosis Study investigators (Boston). JAMA 2001. Prof. Prof.10:259–264. Dr. Lancet 2002. Ferrari 44 . Steve Humphries and his collaborators (London). Department NEUCLID. Daniel Slosman and the technicians from the Division of Nuclear Medicine. Patrick Garnero (Lyon). Dr. Sam Deutsch and Urmilla Chudhury. Suzanne Suter and her collaborators at the Department of Pediatrics. Prof. i. from the Department of Medical Genetics.e. I am indebted to all the volunteers who participated in our studies and to the Swiss National Science Foundation (SNF). Prof. Cooper C. The Study of Osteoporotic Fractures Research Group [see comments]. and therapy. we should do any efforts to bring this increasing knowledge from the bench to the bedside. 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Nagoya. pp 52–61 Changes in Dietary Fatty Acids and Life Style as Major Factors for Rapidly Increasing Inflammatory Diseases and Elderly-Onset Diseases Harumi Okuyama. The major elderly-onset diseases in Japan are cancer. 2005. atherosclerosisrelated diseases and pneumonia. However. the mortality from infectious diseases decreased rapidly toward 1960 (fig. Aging. the disease pattern has changed during this period and the mortality from tuberculosis and pneumonia decreased toward 1970. Kazuyo Yamada Department of Preventive Nutraceutical Sciences. bronchus. Thereafter. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. World Rev Nutr Diet. which is associated with increasing cancers of the bronchi and lungs. Karger. This increase in pneumonia is likely to be allergic in part. began to increase even when it was age-adjusted. prostate and esophagus) is prominent. and the Japanese are currently enjoying the world’s longest life expectancy among the countries with relatively large populations. and Kinjo Gakuin University College of Pharmacy. ␻–6) and enhanced arachidonic acid (AA. Masafumi Ito. Nagoya City University. Graduate School of Pharmaceutical Sciences. vol 95. Although the mortality from cardiovascular diseases is currently much lower in Japan than in the USA (⬃1/4). Because . Japan After World War II (ended in 1945). trachea. Elevation of inflammatory tone is a likely major cause for these diseases. 1). Yoichi Fujii. Basel. ␻–6) cascade [1]. Yuko Ichikawa. but it is generally accepted that populations suffering from allergic hyperreactivity have increased several folds during the past 40 years in Japan. pancreas. and the increase in cancers of the US type (colorectum. lung. the mortality from pneumonia. Allergic hyper-reactivity is not directly associated with mortality.Simopoulos AP (ed): Nutrition and Fitness: Mental Health. but not tuberculosis. which is brought about by excessive intake of linoleic acid (LA. Cancer is the leading cause of death after 1981. Statistics and Information Department. DHA). inflammatory mediators) are competitive at many steps of enzyme reactions and receptors. These environmental factors could be modified by changing the life style. 2]. In phospholipids. Changes in life style such as decreased physical activity and overnutrition in older populations lead to unfavorable energy balance. is an important factor in regulating the inflammatory tone and related diseases [1.(1947–2002) 250 200 Cerebrovascular diseases Rate per 100. particularly the ␻–6/␻–3 ratio. besides choosing foods to keep a good ␻–6/␻–3 fatty acid balance. Annual mortality trends by leading causes of death in Japan (Vital statistics of Japan. not only the absolute amounts of ␻–6 and ␻–3 fatty acids. Japan). Diet and Life Style in Inflammatory Diseases 53 . EPA→docosahexaenoic acid. but their balance. (2) ␻–6 series (linoleic acid→arachidonic acid). sweating conditions) is a likely cause for enhanced skin and mucosal sensitivity to allergens in younger populations. Ministry of Health. Reduced frequency of skin exposure to environmental changes (temperature. and (3) ␻–3 series (␣-linolenic acid → eicosapentaenoic acid. ␻–6 and ␻–3 fatty acids and their metabolites (eicosanoids. Competition among Fatty Acids in Three Metabolic Series in Mammals Fatty acids are classified into three series depending on their metabolism in mammals: (1) saturated and monounsaturated fatty acid series. 1.000 Tuberculosis Changes in classification of diseases advised Malignant neoplasma 100 Heart diseases Pneumonia Diseases of liver 0 1950 1960 1970 1980 1990 2000 year Fig. Labour and Welfare. up-regulate cholesterol synthesis. Here is another world in which the chain length and melting point of fatty acids play major role in the regulatory mechanism. while saturated and monounsaturated fatty acids. Regulation of Gene Expression by Fatty Acids Various fatty acids have been shown to exert differential effects on gene expression related to cholesterol and fatty acid metabolism. Therefore. the intakes of saturated. unexpected observations were presented by Broughton et al. regardless of ␻–6 and ␻–3 series. dietary animal fats enriched with saturated and monounsaturated fatty acids also suppressed competitively the production of ␻–6 eicosanoids when ␻–6/␻–3 ratios were high. nutritionists tend to advice people to reduce the intake of animal fats first rather than reducing the intake of linoleic acid (␻–6). one of which is a role in cell proliferation through prenylation and activation of oncogene products.saturated fatty acids are incorporated preferentially into the 1-position while polyunsaturated fatty acids are confined to the 2-position. These observations are nutritionally important. Because eicosanoids are not synthesized from saturated and monounsaturated fatty acids. eicosanoid tone would be elevated unless the intake of ␻–3 fatty acids is increased. Okuyama/Ichikawa/Fujii/Ito/Yamada 54 . Currently. monounsaturated and linoleic acids should be restricted particularly in older people requiring to improve energy balance. animal fats are relatively safe for the diseases caused by over. saturated and monounsaturated fatty acids are not effective as competitors in polyunsaturated fatty acid incorporation. and linoleic acid to a slightly lesser extent. If the intake of animal fats is reduced without reducing ␻–6 fatty acids. [3]. and these ␻–6 and ␻–3 fatty acids compete with each other at the acyltransferase steps.and unbalanced productions of ␻–6 eicosanoids. Recently. Dietary long chain polyunsaturated fatty acids up-regulate ␤-oxidation enzymes. the ␻–6/␻–3 ratio of phospholipids is a good marker of eicosanoid production and inflammatory tone [2]. Competition among dietary and de novo synthesized fatty acids occurs not only at the steps of incorporation into various lipids but also at the steps of mitochondrial and peroxysomal ␤-oxidation systems and possibly at the step of excretion to skin/hair [4]. The prenyl intermediates in cholesterol synthesis play divergent roles. In this context. which is a major topic in the current lipid nutrition research. The ␻–6 and ␻–3 fatty acids at the 2-position of membrane phospholipids are the major precursors and competitors of eicosanoid synthesis. uncoupling protein and anti-oxidative superoxide dismutase. 9]. the ‘free radical injury’ is used synonymously with ‘lipid peroxide injury’ [6]. 12]. In this hypothesis. the observed effect of free radical reaction inhibitors on longevity could be interpreted in a different way because weight loss was observed by feeding such inhibitors. a simple maize test was not sufficient to estimate the learning ability of rodents accurately [7]. Using this animal model. soybean oil). particularly when salt solution was given as drinking water. no signs of elevated lipid peroxide levels and denatured proteins are noted in vivo [14]. Using a more sophisticated test (operanttype. These inhibitors are likely to have brought about energy restriction. dietary ␣-linolenic acid (perilla oil and flaxseed oil) and DHA were shown to prolong the survival [11. However. thereby accelerating the aging process. which is well known to prolong the survival of rodents. in turn. but fresh tissues tend to contain reduced amounts of lipid peroxides [15]. decompose to form free radicals and injure tissues. Error in a maze test increased along with increasing the degree of unsaturation of dietary oils while those oils affected the longevity little. Although tissues from fish oil-fed animals are enriched with EPA/DHA and are more susceptible to auto-oxidation in vitro. These observations led to a hypothesis that feeding highly unsaturated fatty acids such as fish oil for a long period leads to accumulation of lipid peroxides in tissues. Moreover. DHA was effective in suppressing the stroke-related behavioral changes (loss of circadian rhythm) [13]. In our studies. Cells in tissues are under relatively hypoxic conditions and chain reactions of lipid peroxidation would not Diet and Life Style in Inflammatory Diseases 55 . 2). These results indicate that taking ␻–3 fatty acids and restricting ␻–6 fatty acids are beneficial for the maintenance of brain functions in aged rats [9]. brightness-discrimination learning test). some inhibitors of free radical reactions prolonged the survival of mice. impaired learning behavior was reversed by DHA (␻–3) only when the diet contained relatively low concentrations of linoleic acid (␻–6). which.Evidence Against Lipid Peroxide Theory of Aging The original free radical theory of aging came out from comparing the effect of dietary fish oil and several kinds of vegetable oils with different degree of unsaturation in rats [5]. [8. Oxygen pressure in organs are much lower than in the atmosphere. Stroke-prone. Moreover. we have shown that learning behavior and memory retention are superior in the rats fed ␻–3 fatty acidenriched oil (␣-linolenic acid-rich perilla seed oil and DHA-rich fish oil) through 2 generations compared with linoleic acid (␻–6)-rich oils (safflower oil. The effect of ␻–3 fatty acid-deficiency during pregnancy and lactation was reversed by feeding ␻–3 fatty acids after weaning but not by feeding ␻–6 fatty acid [10] (fig. spontaneously hypertensive (SHRSP) rats develop hypertension and die of stroke. Furthermore. 100 500 300 300 Aged Saf 200 Aged Per 100 200 10 20 30 0 Session (days) * ** * * ** * * * 80 ** Aged Saf * 70 Aged Saf 60 50 40 30 100 0 a 90 Young Per Young Saf 400 Response/session Negative responses (no pellets delivered) Correct response ratio (%) Positive responses (diet pellets delivered) 10 20 0 30 b 10 20 30 Session (days) Fig. and the oxidized vitamin C and glutathione are reduced using energy (NADPH). Brightness-discrimination learning behavior affected by dietary linoleic and ␣-linolenic acids in aged rats [8]. a Diet pellet was delivered for the responses under bright light (positive response) while no pellet was given for the responses under dim light (negative response). Thus in living cells. and the oxidized vitamin E is reduced consuming vitamin C or glutathione. 2. However. which decompose to form stable hydroxyl fatty acids by reaction with reduced form of vitamin E.7 months of age (80% of the mean survival time of the male F0 group fed the safflower oil diet). *p ⬍ 0. The difference between the two groups was statisticallly significant in 2-way ANOVA (p ⬍ 0. occur when appropriate amounts of endogenous antioxidants (vitamins C and E. Hypoxia and Persistent Inflammation Induce Peroxidative Injury Free radical injury is recognized as an early event under various pathological conditions. b Correct response ratio was calculated as 100⫻ positive response/total responses. Diet supplemented with high-linoleic safflower oil or high␣-linolenic perilla oil was given to mothers (F0) and the learning test of male pups (F1) was started at 19. Free radicals produced in vivo attack polyunsaturated fatty acids and form lipid peroxides. elevated levels of free radicals are unlikely to be Okuyama/Ichikawa/Fujii/Ito/Yamada 56 .05).01 in Student’s t test. **p ⬍ 0. and the test was performed once a day for 30 days.05. glutathione) are present. polyunsaturated fatty acids and anti-oxidative vitamins serve as scavengers rather than propagators of free radical reactions [16]. brought about by enrichment of membrane lipids with polyunsaturated ␻–3 fatty acids. Instead, we interpret that free radicals are produced and injure tissues in vivo when cells are exposed to hypoxic conditions, where inflammatory cells are recruited to clean the damaged cells, and eicosanoids serve as chemoattractants. When cells are enriched with arachidonic acid, ␻–6 inflammatory mediators are produced in excess leading to persistent inflammation, and inflammatory cells produce reactive oxygen species. Thus, ischemia and persistent inflammation are the earlier events to increase free radicals. This inflammatory tone is regulated by ␻–6/␻–3 balance of membrane lipids. Now, it has been well established that ischemic conditions are induced by high ␻–6/␻–3 ratios of dietary and tissue polyunsaturated fatty acids through eicosanoid actions. The major risk factor for atherosclerosis was not dietary cholesterol or hypercholesterolemia but high ␻–6/␻–3 ratio of ingested foods as reviewed elsewhere [17, 18]. Choice of Foods for the Prevention of Cancer Cancer research used to focus on detecting environmental carcinogens that initiate DNA damage and carcinogenesis. However, the involvement of persistent inflammation in carcinogenesis has been widely observed. For example, asbestos and glass beads administered to animals do not dissolve easily, hence do not exhibit direct mutagenic activity. However, inflammatory cells are mobilized to surround these substances and tumors are formed. When inflammatory conditions persist, tumors are formed as noted in hepatitis virus infection, chronic hepatitis and hepatic cancer sequences. Subjects suffering from ulcerative colitis develop colon cancer in several times higher frequency. Helicobacter pylori is likely to develop stomach cancer through persistent inflammation. Despite the reducing tendency of the impact of smoking noted, lung cancer, particularly adenocarcinoma type, has been increasing steadily along with the increasing incidence of pneumonia after 1970 in Japan. Japanese intake of linoleic acid increased 2.5-fold from 1960 to 1975, and the increase in meat intake was associated with a decrease in seafood intake during this period. Consequently, the ␻–6/␻–3 ratio of ingested fatty acids increased significantly. Although the intake of animal fats also increased 2.5fold, the current intake of animal fats in Japan is roughly half that of average Americans. For the cancers of the US type, persistent inflammation caused by enhanced linoleic acid and arachidonic acid cascade is interpreted to be a major cause. This interpretation is supported by the following observations. Diet and Life Style in Inflammatory Diseases 57 (1) Oils with low ␻–6/␻–3 ratios (perilla seed oil, flaxseed oil, fish oil) suppress carcinogenesis compared with high linoleic acid oils. (2) Inhibitors of arachidonic acid cascade suppress carcinogenesis, e.g. steroidal and non-steroidal anti-inflammatory drugs, 5-lipoxygenase inhibitors. (3) Knock-out of genes related to arachidonic acid cascade suppresses carcinogenesis, e.g. phospholipase A, cyclooxygenase-2, prostaglandin receptors (EP2, EP4). Despite the presence of many lines of evidence to support the interpretation that the enhanced linoleic acid cascade is a major risk factor for cancers of the US type, epidemiological studies performed in the US do not necessarily support this interpretation. The failure to reveal the causal relationship between the linoleic acid intake and cancer mortality could be explained as follows. (1) In the populations without taking competitive amounts of seafood EPA and DHA, membrane phospholipids are enriched with arachidonic acid even in the group with low intake of linoleic acid. (2) Serum EPA and DHA levels are good markers of seafood intake while serum linoleic and ␣-linolenic acids are not [19]. High linoleic acid levels in tissues are likely to reflect high seafood intake because EPA and DHA inhibit the elongation and desaturation of linoleic acid to form long chain polyunsaturated fatty acids. (3) In the nested serum samples, preferential loss of long chain polyunsaturated fatty acids during storage leads to increased proportions of linoleic, saturated and monounsaturated fatty acids. Another process of fatty acids influencing carcinogenesis is through prenyl intermediates in cholesterol synthesis. Saturated and monounsaturated fatty acids, and linoleic acid to a slightly lesser extent, stimulate cholesterol synthesis and are likely to up-regulate prenyl-intermediates and activate oncogene products. Thus, various fatty acids appear to affect carcinogenesis mainly through both the linoleic acid cascade and prenyl intermediate pathway, and the relative importance of these two pathways is likely to differ depending on the sites (tissues or cells) of carcinogenesis. At present, we interpret that the impact of the linoleic acid cascade (persistent inflammation) is greater than that of elevated prenyl intermediates for the promotion of cancers of the US type or that the impact of animal fats through prenyl intermediates is overcome by ␻–3 fatty acids, because their incidence was much lower in the Greenland natives than in the Danes; both populations took large amounts of saturated and monounsaturated fatty acids (⬃30 energy %) but the former took much greater amounts of ␻–3 fatty acids and lesser amounts of ␻–6 fatty acids. Okuyama/Ichikawa/Fujii/Ito/Yamada 58 Evaluation of Vegetable Oils by Their Fatty Acid Composition and Minor Anti-Nutritional Factors Vegetable oils are nutritionally classified primarily by their fatty acids; saturated fatty acid-rich oil (palm and coconut oils), oleic acid-rich oil (olive, canola, high-oleic safflower and high-oleic sunflower oils), linoleic acid-rich oil (high-linoleic safflower, corn, soybean, sesame, peanut and rice oils) and ␣-linolenic acid-rich oil (perilla, flaxseed and chia oils). Obviously, high-linoleic acid oil should be avoided in most of industrialized countries. The Japan Society for Lipid Nutrition adopted a proposal that the direction of nutritional recommendation should be changed so as to reduce the intake of linoleic acid [20]. Saturated and monounsaturated fatty acids are not converted to inflammatory lipid mediators and are relatively safe for the eicosanoid-related diseases. However, the safety of these oils has not been established in animal experiments; the intake of these oils in large quantities should be avoided because the presence of minor anti-nutritional factors is suspected (canola, olive, corn, higholeic safflower, high-oleic sunflower, evening primrose, partially hydrogenated soybean and partially-hydrogenated canola oils) [11, 12, 21]. ␣-Linolenic acid is preferentially ␤-oxidized, excreted to skin and does not accumulate in tissues in large amounts compared with saturated, monounsaturated and linoleic acids. It is converted to EPA and DHA in part to suppress thrombotic and inflammatory tendency. The demerits of ␣-linolenic acid-rich oils are their instability to heat and easy inflammability under heating conditions although ␣-linolenic acid is anti-inflammatory in the body. Use of electric frying pan is recommended for ␣-linolenic acid-rich oils; those stabilized with vitamin E and C ester can be used safely for baking meat, vegetable, egg and seafood at 200⬚C setting. Conclusions – Recommended Choice of Foods and Fatty Acids for Healthy Aging The so-called cholesterol hypothesis lost its bases, and those with high cholesterol levels were found to exhibit lower cancer incidence and longer survival among older people in the Western countries and among the general population over 40 years old in Japan. Nutritional values of foods of animal origin are evaluated by their content of ␻–6 and ␻–3 fatty acids. Butter and meats from ruminants (cattle and sheep) contain relatively small amounts of linoleic acid because ruminant bacteria convert linoleic acid to saturated and monounsaturated fatty acids, hence these are relatively safe. The ␻–6/␻–3 balance of chicken and pork meats depends on that of Diet and Life Style in Inflammatory Diseases 59 their feed, and those with decreased ␻–6/␻–3 ratios are recommended. Increased intake of seafood is recommended for the prevention of cardiovascular diseases, cancer and other inflammatory diseases. Currently, on the average the Japanese ingest the largest amounts of seafood and associated endocrine disturbing substances (e.g. dioxin) among the industrialized countries. The beneficial effects of seafood ␻–3 fatty acids have been well established but the relative impact of dioxin on endocrine systems remains to be evaluated in our food environment. Among vegetable oils, perilla oil and flaxseed oil with very low ␻–6/␻–3 ratios are recommended. 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Packer L: Tocopheroxyl radical persistence and tocopherol consumption in liposomes and in vitamin E-enriched rat liver mitochondria and microsomes. Okuyama H: Effect of rapeseed and dietary oils on the mean survival time of stroke-prone spontaneously hypertensive rats. 2003.264:13448–13452. Miyazaki M. Hasegawa K. Minami M. Hamazaki T. Free fatty acid fractions from some vegetable oils exhibit reduced survival time-shortening activity in stroke-prone spontaneously hypertensive rats. Kobayashi T. Tajima K. Nomura M. Lipids 1998. J Health Sci 2000. Biol Pharm Bull 1996. Basel. Watanabe S. Maki S. Nagaya T. Okuyama H: The Japan Society for Lipid Nutrition recommends to reduce the intake of linoleic acid. Watanabe S. World Rev Nutr Diet. Kuriki K. Hamaue N. Sato J. Karger. Ikemoto A: n–6/n–3 ratio of dietary fatty acids rather than hypercholesterolemia as the major risk factor for atherosclerosis and coronary heart disease. recent studies demonstrate that extensive sports and work patterns (e. vol 95. Well into the 20th century. Karger. it was a common belief that too much exercise would shorten one’s life. with the notable exception of the Greeks and Romans. pp 62–72 Physical Activity for Health: An Overview Mark L. 3]. Basel. employment or in communities with subsistence agriculture were often so great as to view time to oneself or one’s family as time for physical rest. However. organisation and facilities were usually required. World Rev Nutr Diet. Monash Asia Institute. with mechanization. the trend. there were few examples of regularized athletics and sports in society. As a matter of fact. weaknesses. opportunities and threats) analysis of the overall decline in physical activity takes this issue of the health limits of physical activity into account (table 1). has been for people to reduce their levels of physical activity.Simopoulos AP (ed): Nutrition and Fitness: Mental Health. 2005. computerization. Until the late 19th and the 20th centuries. the physical requirements of work in servitude. Moreover. lumberjacks) can outstrip energy intakes in their energy requirements and can lead to immune dysfunction [3]. and urbanization. there are some notable national exceptions. A SWOT (strength. which demonstrate that these trends can be countered [1]. This is because physique and performance needed recognition and admiration and because settlement.g. and so was relative wealth and the time to pursue such activity. in Finland and Canada. Not only public health strategies. Melbourne and International Union of Nutritional Sciences. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. not to do so. Wahlqvist Asia Pacific Health and Nutrition Centre. passive leisure. Australia The Community Decline in Physical Activity In general. Aging. Melbourne. It is increasingly clear that. but national leadership and infrastructural programmes are likely to be required from an early age for the reversal of this downward trend in physical activity and associated fitness. invites a major burden of chronic disease and disability and premature death [2. . gesticulation whilst talking. 2). Physical activity – optima • • • Walking or other aerobic activities (6 days/week.g. respiratory. beyond that which is ‘self-paced’ (what one does without thought – e. when the theme was ‘Move for Health’. CNS) Opportunities • Replace physical activity at work with physical activity as leisure (sport) • More time for education. Physical activity – goals • • • • • Include physical activity in workaday week and travel (purposeful physical activity) Find enjoyable leisure-time physical activity (personal and social fulfillment) Overcome seasonal. 1–2 h/day) Strength training through multiple repetitions against resistance (3–4 days/week) Integrated with goal – Personal development – Social development Table 3.g. the degrees of health achievement through exercise were depicted graphically (fig. Physical Activity for Health 63 . locality and situational barriers to physical activity Improved sense of well-being Reduce burden of disease The optima for physical activity. For World Health Day in 2002. restless movement whilst awake or asleep). social networking Threats • Eco-nutritional disease (END) or chronic non-communicable diseases (CNCDs) Table 2. are probably much as shown in table 2.Table 1. Decline in physical activity SWOT analysis Strengths Weaknesses • Avoid tissue and system • Detrimental body composition • Decreased system reserve damage through excess (e. physical activity goals and targets could be formulated as in tables 3 and 4. CV. In turn. The most obvious and impressive consequence of physical inactivity is obesity. 1). in the face of protein malnutrition with growth retardation and muscle wasting [4] (fig. 1. whilst the quantity and quality of food intake have become important issues. This constitutes the socalled ‘Double Burden of Disease’ [5. unexpected but reasonable demands for strength (e. carrying a load upstairs. Men Women Iran (south) UAE Saudi Arabia Brazil Canada USA Czech Republic Netherlands Germany England China Japan PNG (urban) New Zealand Australia 50 40 30 20 10 0 10 0 Prevalence of obesity (%) 20 30 40 50 Fig. shoveling snow. even with economic development [7]. Physical activity – targets • • • Walk most days irrespective of time of year. Energy Throughput. PNG ⫽ Papua New Guinea. moving a log) Keep active and strong with advancing years. Yet the prevalence of obesity began to escalate and. 6]. where prevalence is interesting worldwide. irrespective of the stage of economic development and. often. energy intake remained largely unchanged. most of the obesity epidemic could probably have Wahlqvist 64 . through repetitive resistance movement.Table 4. at least 20 min one way and 20 min return Be strong enough. Food Intake and Body Composition Throughout much of the 20th century. Global prevalence of obesity. UAE ⫽ United Arab Emirates. BMI ⱖ30.g. to undertake ADL and sudden. fat stores to be appropriate and directed away from the abdomen – and the nature of intra-daily and day-to-day fluctuations in body water (and sodium). 2. is a call to individuals. If this phenomenon could be generalized across the community. the slogan for World Health Day 2002. One of the best example of this is Japan. (‘Agita’ in Portuguese means shake – Agita Mundo means shake the world. ‘Move for Health’: World Health Day 2002. compared to the USA where they now exceed 20%. people who walk. where people have continued to walk a lot. Agita Mundo – Move for Health. It is energy throughput at higher levels which is more important than energy intake in determining the risk of positive energy balance (and. where they have been regular exercisers. and obesity (BMI ⱖ30) prevalences have remained as low as about 3%. where he demonstrated that middle-aged runners actually eat more and lose body weight (fat) [8]. This is seen by reference to the studies of Peter Wood at Stanford University. sub-groups in the population have not experienced the general trend towards obesity. say by making walking. People need to understand more clearly what weight represents – muscle and bone mass to be optimized. without the need to be preoccupied with food intake. Physical Activity for Health 65 .) been avoided if physical activity levels had remained adequate. This means education about body composition and not pre-occupation with weight as the key health end-point in physical activity programmes. therefore. cycling and jogging more attractive. For example. substantial improvement in individual fitness and body composition would be achieved. communities and countries to associate action for health with the public health task of prevention. overfatness). Also.Fig. jog or run regularly are generally leaner. food component (essential macro. although physical activity is central (fig. Wahlqvist 66 . 3). There is increasing evidence that the energy density: Energy density ⫽ Energy (cal or kJ) Mass of food (g or kg) is a determinant of energy balance [14. 3. Nutrient Density. 15]. with greater levels of regular physical activity. are several. must be careful to have most of their food nutritious as judged by their food component density. nevertheless.Urbanisation Psychological stressors Pollutants Neuro-hormonal Physical inactivity Food supply Maternal health and nutrition Energy balance Intra-abdominal fat Pathological disorders Growth and development Fig. It is now appreciated that body composition and fat distribution are major determinants of total and disease specific mortality [9–13].and micro-nutrients. Mg or ␮g) or food component density Energy (e. since the errors in energy intake are more likely to be corrected (through the set of appetite. phytonutrient density ⫽ Mass of nutrient or phytonutrient or food component (e. and the energy cost of carriage of increased body mass). this will be less critical when one is physically active. 100 kJ) The inactive. Pathways to abdominal obesity. Again. However. From Wahlqvist [15].g. The pathways to abdominal obesity. other biologically active and favourable food components like phytonutrients) density is less critical.g. however. so it is likely that we will find the same for appropriate levels of maternal physical activity preconception and during pregnancy. functional status [20] and perceived health status [21] (fig. with its intergenerational effects on insulin resistance [18]. Physical activity as a requisite for human species • • • • • • Conception and pregnancy Childhood. and plays a role in the expression of gestational diabetes. puberty and adolescence The reproductive years Later life Inter-‘life stage’ considerations Inter-generational considerations Physical Activity for Life Just as we have to realize with the long-term effects of maternal nutrition and intra-uterine life on later life morbidity and mortality. diabetes • Neoplasia • Bone health Physical Activity for Health 67 . more work is required in this area. as there has been much debate about appropriate work patterns and sporting engagement for pregnant women [16].Well-Being and the Domains of Health There is little doubt that regular physical activity is a key determinant of well-being and mood [19]. Preventive Physical Activity The burden of disease in contemporary economically advanced societies is located amongst the following health domains: • Cardiovascular disease • Metabolic disorders e. Nevertheless.g. we do know that physical activity affects gene expression [17]. 4). and lactation (table 5). However.Table 5. Physical Activity. obesity. We can expect that regular physical activity will displace the onset of morbidity towards the end of life [28]. in preventive programmes. as well as prolong it [28. gender.8 10 17. as evidenced in the Harvard Alumni Study [30. Physical activity features highly in the contribution to Burden of Disease [22. 29]. abdominal body fatness. and osteoporosis [26] (fig.6* 5 0 18–44 45–64 65 or older Age (years) Fig. [32]. blood pressure. the Burden of Disease and Injury is attributed to selected risk factors as shown in figure 5. cancer [25]. 4.001.2 Prevalence of fair or poor health status % 45 40 37. 6). Inter alia. 23] and. 31] and in Finnish studies by Pekkanen et al. p ⬍ 0.7 25 20 17. physical activity appears to be protective against disease by • improving cardio-respiratory function • improving lipid profiles. *Significant difference in likelihood of fair or poor health status across physical activity groups after adjustment for age. • • • Immune function Cognitive function Mood In Australia. Disease-specific survivals are prolonged with regular physical activity.9* 16.0 6. Resistance or strength training is relevant for quality of sleep and depression [27].2* 9. therefore. Wahlqvist 68 . race/ethnicity. smoking status and BMI. education.1 35 30 24.6 15 12. This can be seen in a number of studies of diabetes prevention [24].Level of moderate or vigorous physical activity Inactive Insufficient level of physical activity Recommended level of physical activity 50 45. Prevalence of fair or poor health status by age and level of physical activity. What makes us sick Proportion of total burden attributed to selected risk factors. there is overlap between secondary and tertiary prevention and therapeutics in any case. 1999. To some extent. Not to have them is to encourage Eco-nutritional Disease (END). 5. Published by the Australian Institute of Health and Welfare. ‘The Burden of Disease and Injury in Australia’. conducive to regular physical activity are essential for community health. with ageing populations is the reduction in the problems of: • Sarcopenia and frailty • The growing burden of nutritional and metabolic diseases • Senescence At least some cases of sarcopenia can be expected to be preventable and reversible [33. Therapeutic Physical Activity The clear preventive health role of physical activity may well be translated into therapeutics. Eco-Nutrition and Physical Activity Healthy habitats and precincts. Favourable eco-nutritional precincts will: • Link family life. Australia 1996 Male Female Tobacco Physical inactivity Hypertension % Alcohol Overweight and obesity Lack of fruit/veg lllcit drugs Occupation Unsafe sex 0 2 4 6 8 10 12 Fig. Of great importance. 34]. leisure and work Physical Activity for Health 69 . Wahlqvist 70 . dancing. 6. swimming. playing. rectum Breast Ovary KEY Endometrium Decreases risk convinicing Cervix Decreases risk probable Prostate Thyroid Increases risk probable Increases risk possible Decreases risk possible Lodine Increases risk convinicing Kidney Bladder V od es bl ta e eg n si Fr Ca r e ot in C in fo als er m ta Vi od fo id no s uit in M s) od in fo Ce re ain s gr ( als he re fib rc a St N / SP Ph y a sic ty ivi ct la a Te ion at er g fri Re Fig. best achieved in safe. skiing or gardening • Provide contact with various plant and other animal species. 36]. its variety and the requirement for biodiversity on human health • Movement. The logic of describing chronic disease as ‘eco-nutritional disease’ becomes apparent when considering: • The major importance of food. • Be safe and congenial for walking. skipping. 1997. The term ‘chronic disease’ says nothing about the aetiology or pathogenesis. climbing. cycling.Mouth and pharynx Nasopharynx Larynx Oesophagus Lung Selenium Stomach Wholegrain Pancreas Gallbladder Liver Colon only Colon. pleasurable and sustainable precincts • The required ‘environmental buffer zones’ to minimize the risk of known and emerging transmissible pathogens [35. Source: World Cancer Research Fund/American Institute for Cancer Research. Nutrition and physical activity in the prevention of cancer. Can J Publ Health 2004. Report of a WHO Consultation in Obesity. Am J Epidemiol 2004. World Health Organization: Obesity: Preventing and Managing the Global Epidemic. Geneva. Chakravarthy MV.14:1132–1143. Pavlou KN (eds): Nutrition and Fitness Metabolic Studies in Health and Disease. Kuller L. Schiffman S: Biological and psychological benefits of exercise in obesity. Haskell WL: Metabolism of substrates: diet. 1998.5:20–31. Sydney. Wylie-Rosett. Washington. Bjorntorp P: Abdominal fat distribution and disease: an overview of epidemiological data. Cameron C. Geneva. Mann J: Free sugars and human health: Sufficient evidence for action? Lancet 2004. Lumbers ER: Exercise in pregnancy: Physiological basis of exercise prescription for the pregnant woman. Alderman MH: Exercise. Physical Activity for Health 71 . 1994. Luthy DA: Prospective study of gestational diabetes mellitus risk in relation to maternal recreational physical activity before and during pregnancy. Bjorntorp P: Regional fat distribution – Implications for type II diabetes. Kelsey S.363:1068–1070.24:15–18. Newman AB. socializing and integrated with the natural world. Karger. Wahlqvist ML (eds): Exercise and Obesity. in Hills AP. pp 89–101. pp 5–9. pp 103–114. Proceedings of Wrestling with Obesity. Moriarty DG. Prev Med 2003.44:358–363. and cardiovascular mortality. Jebb SA: Obesity in Britain: Gluttony or sloth? BMJ 1995. Terry RB. Int J Obes 1992. Fed Proc 1985. in Simopoulos AP. Williams MA. Miller RS. Russell SJ. FitzGerald S. Brach JS. Booth FW. and exercise. Dempsey JC. J Physiol 2002.Conclusion We seek a unifying strategy for both health advancement and health optimization which is sustainable. thinking. Van Swearingen JM. Mokdad AH: Associations between recommended levels of physical activity and health-related quality of life. Bauman A: Twenty-year trends in physical activity among Canadian adults. caloric intake. Heath GW. Acta Med Scand 1988. Smith-Gordon. 1994. Cohen HW.37:520–528. Am J Prev Med 2003. Kriska AM: Physical activity and functional status in community-dwelling older women.12:427–437. Spangenburg EE: Exercise and gene expression: Physiological regulation of the human genome through physical activity. Fang J. World Rev Nutr Diet. moving. 1996.543:399–411. Lee I-M.25:283–289. Dashow EE. Giles WH. immunology and nutrition. 1997. Brown DW. Ann Med 1992. Smith-Gordon. Wahlqvist ML: Urbanisation as a contributor and challenge in endemic obesity. Gillespie S.95:59–63. Asia Pacific J Clin Nutr 2003.159:663–670. Bjorntorp P: The associations between obesity. Kaplan RC. Hills AP. Sorensen TK. Diabetes Care 1991. body mass index. Haddad L: Attacking the double burden of malnutrition in Asia and the Pacific. adipose tissue distribution and disease. Arch Intern Med 2003. Balluz LS. Findings from the 2001 Behavioral Risk Factor Surveillance System survey. Khor GL. Bjorntorp P: Metabolic implications of body fat distribution. Sharif ZM: Dual forms of malnutrition in the same households in Malaysia – A case study among Malay rural households. London.163:2565–2571. 2001. This must involve us continuing as our own machines. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Craig CL.723(suppl):121–134. World Health Organization. Basel.311:437–439. Philippines and International Food Policy Research Institute. 2001. J Sci Med Sport 2002. Asian Development Bank. Ford ES. Wood PD. London. lipoprotein metabolism. Nieman DC: Exercise. Prentice AM. Wahlqvist ML (eds): Exercise and Obesity.16(suppl 4): S19–S27. Bennett PH. Diabetes Care 1997. Publ Hlth Nutr 2002. The Harvard Alumni Health Study. et al: Effects of walking on mortality among nonsmoking retired men.20:537–544. Cannon JG. Circulation 2000. Roubenoff R. Morganti CM.29:2049–2054. Rosenberg IH: Standardization of nomenclature of body composition in weight loss. Lee I-M. nutrition and public health policies – The rationale for an eco-nutritional disease nomenclature. Am J Clin Nutr 1997. Lee I-M: Physical activity and coronary heart disease in men. Hu YH. Petrovitch H. Washington. Lipsitz [email protected]. Hakim AA. Fiatarone MA: A randomized controlled trial of the effect of exercise on sleep. the compression of morbidity. Monash University. Singh NA. 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Sleep 1997.272: 1909–1914. Kehayias JJ. Wang JP. Pan XR. Paffenbarger RS:. Howard BV: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. Lin J. Tuomilehto J: Reduction of premature mortality by high physical activity: A 20-year follow-up of middle-aged Finnish men. Wang JX.80:952–958. 1997. Nelson ME. Sesso HD. Kehayias JJ. Asia Pacific J Clin Nutr 1998. Clements KM. Zheng H.au Wahlqvist 72 . Solares GR.i:1473–1477. Clements KM. Burchfiel CM. Victoria 3800 (Australia) E-Mail mark. Bull World Hlth Org 2002. Flataroone MA. Marti B. N Engl J Med 1994. Evans WJ: Exercise training and nutritional supplementation for physical frailty in very elderly people. Galbraith S. Wahlqvist Asia Pacific Health and Nutrition Centre. dynamics and directions for public health action. J R Soc Med 1996. Cao HB. Roberts SB.89:64–68. Heymsfield SB. Asia Pacific J Clin Nutr 2002. Wahlqvist ML: Chronic disease prevention: A life-cycle approach which takes account of the environmental impact and opportunities of food. Evans WJ: Effects of highintensity strength training on multiple risk factors for osteoporotic fractures.22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 Chopra M. and the health of the elderly. Fiatarone MA. cessation or disorder of body functions. In 1986. filterable viruses. 2]. and bMedical Pharmacology and Physiology.. or some part or organ of the body.b Departments of aBiomedical Sciences. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. 2005. a departure from the state of health. it seems reasonable to suggest that physical inactivity is a medical problem of great impact. USA Physical inactivity annually produces 334. Pathologically. 6] to provide a framework for the claim that physical inactivity is a disease. or impaired. in which its functions are disturbed or deranged. World Rev Nutr Diet. respectively [3]. deranged. the expenditure in the US for physical inactivity was USD 77 and USD 150 billion (expressed in 2. physical inactivity is acknowledged by the Centers for Disease Control (CDC) as the actual cause of the deaths [4]. Frank W. systems or organs.144 deaths in the United States and ⬎2 million deaths worldwide [1. This review will use arguments presented in debates as to whether obesity is a disease [5. Columbia. Aging.’ [9]. pp 73–79 Physical Inactivity Is a Disease Simon J. and Dalton Cardiovascular Center. Karger. disease is an alteration of state of the human body…or of some of its organs or parts interrupting or disturbing the performance of vital functions. Bootha. University of Missouri-Columbia. environmental or inherent deficiencies. • ‘An interruption. Basel. any departure for the state of health presenting marked symptoms…various forms of disease may be caused by parasites. a morbid physical condition. Indeed whereas the chronic diseases are recognized as the medical factor for the deaths and economic costs. • ‘A condition in which bodily health is seriously attacked. especially when caused by a structural change’ [7]. . Physical inactivity is one of the 10 leading global causes of death and disability [2]. Thus. vol 95.000 US dollars) in direct and combined direct and indirect costs. Mo. Epidemiological data indicate that physically inactive humans have an increased prevalence of 25 chronic diseases (table 1).Simopoulos AP (ed): Nutrition and Fitness: Mental Health. Heshka and Allison [5] present some of the typical definitions of disease: • ‘Condition of the body. Leesa. and nutritional.’ [8]. The next sections will answer the question as to whether physical inactivity fits the definition of ‘disease’. potentially producing a pulmonary embolism Increased release of insulin due to insulin resistance Decreased blood HDL Increased prevalence of coronary artery disease Depressed immune response Increased prevalence of breast. memory. Selected samples of alterations with physical inactivity Tissue/physiological characteristic Dysfunction with physical inactivity Hippocampus Decreased neurogenesis. leading to greater prevalence of atherosclerosis Increased post-prandial hypertriglyceridemia Increased prevalence of coronary artery disease Increased post-prandial hyperglycemia and hyperinsulinemia Increased prevalence of coronary artery disease and type 2 diabetes Increased thrombi when sitting on long-distance airline flights. potentially leading to increased blood pressure Less nitric oxide production and lower vasorelaxation in response to vasodilators Less protection from ischemia Increased blood C-reactive protein and tumor necrosis factor-␣. and pancreatic cancers Increased amount of body fat Increase in all the co-morbidities related to obesity Smaller mass of skeletal muscle Premature sarcopenia and physical frailty resulting in premature institutionalization Increased resistance to insulin leading to pre-diabetes Increased prevalence of type 2 diabetes Shorter durations of the ability to perform low level work loads and a greater incidence of muscle fatigue-related work injuries Less calcification and strength Increased prevalence of osteoporosis and broken hips Acceleration in many of the signs and symptoms associated with aging. such as premature osteoporosis and physical frailty Myocardial cells of heart Sympathetic nervous system Vascular endothelial cells in heart Pro-inflammatory milieu in blood Plasma triglycerides Plasma glucose Deep venous thrombosis Pancreas Blood HDL Immunity Body fat Skeletal muscle. and learning Increased prevalence of dementia and Alzeheimer’s disease Lower contractility. size Skeletal muscle. ‘Economy-class syndrome’.Table 1. colon. maximal stroke volume and maximal cardiac output Contributes to decreased aerobic fitness Increased resting sympathetic drive. insulin-mediated glucose uptake Work endurance Bones Aging Lees/Booth 74 . heart. or ‘a condition in which bodily health is seriously attacked. muscle strength.The characteristics of physical inactivity are presented in table 1. A well known example that implies a neurochemical drive for physical inactivity is the spontaneous decrease in physical activity with aging in both rats [10] and humans [11]. Thus. Three examples are given: (1) Physical inactivity begets obesity. ‘or of some of its organs or parts interrupting or disturbing the performance of vital functions’. heart. Thus. fibrinolysis. according to Bray [13] fits the definition for the neurochemical basis of disease. leptin’s function is deranged or disturbed in most obese individuals and. deranged. the majority of obese Physical Inactivity Is a Disease 75 . cessation or disorder of body functions. cancer. carbohydrate oxidation. obese humans have paradoxically elevated leptin levels. or who exhibit subnormal secretion of the hormone. peripheral nervous system. it is likely that a change in a biological drive could be responsible for decreased physical activity with age. On the other hand. treatment of obesity using recombinant leptin seems to be only effective in individuals with a rare homozygous mutation in the gene for leptin or its receptor. obesity. skeletal muscle. as documented in Chakravarthy and Booth [1]. eight examples (brain. Thus. coronary heart disease. and work endurance) ‘in which its functions are disturbed or deranged’. and bones) of ‘some part or organ of the body’ or ‘of some of its organs or parts’ are given with ten examples (decreased brain. Bray’s argument can be extended to positive feedback loops where physical inactivity alters a molecule whose directional change is associated with a further decrease in physical activity. The data supporting the aforementioned positive feedback loop is that increased blood leptin results in greater physical activity and energy expenditure in normal mice [14] and in increased physical activity in parallel with a decrease in their obesity in the rare human condition of leptin deficiency [15]. blood. Leptin plays a central role in regulating body weight. [11] state that decreased physical activity with aging appears to be the key factor involved in producing sarcopenia. Morley et al. lipid oxidation. bone strength. type 2 diabetes. In most cases. immune. indicative of leptin resistance [12]. immune cells. or impaired’. systems or organs’ and seven examples (increased Alzheimer’s disease. providing evidence for the supposition that the putative neurochemical basis of a drive for physical activity becomes deranged or impaired with aging. Another rationale for categorizing physical inactivity as a disease is that the level of voluntary physical activity can be manipulated by various chemical changes. which is associated with increased serum leptin and leptin resistance. physical inactivity fits the presented definitions of disease. or ‘an interruption. causing more physical inactivity. physical frailty. However. Other evidence for neurochemical changes regulating voluntary physical activity follows. and osteoporosis) of ‘a departure from the state of health’. Using the above definitions as a guide. adipose tissue. aerobic fitness. further lowering muscle mass [18]. (3) Training raises muscle GLUT4 protein [19]. The latter approach is fundamental in preventative medicine. One advantage of classifying physical inactivity as a disease will be to challenge the current logic of the majority of studies which employ exercise training and designate the sedentary group as the control group. voluntary physical activity. healthy active subjects must be designated as the control. These examples suggest potential positive chemical feedbacks by which physical inactivity and activity creates molecular changes associated with less and more. Does sedentary lifestyle ‘cause’ the onset of some chronic diseases? Invariably. However. The goal of such an experimental design is to delineate mechanisms of partial reversal of the disease symptoms by exercise. the research community would answer this question with a ‘yes’. respectively. Thus physical activity enhances muscle GLUT4 and higher muscle GLUT4 levels are associated with more voluntary running. disease control group. The proposed revised logic of control group designation would have to emulate the following question and answer. (2) Aging is associated with decreased physical activity. 1.Treatment group Disease control Clinical trial Sedentary lifestyle: Disease group Preventative medicine Healthy control Fig. In the experimental design of an ‘exercise physiology’ clinical trial. are leptin resistant [16] and have decreased voluntary physical activity [17]. individuals who have higher than normal blood leptin. most experiments from the research community are not designed Lees/Booth 76 . Mice engineered to overexpress GLUT4 in skeletal muscle ran four times further in voluntary running wheels [20]. the sedentary disease group subjects are either prescribed an exercise treatment or assigned to the continued physically inactive. Schematic representation outlines the difference between clinical trial and cause and effect research in preventative medicine. In order to effectively delineate the mechanisms underlying how physical inactivity causes chronic disease. which lowers the chemical drive to maintain muscle mass so that with smaller muscle mass even less physical activity is undertaken. By extension. unfortunately. As a result of the designation of the sedentary group as the control group. poor diet. etc. the sedentary group is designated as the control and the exercise group as the treatment. A tenet of medicine is that understanding the molecular mechanisms of diseases provides the scientific basis for therapy and prevention. 1). It is therefore anticipated that future research will investigate the molecular mechanisms of decreasing physical activity from its genetically selected higher level Physical Inactivity Is a Disease 77 . These types of experiments are fine when the goal of the experiment is to determine the effectiveness of exercise as a treatment to restore the healthier condition. Molecular proof for the aforementioned concept is that while skeletal muscle unloading and overload may share some common regulatory units on the ␤-myosin heavy chain (␤MyHC) promoter. the clinical design logic breaks down when extrapolated to a search for cause and effect. the only way to truly decipher the mechanisms of disease prevention is to actually study the process itself as it is evoked by decreased physical activity. the sedentary group in the general population is analogous to the disease group of a clinical trial and the subjects are currently randomly assigned to continued inactivity (placebo) or given the ‘exercise’ treatment. A further reason not to designate the sedentary group as the control group is the misinterpretation by the general population and most of the scientific community that a sedentary state is the normal physiological condition. Again. Further.to prove this. In this experimental design. a 293-bp promoter region of ␤MyHC responded to mechanical overload of the mouse soleus muscle. the general population and the much of the scientific community devalue physical inactivity research. they have separate regulatory regions for unloading and overload. and thus must have different transcriptional activations. For example. physical activity is misinterpreted as abnormal with the application of physical activity being a ‘tool’ to cure rather than viewing physical activity as the norm whose deficiency is the actual cause of chronic disease. this experimental design does not allow for the delineation of mechanisms related to diseases caused by a sedentary lifestyle. of 16% of the deaths in the United States [4]. with poor nutrition. The vast majority of experiments in exercise research that are related to disease are set up to imitate a clinical trial (fig. It is clear that many mechanisms of physical inactivity that produce maladaptations differ from the mechanisms of exercise that reverse the pathological adaptations. However. A sedentary lifestyle leads to many chronic diseases. whereas it was not sensitive to unloading [21]. increases and decreases in exercise levels do not use the same molecular mechanisms. exercise is considered an inconvenience rather than a required physiological stimulus to maintain normal physiological function as dictated by the acquired human genome. Therefore. proving at the molecular level that. as described above. and is the actual cause. in some cases. Bray GA: Obesity is a chronic. JAMA 2004. Mayer J. New York. Stedman’s Medical Dictionary. This is not a new concept.who. Tavernier J: The ins and outs of leptin receptor activation. 2000. Baumgartner RN. Whitby R. Veldhuis JD. Vandekerckhove J. 1989.25: 1405–1406. A statement in the Declaration of Olympia on Nutrition and Fitness [22] that the current level of physical activity should match more closely our genetic endowment introduced the concept that the true normal condition in ‘exercise’ studies is the physically active.to the sicker physically inactive population because physical inactivity. 1998. Lavens D. Allison DB: Is obesity a disease? Int J Obes Relat Metab Disord 2001.shtml Pratt M. Booth FW: Exercise.W. Friedman JM. Krauss RM.137: 231–243. Flier JS: Obesity wars: Molecular progress confronts an expanding epidemic. Int J Obes Relat Metab Disord 2004. Macera C.int/hpr/physactiv/sedentary. Proc Natl Acad Sci USA 2004. Liang L. FEBS Lett 2003. Lippincott Williams Wilkins. Mokdad AH. DePaoli AM.28:34–38. if continued long enough. Marks JS. De Miranda PB. diabetes mellitus. Morley JE. Nature 1998. Philadelphia. not the sedentary. the body will fail [22].lifestyle1. This old advice holds true today as inadequate opportunities for physical activity impair the attainment of overall health [22] and produce many chronic health conditions.28:63–70. Philadelphia. relapsing neurochemical disease. 2003. Bhasin S. Gerberding JL: Actual causes of death in the United States. 27th edition.395: 763–770. Oxford English Dictionary. Clarendon Press. Mech Ageing Dev 1992. World Health Organization: http://www.[Epub ahead of print]. Heshka S.291:1238–1245. As long ago as the 5th century BC.25:1401–1404. Wang G: Higher direct medical costs associated with physical inactivity. Webster’s Unabridged Dictionary. Lees/Booth 78 . Roubenoff R. Halaas JL: Leptin and the regulation of body weight in mammals. Finer N: Reply: Is obesity a disease? Int J Obes Relat Metab Disord 2001. Elsevier. Ozata M. Zabeau L. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Chakravarthy MV. producing the metabolic dysfunctions which. Nair KS: Sarcopenia. O’Kirwan F. Stroup DF.). Oxford. Licinio J. Random House. Caglayan S. McCann SM. and behavior in leptin-deficient adults.Cell 2004. Wagner AJ. Ross TP. Holloszy JO: Effects of ageing and exercise on soleus and extensor digitorum longus muscles of female rats. Acknowledgment The review was written while supported by NIH AR19393 (F. Yildiz BO. is the actual cause of genes to mis-express proteins. Eyckerman S. Wong ML: Phenotypic effects of leptin replacement on morbid obesity. Hippocratic physicians wrote that if there is any deficiency in food or exercise.B.63:69–77. Cohen P. Brown M. group. hypogonadism. J Lab Clin Med 2001. Peelman F. Kopelman PG.116: 337–350. 2nd edition. result in overt clinical disease. Physician Sportsmed 2000.546:45–50. 2000. not activity. 38:94–104. McCarter RJ. 2003.49:1092–1095. Prev Med 2004. McCarthy JJ. Diabetes 2000. Tsika GL. MO 65211 (USA) Tel. pp 1487–1492. Tsika RW: Segregated regulatory elements direct beta-myosin heavy chain expression in response to altered muscle activity. et al (eds): Principles of Geriatric Medicine and Gerontology. E-Mail boothf@missouri. Stenbit AE. pp XVII–XXIV. Andersen JL. Richter EA: Fiber typespecific expression of GLUT4 in human skeletal muscle: Influence of exercise training. Daugaard JR. Anderson JE.edu Physical Inactivity Is a Disease 79 . Morabia A: Association of physical activity intensity levels with overweight and obesity in a population-based sample of adults. Basel.15:958–969. 1600 East Rollins Road Columbia. Tsao TS. PhD Department of Biomedical Sciences. ⫹1 573 882 6652. McGraw Hill. Vyas DR.17 18 19 20 21 22 Bernstein MS. Galuska D. Pavlou KN: Declaration of Olympia on nutrition and fitness. vol 89. 2001. Simopoulos AP. Karger. Booth. New York. FASEB J 2001. Frank W. Zierath JR. Fax ⫹1 573 884 6890.274:14270–14279. Kristiansen S. in Hazzard WR. World Rev Nutr Diet. Fried LP. Charron MJ: Metabolic adaptations in skeletal muscle overexpressing GLUT4: Effects on muscle and physical activity. University of Missouri-Columbia E102 Veterinary Medical Building. Walston J: Frailty and failure to thrive. J Biol Chem 1999. Costanza MC. Li J. Nielsen JN. Chang KS. Hargreaves M. whereas major changes have taken place in our food supply and in energy expenditure and physical activity [5–18]. whereas Greek Orthodox populations usually do not eat meat on Wednesdays and Fridays. the term ‘Mediterranean diet’ is a misnomer. whereas during evolution it was 2–1:1 (table 1. Nutrition is an environmental factor of major importance [1–4]. pp 80–92 What Is So Special about the Diet of Greece? The Scientific Evidence Artemis P. Basel.000 years. 1). which is not surprising because the countries along the Mediterranean basin have different religions. USA The health of the individual and the population in general is the result of interactions between genetics and a number of environmental factors. No other area in the Mediterranean basin has had as low a death . D. 2005. omega-6 fatty acids and trans fatty acids and a decrease in omega–3 fatty acid intake. Diets are influenced by religious habits. Although Greece and the Mediterranean countries are usually considered as areas of medium high death rates (14. Therefore.74:1 in the United States. that is. (3) a decrease in complex carbohydrates and fiber intake. Simopoulos The Center for Genetics. Furthermore. Aging.0–18.0 per 1. Karger. Washington. and (5) a decrease in protein. industrialized societies are characterized by the following: (1) an increase in energy intake and decrease in energy expenditure. World Rev Nutr Diet. (4) an increase in cereal grains and a decrease in fruit and vegetable intake. but drink wine. the ratio of omega–6 to omega–3 fatty acids is 16. death rates on the island of Crete have been below this level continuously since before 1930 [cited in 20]. antioxidant and calcium intake [5–18]. Nutrition and Health. vol 95. (2) an increase in saturated fat. Recent investigations of the dietary patterns and health status of the countries surrounding the Mediterranean basin clearly indicate major differences among them in both dietary intake and health status. Today. Our genetic profile has not changed significantly over the past 10.Defining the Components of a Healthy Diet and Physical Activity for Health Simopoulos AP (ed): Nutrition and Fitness: Mental Health.C. There is not just one Mediterranean diet but in fact many Mediterranean diets [19]. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. Muslims do not eat pork or drink wine and other alcoholic drinks. fig..000 inhabitants). economic and cultural traditions and diets. Italy.1 15. The Seven Countries Study was the first to establish credible data on cardiovascular disease prevalence rates in contrasting populations (United States. urban 0. rate as the island of Crete. according to data compiled by the United Nations in their Demographic Yearbook for 1948.900 2. trans and total) intake (as percent of calories from fat) and intake of vitamins E and C (mg/day).7 pre-war and about 10. The Greek Diet: Scientific Evidence 81 .00 16.00 5–6.to 10-fold in coronary heart disease [21].00–2. From the inception of the research program an important focus was on the diet and its possible relationship to the etiology of coronary heart disease.3–13. 1. Data were extrapolated from cross-sectional analyses of contemporary hunter-gatherer populations and from longitudinal observations and their putative changes during the preceding 100 years [13]. Cancer and heart disease caused almost three times as many deaths proportionally in the US as in Crete [20].000 Years Fig. Hypothetical scheme of fat.000 1. It was 11. The diet of Crete represents the traditional diet of Greece prior to 1960. with differences found on the order of 5. rural Current United Kingdom and northern Europe Current United States Current India.6 in 1946–1948 [20].74 38–50 [8] [9] [10] [11] [12] [9] [11] Hunter gatherer Industrial Vitamin C 600 30 100 Total fat Vitamin E 30 20 10 mg/day % calories from fat 40 Agricultural Trans Saturated 10 ␻-6 ␻-3 0 0 ⫺4 ⫻ 106 ⫺10. Japan and Greece). Finland. former Yugoslavia. ␻–3. Omega–6:omega–3 ratios in various populations Population ␻⫺6/␻⫺3 Reference Paleolithic Greece prior to 1960 Current Japan Current India.79 1. fatty acid (␻–6. The Netherlands. In 1958 the field work started in Dalmatia in the former Yugoslavia.Table 1.800 1.00 4. 5 40.9%.009 83.57 1. Men examined and followed up.7% or more. The 5-year follow-up found favorable all-cause death rates in Greece.05 1. The Seven Countries Study was designed to investigate relations between diet and cardiovascular diseases.3% and Italy.2 89.9% in Italy.39 Modified from Menotti et al.89 1.7 48. % SE 959 1.8% in Greece to 72.1 28. The outcome for men with prevalent stroke was 100% mortality in 15 years in the Netherlands and in Greece and 57. The main purpose of this analysis was to investigate the risk of dying within 15 years related to the presence of specific chronic conditions as found in population-based field studies in different countries. death rates from all causes were very different among the seven countries. primarily described in terms of the fatty acid composition of the diet. ranging from 46.9 92. 53.1 98.4 89.3 45.938 1.57 1. Bioprotective Nutrients and Mechanisms in the Greek Diet In order to precisely define the foods and their components in the diet of Crete.7 80. Similarly.0 39. 66. For coronary heart disease. In a recent follow-up study on the relation of chronic diseases to 15-year allcause mortality risk from the Seven Countries Study. 47.7% in Greece to 80. Men diagnosed with chronic obstructive pulmonary disease (COPD) had a high risk of dying. Peripheral arterial disease also carried a high risk of death.34 1.6% in Serbia.2 38. and 15-year all-cause death rates in the Seven Countries Study Country Croatia Finland Serbia Japan The Netherlands Italy Greece Survey participation 15-year all-cause n rate. Japan and Italy compared with the other areas. [22].Table 2. the excess risk of any deaths was greater than 60% in all areas except Greece where it was 45.32 1. as well as a lower incidence rate of coronary heart disease [21]. we began a series of studies investigating the components of the traditional Simopoulos 82 .8 36.348 1.281 867 614 1. % Death rate.1% in Japan. large risks were seen for other diseases from 47. with high death rates in Croatia and Finland and low rates in Greece (table 2) [22].8 97. except for Greece.4 1.6%. and cottonseed oil are all very rich in omega–6 fatty acids and the margarines made from them contain trans fatty acids that behave like saturated fats in terms of raising blood cholesterol [43]. fruits. Fruits and vegetables have been associated with lower rates of heart disease [45]. beta-carotene. and goats graze. 39]. anti-inflammatory. and eggs [38. antithrombotic. 30] as well as being essential for normal growth and development [5] and mental health [31].diet of Greece prior to 1960. lycopene. and snails. 29] and influence gene expression [29. the Lyon Heart Study [24–27]. vitamin E. 52]. The vegetable oils such as corn. The livestock obtain a mixture of omega–6 and omega–3 fatty acids from the foods they eat. Recent studies in the serum cholesteryl esters of the people in Crete showed a threefold increase of ALA versus the population of Zutphen (table 3) [44]. Because sheep. the studies by Pella. and the most recent Gruppo Italiano The Greek Diet: Scientific Evidence 83 . purslane (Portulaca oleracea) [32–34]. Our own studies showed that the Cretans obtained ␣-linolenic acid (ALA) by eating wild plants [32–36]. nuts [37]. swine. Because of agribusiness. 42]. game [40]. they obtain omega–3 fatty acids from grass. Wine. 41]. and in general from the leaves and stems of green leafy vegetables. and olive oil provide high amounts of vitamin C. In some areas the swine feed on acorns. Although the investigators of the Seven Countries Study emphasized the low saturated fat intake and the high monounsaturated fat intake from olive oil as the major factors responsible for the biological health effects of the diet of Crete being associated with the lowest rate of coronary heart disease and the longest life expectancy. moss. polyphenols. worms and insects produce eggs balanced in omega–6 and omega–3 fatty acids whereas the US supermarket egg has a ratio of about 20:1 [38. Meat from grazing animals contains omega–3 fatty acids whereas meat from grain-fed animals does not [40]. safflower. This balance of omega–6:omega–3 fatty acids is lost in the Western diets (fig. Omega–3 fatty acids have hypolipidemic. and other antioxidants [45–49]. The importance of a Cretan-type diet rich in ALA. 1) [13. and from eggs [38. as shown by a number of papers in these proceedings [28. fish. snails. the grain-fed animals have higher amounts of omega–6 fatty acids in their meat unlike the animals in the wild. Singh and coworkers [11. which is represented by the diet of Crete in the Seven Countries Study. They also feed on dry fruits and nuts. and the same mixture is found in their meat and in the milk and the cheese and all other dairy products made from the milk [18. fruits and vegetables has been demonstrated in the Diet and Reinfarction Trial (DART) [50]. fruit (figs). 39]. sunflower. and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fresh fish and dry or canned sardines and herring. 39]. Eggs from chickens eating wild greens. and antiarrhythmic properties. vegetables. there is good evidence that foods rich in omega–3 fatty acids and antioxidants could account for the decreased death rate of the people of Crete [23–27]. 51. 1⫾0.1⫾1.Table 3. the omega–6:omega–3 ratio in the Greek diet is between 2 and 1:1 which is very close to the dietary ratio of the Paleolithic diet [8]. The Omega–6:Omega–3 Ratio in the Greek Diet Olive oil being high in monounsaturated fatty acids and low in saturated and omega–6 fatty acids does not compete with the elongation and desaturation of ALA nor with the incorporation of omega–3 fatty acids into the red cell membrane phospholipids [5].60⫾0. and possibly cancer have been extensively reviewed [5. The beneficial effects of such a ratio and their importance in normal growth and development [54–56] and in the prevention and management of cardiovascular disease.0 3.9⫾3.6 1.001 ⬍0. Furthermore.9⫾0.001 ⬍0.5 21.20 11.5 0.4 2.3 2.5 1.001 ⬍0.2⫾1.1 0. hypertension.4⫾3. [44]. Simopoulos 84 . diabetes. The lower omega–6: omega–3 ratio in women with breast cancer was associated with decreased risk [66].1⫾6.7 0. 57–63].9⫾1. a ratio of 4:1 was associated with a 70% decrease in total mortality [24].7 41.3⫾0. arthritis. From Sandker et al. whereas a ratio of 10:1 had adverse consequences [68]. In the secondary prevention of cardiovascular disease.0⫾2.75 ⬍0.001 ⬍0. whereas a ratio of 4:1 with the same amount of omega–3 polyunsaturated fatty acids (PUFA) had no effect [64–65].5:1 reduced rectal cell proliferation in patients with colorectal cancer. Mean fatty acid composition of cholesteryl esters in serum of 92 elderly men from Crete and 97 elderly men from Zutphen Fatty acid 16:0 16:1 18:0 18:1 18:2␻⫺6 18:3␻⫺3 Ratio 18:2/18:1 % methylesters p value Crete Zutphen 11.3 31. A ratio of 2.001 Results are expressed as mean % (by weight) methylesters ⫾ SD. and a ratio of 5:1 had a beneficial effect on patients with asthma.7⫾0. A ratio of 2–3:1 suppressed inflammation in patients with rheumatoid arthritis [67].001 0.9 53.37⫾0.213 ⬍0. per lo Studio della Sopravivenza nell’Infarto miocardico (GISSI)-Prevenzione trial [53].9⫾1. elegans fat-1 gene encoding an omega–3 fatty acid desaturase are capable of producing omega–3 from omega–6 fatty acids. high in monounsaturated fat. [69] and Kang et al. including muscles and milk. omega–6 linoleic acid (LA) was converted to omega–3 ALA. so that at equilibrium. glutathione and other phytochemicals with antioxidant properties [32–36]. the saturated fat intake of the Greek diet is lower than other Western diets [20]. vitamin E. with no need of dietary omega–3 fatty acid supply. The Greek diet then is characterized by being moderate in fat. 71]. leading to enrichment of omega–3 fatty acids with reduced levels of omega–6 fatty acids in almost all organs and tissues. and antitumor properties in animal experiments [45]. Kang provides additional studies [73]. and other phytochemicals is much higher than other diets of the people around the Mediterranean basin because Greeks continue to eat wild greens which are rich sources of ALA. hypocholesterolemic. The beneficial effects of the various compounds found in the vegetables and fruits eaten by Greeks have been shown to have hypoglycemic. Dr. and arachidonic acid (AA) was converted to EPA. about 35%. Even today the mortality from breast cancer is lower in Greece than in the US. Summary of Characteristics of the Greek Diet Because Greeks have a cultural dislike for animal fats. In the current volume. This discovery provides a unique tool and new opportunities for omega–3 research. [24] clearly The Greek Diet: Scientific Evidence 85 . the ratio of omega–6 to omega–3 PUFA was close to 1/1 [70]. [69] clearly shows the ability of both normal rat cardiomyocytes and human breast cancer cells in culture to form all the omega–3s from omega–6 fatty acids when fed the cDNA encoding omega–3 fatty acid desaturase obtained from the roundworm Caenorhabditis elegans.Further support for the need to balance the omega–6/omega–3 fatty acid ratio comes from the studies of Ge et al. The antioxidant and phytoestrogen content. The omega–3 desaturase efficiently and quickly converted the omega–6 fatty acids that were fed to the cardiomyocytes in culture to the corresponding omega–3 fatty acids. low in saturated fat (7–8%). Thus. [70]. Kang et al. [72] in their recent paper showed that transgenic mice expressing the C. Finally. vitamin C. Further studies demonstrated that the cancer cells expressing the omega–3 desaturase underwent apoptotic death whereas the control cancer cells with a high omega–6/omega–3 ratio continued to proliferate [69. and balanced in the omega–6:omega–3 essential fatty acids. the Lyon Heart Study based on the modified diet of Crete described by de Lorgeril et al. Japan and Europe [74]. The study by Ge et al. and raises the potential of production of fat-1 transgenic livestock as a new and ideal source of omega–3 fatty acids to meet the human nutritional needs. Compare this with a meal of potato. ␤-carotene. the total amount of sugar (sucrose. allylthiosulfinates. onions. respectively. calcium. meat. this basic recipe is an ‘antioxidant cocktail’ that is also balanced in omega–6 and omega–3 fatty acids. and ␤-carotene. vitamin C. fish or beans may be added. eggplant. and very rich in monounsaturates. and phytochemicals from green leafy vegetables. and fish. glutathione. vitamin A. meat. canned tomatoes. To this. phenolic compounds from wine and olive oil. What appears to be so special about the Greek diet relative to the other Mediterranean diets is the content of bioprotective nutrients. Today we know that red wine or the juice from Simopoulos 86 . (2) Antioxidants: high amounts of vitamin C. Another important feature is the use of the juice of grapes to make cookies or puddings known as ‘must’ cookies. to the diet on which humans evolved (fig. garlic.7:1 the US. Furthermore. This approach to cooking has the advantage of using a variety of foods all at once that provide vitamins and minerals. The recipe for ‘must’ cookies was developed in classic times. zucchini. mint. or tomato paste is used. Because honey and cinnamon are used in many of the sweets. garlic and herbs. specifically: (1) A more balanced intake of essential fatty acids from vegetable. indoles. monoterpenes. onions and cabbage. potatoes. magnesium. omega–3 fatty acids. the Greeks start with olive oil to sauté onions. flavonoids. potatoes. used in cooking vegetables. salicylates. animal and marine sources.showed cardioprotective and anticancer effects in a French population indicating that such a diet is not only palatable but can be adapted to other populations. rosemary. vitamin E. antioxidants and fiber. polyphenols. 1). carotenoids. potassium. and additional omega–3 fatty acids and antioxidant vitamins from the green leafy herbs and the tomatoes). This basic recipe contains already 8 different foods that contribute a balance of fatty acids (from olive oil. parsley and dill that contain lycopene. omega–6:omega–3 of about 2:1 instead of 15:1 in Europe and 16. one could consider that the traditional diet of Greece even in its present form is the diet that is closer than the diets of other developed countries. is low in saturated fats and omega-6 fatty acids. vitamin E. and either fresh tomatoes. green beans and meat in which only 3 foods are eaten or a New England Boiled Dinner of corned beef. The Greek Way of Cooking In addition to the differences in the food composition there are distinct differences in the way Greeks use food ingredients. especially oregano. and other phytochemicals. high intakes of tomatoes. oregano. mint. phytoestrogens. In other words. simple carbohydrates) is less than it would have been otherwise. parsley. Traditionally. the Greek diet is low in saturated fat. One can see the wisdom of that sauce. is balanced in omega–6 and omega–3 fatty acids. About 14–20 different foods are consumed at a meal by Greeks versus about 6–8 consumed by western Europeans and Americans. Conclusions Since World War II. olive oil and lemon juice (juice of one lemon per egg yolk). which decreases serum cholesterol levels and may also protect against colon cancer. In summary. 79]. Olive oil is the most prominent oil in the Greek diet. This sauce is often served with either fish. meat or over vegetables such as artichokes. In fact. the traditional Greek diet has the following characteristics. the only diet that is consistent with the Paleolithic diet on which humans evolved is the traditional Greek diet as shown by the surveys on the population of Crete and clinical intervention studies using a modification of the diet of Crete [20. the Mediterranean diet. In animal studies and tissue cultures it has been shown that it is the oxidized LDL that is deposited to form atheromas that lead to coronary heart disease [77]. the vitamin C (from the lemons) and vitamin E (from oregano and rosemary) provide the two important antioxidant vitamins that may prevent the oxidation of LDL and free radical formation. broccoli. and is rich in antioxidant vitamins and minerals. Egg lemon sauce is a frequently used sauce with either egg yolks or whole eggs. 76]. balanced in omega–6 and omega–3 fatty acids that are present in every meal since both essential fatty acids are found in vegetable. 24. The diet is: 1 Low in saturated fat. The black olives are high in vitamin E. and marine sources. as a model of a healthful diet. a phenolic compound which inhibits arachidonate lipoxygenase activity.4-dehydroxyphenyl)ethanol. Lemon juice provides vitamin C to prevent the oxidation of LDL cholesterol from the egg yolk. Olives contain 2-(3. It is now clear that there is not one ‘Mediterranean diet’. The Greek diet is based on great variety and moderation. has been the subject of many studies. celery. or cauliflower. Furthermore. Another important aspect of the Greek diet is that the recipes for fish or meat (broiled or baked) always include olive oil. all of which are high in fiber. high in monounsaturated fat. animal. oregano. asparagus. thus decreasing the formation of proinflammatory eicosanoids (leukotriene B4) [78]. and decreases platelet aggregation [75. lowers low-density lipoprotein (LDL) cholesterol. What is then so special or what are the characteristics of such a diet? First and foremost. rosemary and lemon juice added towards the end of cooking so that the olive oil does not oxidize. The Greek Diet: Scientific Evidence 87 .red grapes contains resveratrol that raises high-density lipoprotein (HDL) cholesterol. variety. spices pasta. and energy intake ⫽ energy expenditure [80]. vinegar olives bread cheese yogurt fruits . vegetables. The Lyon Heart Study based on a modified diet of Crete indicated that the diet was responsible for a reduction in total death by 70% and that the traditional Greek diet can be adapted to other Western countries and cultures [24]. the principals of moderation. vegetables.S legumes fish poultry legumes legumes fish F legumes W eggs T poultry legumes pasta meat M legumes S fish Greek column food guide T olive oil. onions vegetables. proportionality. 4 Moderate in the amounts of cereals in the form of bread. 2. variety. The Greek Column Food Guide. 3 Rich in antioxidants as a result of using several herbs in cooking legumes. and legumes since Greeks continue to eat 0. garlic. The most likely components that account for the difference in death rate from cardiovascular disease in the Lyon Heart Study and in the Seven Countries Study is the balance of omega–6 and omega–3 essential fatty acids being 4:1 or less and the high amounts of compounds with antioxidant properties. rice water. meat and fish. the principles of moderation. In long-term (25 years) follow-up studies on cohorts of the Seven Countries Study. high intake of fruit and fish were associated with a lower risk of cardiovascular diseases. usually sourdough bread which has a lower glycemic index than the quick breads used in other Western countries. herbs. 2 High in fruits.5 kg (1 lb) of fruit a day. The guide is based on genetic individuality. lemon.fruit juices nuts. proportionality. wine Genetics Principles Moderation Variety Proportionality Energy intake ⫽ Energy expenditure Fig. Figure 2 illustrates the traditional Greek diet in the form of a Greek column which takes into consideration genetic individuality. and balancing energy intake with energy expenditure [80]. Simopoulos 88 . The traditional Greek diet is very rich in many antioxidant compounds from high fruit and vegetable intake and wine. World Rev Nutr Diet. vol 83. Aravanis C. Childs B (eds): Genetic Variation and Nutrition. vol 92. Basel. World Rev Nutr Diet. Toshima H: The relation of chronic diseases to all-cause mortality risk: The Seven Countries Study. Heart Disease. 1990. Exercise. Nestel P (eds): Genetic Variation and Dietary Response.71(suppl):S189–S196. Obesity. CRC Press.343:1454–1459. The Greek Diet: Scientific Evidence 89 . Pella D. 1997. Karger. Am J Clin Nutr 1986. Giampaol S. Karger. Sugano M. 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Designer Foods. 2003.25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 Renaud S. J Neurosci 1999.9:193–200.34(suppl):S297–S301. Simopoulos AP: Fatty acids. vol 77. 87. Arch Intern Med 1998. pp 107–119. Delaye J. pp 22–40. Jacquard F. Katan MB: Serum lipids in elderly men in Crete and The Netherlands. Boucher P. World Rev Nutr Diet. pp 1–23. N Engl J Med 1986. Martin J-L. Simopoulos AP. mood and cognitive function: The influence of nutrients and physical activity. Simopoulos AP. Duke JA: Common purslane: A source of omega-3 fatty acids and antioxidants. Aravanis C. New York. Karalias N. 2005. Martin JL.55:411–414. vol 92. Mamelle N. Simopoulos AP: The role of fatty acids in gene expression: health implications.61(suppl):S1360–S1367. J Agric Food Chem 1992. Basel. Monjaud I. vol 91. 2005. Bloemberg BP. Simopoulos AP. World Rev Nutr Diet. vol 94. and Cancer. Salem N Jr: n–3 fatty acids in eggs from range-fed Greek chickens (letter). 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Gibson RA: Linoleate inhibits EPA incorporation from dietary fish-oil supplements in human subjects. placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: The Indian experiment of infarct survival — 4. Birch EE. Simopoulos AP: Essential fatty acids in health and chronic disease. Dusal G. Jourdan M-L. Laposata M. Scheppach W.55: 395–399. Simopoulos AP. GISSI-Prevenzione Investigators: Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial.30:33–38.105:1317–1322. Rao CV. Lancet 1999. Lavillonnieree FF. France. Chajes V: n–3 and n–6 fatty acids in breast adipose tissue and relative risk of breast cancer in a case-control study in Tours. Karger. Kasper H: Missing anti-proliferative effect of fish oil on rectal epithelium in healthy volunteers consuming a high-fat diet: potential role of the n–3:n–6 fatty acid ratio. double-blind.124:612–620. Pella D. Chen Z. Basel. Broughton KS. Hamazaki T. Sharma JP. Burr ML.98:78–83. Cleland LG (eds): Omega–6/omega–3 essential fatty acid ratio: The scientific evidence. Kang JX: Effects of adenoviral transfer of Caenorhabditis elegans n–3 fatty acid desaturase on the lipid profile and growth of human breast cancer cells.22:537–544. Eur J Cancer Prev 1995.49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 Weisburger JH: Mechanisms of action of antioxidants as exemplified in vegetables. Kifer RR. Basel. Pace BK. Rastogi SS. vol 92. Cluette-Brown J. Leaf A. Ferrari P. J Pediatr 1994. Anticancer Res 2002. fish and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART).70 (suppl):S560–S569. mucosal fatty acids.13:219–230. N Engl J Med 1988. Jameson D.ii:757–761.354:447–455. Richter A. World Rev Nutr Diet. Singh RB. Body G. Leaf A. Galli C. Lipids 1999. Le Floch O. Ann Nutr Metab 1999.65:1011–1017.360:1455–1461. Gilbert JF.4:231–237. 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D’Angelo M. Richteer A. Kasper H: Effects of fish oil on rectal cell proliferation. Dusel G. Rogers S. Johnson CS. Rao CV. Rastogi V. Kang ZB. Hoffman D. tomatoes and tea. Fehily AM. Cleland LG. vol 66. 1991. J Pediatr Opthalmol Strabismus 1993. Deadman NM: Effect of changes in fat. Hale L. Simopoulos AP: The traditional diet of Greece and cancer. Lancet 1989. Saraswati Ghosh. Liebman M. Prestidge C: Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants. Moshiri M: Randomized. Uauy R.43:127–130. Neumann MA. Uauy R. Birch DG. Berry EM: Effect of an Indo-Mediterranean diet on progression of coronary artery disease in high risk patients (Indo-Mediterranean Diet Heart Study): A randomised single-blind trial. Bostner A. Richter F. Martin RE. Tyson J: Safety and efficacy of ␻–3 fatty acids in the nutrition of very low birth weight infants: Soy oil and marine oil supplementation of formula. Reddy BS. Pinault M. and prostaglandin E2 release in healthy subjects. Knapp HR (eds): Fatty Acids and Lipids from Cell Biology to Human Disease. Birch E. Kleppinger KM: Reduced asthma symptoms with n–3 fatty acid ingestion are related to 5-series leukotriene production. Lancet 2002. Singh RB. N. Lucchini F. Chen Z. Simopoulos AP. Kang ZB: Fat-1 mice convert n–6 to n–3 fatty acids. Ge Y.. Basel. The Lifesaving Nutritional Program Based on the Diet of the Island of Crete. Dorella M. Urquiaga I. Nutrition and Health 2001 S Street.61:347–350. Kohyama N. Rotondo S. vol 95.30:54–61. E-Mail cgnh@bellatlantic. Basel. Arterioscler Thromb 1992. Artemis P. Greek column rather than an Egyptian pyramid. Karger. Karger. Pagnan A. La Vecchia C. 2000. 1999. Wu L. Basel. Basel. Eur J Can Prev 1995. World Rev Nutr Diet. Kang JX: Balance of omega–6/omega–3 essential fatty acids is important for health: The evidence from gene transfer studies. Biosci Biotechnol Biochem 1997. de Gaetano G: Protection from cardiovascular disease by wine and its derived products. Karger. Nutr Today 1995.427:504. Sorgato F. World Rev Nutr Diet. Robinson J: The Omega Diet. MD The Center for Genetics. vol 92. et al: Effect of dietary monounsaturated and polyunsaturated fatty acids on the susceptibility of low density lipoproteins to oxidative modification.12:529–533. Fax ⫹1 202 462 5241. Levi F. The gene transfer of omega–3 fatty acid desaturase. 1990–92.4:389–417. Wang J. Brown J. Proc Natl Acad Sci USA 2001. pp 122–139.98:4050–4054. Nagata T. Sekiya K: Inhibition of arachidonate lipoxygenase activities by 2-(3. 2005. pp 90–113. Kang JX. Bonanome A. Leaf A. Negri E: Cancer mortality in Europe. DC 20009 (USA) Tel. a phenolic compound from olives. Opportuno A. World Rev Nutr Diet. Nature 2004. Leighton F: Wine and health: Evidence and mechanisms. vol 87. Biffanti S. Fujimoto S. Lapasota M. pp 23–36.4-dihydroxyphenyl)ethanol. ⫹1 202 462 5062. 2005. New York. Harper-Collins. vol 95.70 71 72 73 74 75 76 77 78 79 80 Kang ZB. Simopoulos.W. 2003.net Simopoulos 92 . Karger. Simopoulos AP: The Mediterranean food guide. Kang JX: Adenoviral transfer of Caenorhabditis elegans n–3 fatty acid desaturase optimizes fatty acid composition in mammalian heart cells. Kang JX: The Importance of omega–6/omega–3 fatty acid ratio in cell function. Suite 530 Washington. pp 93–102. World Rev Nutr Diet. we do not have the gene capable of converting omega–6 to omega–3 fatty acids. This is the consequence of modern agriculture.. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. 2005. The lipid pattern of our diets renders our tissues very high in omega–6 fatty acids.) [4]. As a result.Simopoulos AP (ed): Nutrition and Fitness: Mental Health. pp 93–102 Balance of Omega–6/Omega–3 Essential Fatty Acids Is Important for Health The Evidence from Gene Transfer Studies Jing X. indicating that modern diets are deficient in omega-3 fatty acids but too high in omega–6 fatty acids compared with the diet on which humans evolved and their genetic patterns were established (omega–6/omega–3 ⬵ 1:1) [1. 2]. and processed foods [1–3]. etc. elegans into cultured human cells and whole animals (mice) to render them capable of converting omega–6 to omega–3 fatty acids. vol 95. cancer. The fat-1 gene. agribusiness and aquaculture with excessive production of vegetable oils. encoding the converting enzyme omega–3 fatty acid desaturase that catalyzes conversion of omega–6 to omega–3 fatty acids. Mass. Although it is generally recognized that a lower ratio of omega–6/omega–3 fatty acids is more desirable in reducing the risk of many chronic diseases. Karger. Boston. Aging. we have recently used a gene transfer approach to create such a ratio in mammalian cells and studied its impact on cell function and physiology [5–6]. Basel. the optimal ratio has not been well defined. the emphasis on grain feeds. World Rev Nutr Diet. The high omega–6/omega–3 ratio may contribute to the high prevalence of many modern diseases (heart disease. and appears to be a major problem of modern nutrition. a high omega–6/omega–3 ratio exists in our body tissues. Kang Massachusetts General Hospital and Harvard Medical School. The resulting transgenic cells and mice can produce omega–3 from omega–6 fatty acids and . is found in the roundworm Caenorhabditis elegans but missing in mammals [5]. In order to examine the potential beneficial effects of a balanced ratio of omega–6/omega–3 fatty acids (⬃1:1). Since this change in dietary omega–6/omega–3 ratio occurred within too short a time to affect genetic adaptation significantly. We transferred the fat-1 gene from C. USA The ratio of omega–6 to omega–3 essential fatty acids in today’s Western diets is around 15–20:1. Our previous studies have demonstrated an antiarrhythmic effect for omega–3 fatty acids when supplemented to Kang 94 . namely. We constructed a recombinant adenovirus (Ad. Our results showed that the fatty acid profiles were remarkably different between cells expressing the fat-1 gene and control cells [5. we determined if the gene transfer-induced change in the omega–6/ omega–3 ratio would provide the beneficial effects of omega–3 fatty acids as observed with fatty acid supplementation.fat-1) carrying both the fat-1 gene and the green fluorescent protein (GFP) gene and another adenovirus (Ad. We found that the amount of prostaglandin E2 produced by the cells expressing the fat-1 gene was significantly lower than that produced by the control cells (30–50% reduction) [5. We also measured the production of prostaglandin E2 (PGE2). Thus.GFP. Similar effects were observed in all cell types that we have tested [7–9]. In cells expressing the fat-1 gene (omega–3 fatty acid desaturase). 7–9]. leading to a dramatic reduction of the omega–6/omega–3 ratio from 9–15:1 in the control cells to about 1:1 (table 1).have a balanced omega–6/omega–3 ratio (⬃1:1) without the need of exogenous omega–3 supplementation. These results indicate that gene transfer of the omega–3 fatty acid desaturase can effectively modify cellular fatty acid composition (the omega–6/omega–3 ratio) and the generation of eicosanoids. we used a virus-mediated gene transfer strategy.GFP) carrying the GFP gene alone (as control) and used them to infect various mammalian cells. the transgenic cells and mice can serve as a unique model for elucidating the importance of the ratio of omega–6/omega–3 fatty acids. Use of these cells and animals for study of omega–3 fatty acids can eliminate the potential confounding factors of diet or supplement. 20:4␻–6 to 20:5␻–3. 8]. one of the major ecosanoids derived from 20:4␻–6 (AA). Next. The data obtained so far from these studies (in vitro and in vivo) are summarized as follows. all types of omega–6 fatty acids were largely converted to corresponding omega–3 fatty acids. Cellular Studies In order to introduce the fat-1 gene into mammalian cells efficiently. Following the virus-mediated gene transfer. neurons. the contents of omega–3 fatty acids significantly increased whereas the levels of omega–6 fatty acids decreased in the fat-1 transgenic cells. 7–9]. 22:4␻–6 to 22:5␻–3 and 22:5␻–6 to 22:6␻–3. cellular lipids were extracted and fatty acid composition was analyzed by gas chromatography to determine if the expression of the fat-1 gene in mammalian cells could change their lipid profile. 7. 18:2␻–6 to 18:3␻–3. 7–9]. 20:2␻–6 to 20:3␻–3. 20:3␻–6 to 20:4␻–3. endothelial cells and human breast cancer cells [5. As a result. in the fat-1 and control cells by using an enzyme immunoassay [5. including heart cells. 0b v–3 polyunsaturates 18:3␻–3 20:4␻–3 20:5␻–3 22:5␻–3 22:6␻–3 Total 0.Table 1.0a 2. leading to an increase in apoptotic cell death and a decrease in cell proliferation [7].9b ␻–6/␻–3 ratio Values are means of four measurements.6a 15. In human breast cancer cells (MCF-7). Polyunsaturated fatty acid composition of total cellular lipids from the control heart cells and the transgenic cells expressing a C.1b 1.2a 1. elegans fat-1 cDNA Mol% of total fatty acids Control fat-1 v–6 polyunsaturates 18:2␻–6 20:2␻–6 20:3␻–6 20:4␻–6 22:4␻–6 22:5␻–6 Total 14.0 to 0. As shown in figure 1. As shown in figure 2. neonatal rat cardiac myocytes expressing the fat-1 gene were tested for their susceptibility to arrhythmias induced by arrhythmogenic agents.2a 36. This suggests that gene transfer of the omega–3 desaturase into heart cells can provide the antiarrhythmic effect of omega–3 fatty acids. a large number of the cells expressing fat-1 gene underwent apoptosis.2b 1.0b 15.7a 0. cardiac myocytes [10]. whereas the cells expressing the fat-1 gene could sustain regular beating (resistant to the arrhythmogenic stimulus).2a 4.8 and the level of PGE2 by about 40%.01) between control and fat-1.3b 0.0b 0.6a 6. as indicated by morphological Omega–6/Omega–3 Ratio in the Gene Transfer Studies 95 . such as high concentrations of extracellular calcium.8a 1.2b 0. the control cells promptly exhibited arrhythmia characterized by spasmodic contractures and fibrillation.6a 0. similar to the effect of omega–3 fatty acid supplementation [10].2b 0.1b 1.4a 14.5b 3. when challenged with a high [Ca2⫹] (7. Values for each fatty acid with the same superscript letter do not differ significantly (p ⬍ 0.2a 1.5 mM).8a 9. gene transfer of the omega–3 desaturase reduced both cellular omega–6/omega–3 fatty acid ratio from 12. To see whether the gene transfer can provide a similar protective effect.0b 0.3a 17.1a 5.4b 4.4a 0. Ad. cell death was examined using a fluorescence microscope. Effect of expression of the C. whereas the fat-1 cells could sustain regular beating.GFP ↑Ca2⫹ (7.fat-1 Fig. control) or Ad.fat-1 (right). Cultured (spontaneously beating) neonatal rat cardiac myocytes infected with Ad. elegans ␻–3 fatty acid desaturase in cardiac myocytes on their susceptibility to arrhythmia.GFP.GFP.GFP (control) or Ad.fat-1 were challenged with 7. Kang 96 .5 mM) Ad. 2. Three days after infection. 1.5 mM) Fig.GFP (left. The brighter looking spots are the nuclei of apoptotic cells. Ad.GFP.GFP Ad. Upper panels: Infected cells were directly visualized at 510 nm of blue light.GFP. MCF-7 cells were infected with Ad. The control cells promptly exhibited arrhythmia (spasmodic contractures and fibrillation).fat-1 ↑Ca2⫹ (7. The gene transfer induces apoptosis of MCF-7 cells. Lower panels: Cells were stained with Hoechst dye for nuclei and observed under 480 nm fluorescent light.5 mM extracellular calcium. in response to cytokine exposure (TNF-␣ 5 U/ml. In addition. 43. As shown in figure 3. These observations confirm the protective effects of omega–3 fatty acid supplementation on neuron death [14.fat-1 cells was significantly (⬃50%) higher than that of cells infected with Ad. and VCAM-1 was reduced by 42. fat-1 compared to control vector infected HUVEC supported ⬃50% less firm adhesion with almost no effect on the rolling interactions of THP-1 cells [9]. expression of fat-1 significantly reduced omega–6/omega–3 fatty acid ratio from about 9 to 1 [9]. 4 h) [9].changes (small size with round shape or fragmentation) and nuclear staining (bright blue).GFP. the total number of viable cells in the cells infected with Ad. apoptosis was induced by 24 h of growth factor withdrawal and detected by Hoechst staining. MTT analysis indicated that proliferative activity of cells infected with Ad.fat-1 were apoptotic whereas only 10% dead cells found in the control cells (infected with Ad. This change in cellular omega–6/omega–3 ratio led to a decrease in the surface expression of adhesion molecules (markers of inflammation). We have also determined the effect of fat-1 expression on neuronal apoptosis. Accordingly. In primary culture of human umbilical vein endothelial cells (HUVEC). 15] and Omega–6/Omega–3 Ratio in the Gene Transfer Studies 97 . adhesion.GFP.GFP. Following gene transfer. Under laminar flow and a defined shear stress of ⬃2 dyn/cm2. and an up-regulation of apoptosis-inducing genes in MDA-MB-231 cells [unpubl.fat-1 was significantly lower than that of cells infected with Ad. These results indicate that expression of the fat-1 gene in HUVEC inhibit cytokine induction of the endothelial inflammatory response and firm adhesion of monocytes.GFP).fat-1 was about 30% less than that in the control cells. which could significantly reduce the neuronal omega–6/omega–3 fatty acid ratio from 6 to 1. Statistical analysis of apoptotic cell counts showed that 30–50% of cells infected with Ad. MTT analysis indicated that the viability of Ad.GFP.5 and the production of prostaglandin E2 by 20%. DNA microarray assays showed that the gene transferinduced change in omega–6/omega–3 fatty acid ratio could result in a downregulation of a number of genes involved in cell proliferation. We then examined whether changes in the adhesion molecule profile were sufficient to alter endothelial interactions with monocytes. and 57%. resulted in protection from growth factor-withdrawal-induced apoptotic cell death of rat cortical neurons [8]. The quantity of the adhesion molecules (as determined by immunoassay). ICAM-1. These results are consistent with the reported anti-cancer effects of omega–3 fatty acid supplementation [11–13].GFP. suggesting that a balanced omega–6/omega–3 fatty acid ratio may have an antiatherosclerotic effect. data]. We found that the expression of the fat-1 gene.GFP. respectively. angiogenesis and invasion.GFP [8]. the most prevalent white blood cell type found in atherosclerotic lesions. E-Selectin. Accordingly.fat-1 underwent (⬃60%) less apoptosis than those infected with Ad. cortical cultures infected with the Ad.GFP. Both transgenic and wild-type mice are maintained at a diet high in omega–6 fatty acids (mainly linoleic acid) with very little omega–3 fatty acids Kang 98 . Cells were infected with Ad-GFP (left panels.fat-1 Fig.GFP Ad. control) or Ad-GFP-fat-1 (right panels). We have now successfully generated mice expressing the fat-1 gene [6]. elegans omega–3 fatty acid desaturase in mice. Cell death was examined after 24 hours of growth factor withdrawal using a fluorescent microscope. Photomicrographs showing the protective effect of the fat-1 gene on neuronal apoptosis. We then microinjected the expression vector into fertilized eggs to produce transgenic mouse lines.Ad. highlight the importance of omega–6/omega–3 ratio in this neuroprotectve effect.GFP. 3. we modified the fat-1 gene encoding this protein by optimization of codon usage for mammalian cells and coupled it to a chicken ␤-actin promoter. Animal Studies To heterologously express the C. Bright-field (upper panels) and Hoescht staining (lower panels) images showing appoptotic cells. 20:4␻–6 40 22:6␻–3 22:4␻–6 30 22:5␻–6 18:2␻–6 18:3␻–3 20 50 60 20 22:6␻–3* 22:5␻–3* 22:5␻–6 22:4␻–6 20:5␻–3* 20:4␻–6 18:2␻–6 TM 18:3␻–3* Detector signal WT 30 40 50 Column retention time (min) 60 Fig. upper panel) and a fat-1 transgenic mouse (TM. 4. 20:4␻–6) with trace (or undetectable) amount of omega-3 fatty acids. wild-type mice have little or no omega–3 fatty acid in their tissues because the animals naturally cannot produce omega–3 from omega–6 fatty acids. 18:2␻–6) and arachidonic acid (AA. 22:4␻–6 and 22:5␻–6) are remarkably lower whereas ␻–3 fatty acids (marked with *) are abundant in the transgenic muscle (lower panel) compared with the wild-type muscle in which there is very little ␻–3 fatty acid (upper panel). lower panel). In the wild-type animals. Note. Under this dietary regime. the polyunsaturated fatty acids found in the tissues are mainly (98%) the omega–6 linoleic acid (LA. (⬃0. Partial gas chromatograph traces showing the polyunsaturated fatty acid profiles of total lipids extracted from skeletal muscles of a wild-type mouse (WT. the levels of ␻–6 polyunsaturated acids (18:2␻–6.1% of total fat supplied). Both the wild-type and transgenic mice were 8 weeks old female and fed with the same diet. whereas the fat–1 transgenic mice have significant amounts of omega–3 fatty acids (derived from omega–6 fatty acids) in their tissues [6]. there are large amounts of Omega–6/Omega–3 Ratio in the Gene Transfer Studies 99 . 20:4␻–6. In contrast. Figure 4 shows the differential fatty acid profiles of total lipids extracted from skeletal muscles of age and sexmatched wild-type and transgenic mice. 8 2.9 1.7 27.8 17.0 16.7 5.5 1.9 26. the levels of the ␻–6 fatty acids LA and AA in the transgenic tissues are significantly reduced.7 46.5 1. including linolenic acid (ALA. eicosapentaenoic acid (EPA.3 0. The transgenic mice appear to be normal and healthy.8 0. 18:3␻–3). The resulting ratio of omega–6 to omega–3 fatty acids in the tissues of transgenic animals is close to 1.3 3. omega–3 polyunsaturated fatty acids.7 0. which is impossible in wild-type mammals.4 11.6 12. in the tissues of transgenic mice. Accordingly.9 1. Therefore.6 22.8 0. 22:5␻–3) and docosahexaenoic acid (DHA. Our data clearly show that the transgenic mice expressing the fat-1 gene are capable of producing omega–3 fatty acids from omega–6 fatty acids. Availability of these animals allows us to produce two different fatty acid profiles in experimental animals by feeding them just a single diet.0 32.3 23.9 19. docosapentaenoic acid (DPA. resulting in enrichment of omega–3 fatty acids in their organs/tissues without the need of dietary omega–3 supply.0 14. 22:6␻–3).5 11. including muscle and milk (table 2).4 2.7 2. Comparison of the omega–6/omega–3 ratios and AA/(EPA⫹ DPA⫹DHA) ratio in various organs and tissues between a wild-type mouse (WT) and a fat-1 transgenic mouse (TG) Muscle Milk RBC Heart Brain Liver Kidney Lung Spleen Omega–6/omega–3 AA/(EPA⫹ DPA⫹DHA) WT TG WT TG 49.3 15.5 32. The omega–6/omega–3 fatty acid ratio is (18:2␻–6 ⫹ 20:4␻–6 ⫹ 22: 4␻–6 ⫹ 22:5␻–6)/(18:3␻–3 ⫹ 20:5␻–3 ⫹ 22:5␻–3 ⫹ 22:6␻–3).2 2. this novel mouse model is desirable for us to address the authentic biological effects of omega–3 fatty Kang 100 . This omega–3 rich profile of lipid with a balanced ratio of omega–6 to omega–3 and an even more balanced AA/(EPA⫹DPA⫹DHA) can be observed in all of the organs/tissues.2 1. 20:5␻–3). indicating a conversion of omega–6 to omega–3 fatty acids.9 0.2 1.Table 2.6 0.5 Both the wild-type and transgenic mice were 8-week-old females and fed with the same diet.7 2.8 3. g. the transgenic mice have a much lower tumorigenicity of melanoma than wild-type animals. Thus. elegans omega–3 fatty acid desaturase to mammalian cells can dramatically balance cellular omega–6/omega–3 fatty acid ratio and provide beneficial effects of omega–3 fatty acids. meat. These results support the notion that excessive amounts of omega–6 fatty acids and a very high omega–6/omega–3 ratio promote the pathogenesis of many modern diseases (heart disease. cancer. milk and eggs) by generating large fat-1 transgenic animals/livestock (e. without the need for supplementation with exogenous omega–3 fatty acids. when maintained on a high omega–6/omega–3 diet. without confounding factors of diet. Omega–6/Omega–3 Ratio in the Gene Transfer Studies 101 . these studies are underway]. the fat-1 transgenic mice have lower levels of blood triglyceride and appear to be less susceptible to atherosclerosis. cow. sheep and chicken) with this technology. the wild-type mice behaviorally exhibit hyperactivity whereas the fat-1 mice do not [unpublished data. I expect that our ongoing studies using fat-1 transgenic mice will provide more meaningful and definite information in the near future. This genetic approach in modifying omega–6/omega–3 ratio is helpful for studying the importance of omega–6/omega–3 fatty acid ratio in a biological system. In addition. while balancing or reducing the ratio of omega–6/omega–3 fatty acids may decrease the risk of these diseases. our observations in vivo obtained so far are consistent with the in vitro data and support the notion that a balanced ratio of omega–6/omega–3 fatty acids is more desirable in reducing the risk of many diseases. In addition. our studies have demonstrated a novel and effective approach to modifying fatty acid composition of mammalian cells.).g. and have obtained some exciting preliminary data. This genetic approach may be a cost-effective and sustainable way of producing omega–3 essential fatty acids for the increasing demand in the future. For example. our discovery in transgenic mice provides a new strategy for producing omega–3 fatty acid-rich foodstuff (e. our data derived from these gene transfer studies clearly show that a low or balanced omega–6/omega–3 fatty acid ratio exerts many beneficial effects either in vitro or in vivo. pig.acids and omega–6/omega–3 ratio in the body. challenging lungs with LPS or bleomycin produces less severity of pulmonary inflammation and fibrosis in the transgenic mice than wild-type animals. Conclusions Our findings as presented here clearly indicate that gene transfer of the C. we have just begun to examine the potential differences in physiology and pathophysiology between the transgenic and wild-type mice. Indeed. etc. Most recently. Although more studies are needed. Chen ZH.79: 961–970. Wang J.275: 35215–35223. Fax ⫹1 617 726 6144. Kang JX: Adenoviral gene transfer of C. Romey G. elegans n–3 fatty acid desaturase on the lipid profile and growth of human breast cancer cells.edu Kang 102 . Kang JX. Kang ZB: Fat-1 transgenic mice convert n–6 to n–3 fatty acids. Lo EH. MA 02129 (USA) Tel. Lauritzen I. Weber PC: A new era for science in nutrition. World Rev Nutr Diet. Simopoulos AP. Cave WT Jr: Omega-3 polyunsaturated fatty acids in rodent models of breast cancer. Basel. Anticancer Res. ⫹1 617 726 8509. vol 92. Jun-ichi Miyazaki for providing the CAG promotor. Lin Wu and Zhao B.45:1048–1053. elegans n–3 fatty acid desaturase optimizes fatty acid composition in mammalian cells.94:1774–1780. Meiler S. Bougnoux P: N–3 polyunsaturated fatty acids and cancer. The author is also grateful to Ms. Karger. Chen ZH. Kang JX: Inhibition of neuronal apoptosis by adenoviral gene transfer of C. EMBO J 2000. Room 4433 Charlestown.22:537–544.2: 121–126. This work was supported by grants from the National Institutes of Health. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Simopoulos AP: Human requirement for n–3 polyunsaturated fatty acids. Rosenzweig A: Expression of the fat-1 gene alters lipid profile and inhibits the inflammation of human endothelium by reducing the transcriptional activity of NFkB. J Neurochem 2002. World Rev Nutr Diet. Kang to this work and thank Dr.Acknowledgements The author would like to acknowledge the contributions of Jingdong Wang. 2002. Lau A. Leaf A. J Biol Chem 2000. 2003. Brown J. Kang ZB. Heurteaux C. Karger.82:1360–1366. elegans fat-1 cDNA and Dr. Kang JX. 2002 American Heart Association Annual Meeting Abstract (Publication ID:1228).19:1784–1793. Ge Y. the American Cancer Society and the American Institute for Cancer Research. Wu L. Breast Cancer Res Treat 1997.83:217–244. Poultry Science 2000. Akbar M. Ge Y. Circulation 1996. Connolly JM: Omega–3 fatty acids as cancer chemopreventive agents. Kang JX: Effect of adenoviral gene transfer of C. Blondeau N. Laposata M. E-Mail kang. Wang XY. Proc Natl Acad Sci USA 2001. Jing X. 1998.98:4050–4054.427:504. Nature 2004. Curr Opin Clin Nutr Metab Care 1999. Rose DP. Natalie Landman for her technical assistance. Kang Massachusetts General Hospital 149–13th Street. Pharmacol Ther 1999. elegans n–3 fatty acid desaturase. Chen ZH.harvard. Leaf A: Antiarrhythmic effects of polyunsaturated fatty acids.jing@mgh. Simopoulos AP. Edsall L: Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n–3): Role of phosphatidylserine in antiapoptotic effect. Leaf A. Am J Clin Nutr 1987. et al (eds): The return of omega–3 fatty acids into the food supply: Land-based animal food products and their health effects. Recent studies. Basel. Kim HY. Cleland LG (eds): Omega-6/omega-3 essential fatty acids ratio: The scientific evidence. vol 83. John Browse for generously providing the C. Ge Y. Lazdunski M: Polyunsaturated fatty acids are potent neuroprotectors. Laposata M. Brown J. Widmann C. Landman N. Kang JX.46:239–246. both in vivo and in vitro [4. and often the first. This hypothesis was consistent with experimental evidence suggesting that ␻–3 polyunsaturated fatty acids (PUFA). As a matter of fact. Vieillissement et Maladies Cardiovasculaires (NVMCV). parallel those of CHD. which showed a significant reduction in total and cardiovascular mortality (both by about 30%) in patients who had at least 2 servings of fatty fish per week [3]. the epidemiology and potential preventive approaches of SCD should. this mode of death is a major public health issue. SCD occurs without prodromal symptoms and out of hospital. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. since no benefit was observed on the incidence of nonfatal AMI. Aging. Université Joseph Fourier. 5]. The authors suggested that the protective effect of fish might be explained by a preventive action on ventricular fibrillation (VF). vol 95. UFR de Médecine et Pharmacie. In most cases. and it accounts for about 50% of cardiovascular mortality in developed countries [1]. pp 103–114 Dietary Prevention of Coronary Heart Disease: The Lyon Diet Heart Study and After Michel de Lorgeril. 2005. the dominant fatty acids in fish oil and fatty fish. manifestation of coronary heart disease (CHD). investigators used quite different definitions with a time frame of 3 h or even 24 h in the old World Health Organization definition. Patricia Salen Laboratoire Nutrition.Simopoulos AP (ed): Nutrition and Fitness: Mental Health. any treatment aimed at reducing CHD should reduce the incidence of SCD. In the . Karger. in theory. The magnitude of the problem is considerable as SCD is a very common. however. In many studies. France Sudden cardiac death (SCD) is usually defined as death from a cardiac cause occurring within one hour from the onset of symptoms [1]. have an important effect on the occurrence of VF in the setting of myocardial ischemia and reperfusion in various animal models. The hypothesis that eating fish may protect against SCD is derived from the results of a secondary prevention trial. Basel. the Diet And Reinfarction Trial (DART). World Rev Nutr Diet. In other words. Since up to 80% of SCD patients had CHD [2]. Grenoble. survivors of AMI [16] and healthy men [17] receiving fish oil were shown to improve their measurements of heart rate variability. Also. This illustrates the potential of diet to modify the structure and biochemical composition of cardiac cells. they are the precursors to a broad array of structurally diverse and potent bioactive lipids (including eicosanoids. Other clinical data show suppression (by more than 70%) of ventricular premature complexes in middle-aged patients with frequent ventricular extrasystoles randomly assigned to take either fish oil or placebo [15]. it was also apparent that saturated fatty acids are proarrhythmic as compared to unsaturated fatty acids.same studies. it seems that the very potent inhibitory effects of ␻–3 PUFA on the fast sodium current. In competition with ␻–6 PUFA. Nair and colleagues have also shown that a very important pool of free (non-esterified) fatty acids exists in the normal myocardium and that the amount of ␻–3 PUFA in this pool is increased by supplementing the diet in ␻–3 PUFA [7]. 14]. suggesting other mechanisms by which ␻–3 PUFA may be antiarrhythmic. Billman and colleagues recently demonstrated a striking reduction of VF after intravenous administration of pure ␻–3 PUFA. which are thought to play a role in the occurrence of VF during myocardial ischemia and reperfusion [13. these fatty acids are preferentially incorporated into membrane phospholipids [7]. It is important to remember that the lipoprotein lipase is particularly active following the consumption of ␻–3 PUFA [8]. Using an elegant in vivo model of SCD in dogs. So far. as was also observed in other excitable tissues such as neurons. INa [10. including ␻–3 fatty acids in higher amounts than the other fatty acids [7]. thus further increasing the pool of free ␻–3 fatty acids that can exert an antiarrhythmic effect. phospholipases and lipases quickly release new fatty acids from phospholipids. One hypothesis is that the presence of the free form of the ␻–3 PUFA in the membrane of every cardiac muscle cell renders the myocardium more resistant to arrhythmias. are the major contributors to the antiarrhythmic actions of these fatty acids in ischemia. ␻–3 PUFA act by shifting the steady-state inactivation potential to more negative values. Another important aspect of the implication of ␻–3 PUFA in SCD is their role in the metabolism of eicosanoids. including both the long chain fatty acids present in fish oil and ␣-linolenic acid. Briefly. de Lorgeril/Salen 104 . and the L-type calcium current. These authors have found the mechanism of this protection to result from the electrophysiological effects of free ␻–3 PUFA when these are simply partitioned into the phospholipids of the sarcolemma without covalently bonding to any constituents of the cell membrane. 11]. ICaL [12]. In case of ischemia. After dietary intake. probably by modulating the conduction of several membrane ion channels [9]. prostaglandins and thromboxanes). their parent ␻–3 PUFA occurring in some vegetable oils [6]. came from two randomized trials testing the effect of ethnic dietary patterns (instead of that a single food or nutrient). 19]. i. Patients (n ⫽ 11. Whereas the incidence of SCD was markedly reduced in both trials. They found that the risk of SCD was 50% lower for men who consumed fish at least once a week than for those who had fish less than once a month.and sex-matched controls [20].000 participants with a followup of 11 years). considerably enhanced the validity of the findings. 22]. Their data indicated that the intake of about 5–6 g of ␻–3 PUFA per month (an amount provided by consuming fatty fish once or twice a week) was associated with a 50% reduction in the risk of cardiac arrest.324) surviving a The Lyon Diet Heart Study 105 . in the secondary prevention of CHD [18.e. especially the way of classifying deaths in the Western Electric Study [24]. the consumption of fish was not related to non-sudden cardiac death suggesting that the main protective effect of fish (or ␻–3 PUFA) is related to an effect on arrhythmia. The GISSI-Prevenzione trial was aimed at helping in addressing the question of the health benefits of foods rich in ␻–3 PUFA (and also in vitamin E) and their pharmacological substitutes [25]. Albert et al examined the specific point that fish has antiarrhythmic properties and may prevent SCD [23]. This again illustrates the limitations of observational studies and the obvious fact that only randomized trials can definitely provide a clear demonstration of causal relationships. These results are consistent with those of DART [3] but differ from those of the Chicago Western Electric Study. the main vegetable ␻–3 PUFA. Interestingly. including various antioxidants. a Mediterranean type of diet (consistent with a modified diet of Crete) and an Asian vegetarian diet. in which there was a significant inverse association between fish consumption and non-sudden cardiac death. but not with SCD [24]. however. the SCD endpoint is not reported. compared to that of age. the red blood cell membrane level of ␻–3 PUFA. Several methodological factors may explain the discrepancy between the two studies. which also were consistent with the results of many (but not all) cohort studies suggesting that consumption of one to two servings of fish per week is associated with a marked reduction in CHD mortality as compared to no fish intake [21. In that study. the use of a biomarker. as put forward in DART [3]. In most studies.Support for the hypothesis of a clinically significant antiarrhythmic effect of ␻–3 PUFA in the secondary prevention of CHD. the number of cases was very small and the antiarrhythmic effect cannot be entirely attributed to ␣linolenic acid as these experimental diets were also high in other nutrients with potential antiarrhythmic properties. In a large prospective study (more than 20. These findings were extended by the population-based case-control study conducted by Siscovick and colleagues on the intake of ␻–3 PUFA among patients with primary cardiac arrest. The two experimental diets included a high intake of essential ␣-linolenic acid. However.70–0. The exact definition of SCD was not given in the paper. Secondary analyses provided a clearer profile of the clinical effects of ␻–3 PUFA (table 1).96) recent AMI (⬍3 months) and having received the prior advice to come back to a Mediterranean type of diet (consistent with a modified diet of Crete) were randomly assigned supplements of ␻–3 PUFA (0. not high in ␻–6 PUFA and low in saturated fats.80 (0. the clinical events were validated by an ad-hoc committee of expert cardiologists [25]. vitamin E (300 mg daily).94) 0.76–1. Clinical efficacy of (␻–3) PUFA in the GISSIPrevenzione Trial [modified from 25]: see text for comments Relative risk (95% CI) Death.21) 1. who presumably used the current definition of SCD. by definition.70 (0. nonfatal AMI and stroke Overall mortality Cardiovascular mortality Sudden cardiac death Nonfatal cardiovascular events Fatal and nonfatal stroke 0. both or none (control) for 3.56–0.99) 0. The primary efficacy endpoint was the combination of death and non-fatal AMI and stroke. 19]. and associated with a moderate consumption of alcohol (see below for further comments).96 (0. large-scale observational studies [21–24] and experimental studies [4–7].76) 0. a result comparable to that of DART [3]. but rich in oleic acid. it was the effect on SCD (45% lower) that accounted for most of the benefits seen in the primary combined endpoint and both overall and CV mortality.Table 1. Overall mortality was reduced by 20% and CV mortality by 30%.85 (0. which together strongly support an effect of ␻–3 PUFA in relation with SCD. various antioxidants and fiber. This suggests a positive interaction between ␻–3 PUFA and some components of the Mediterranean diet which is.67–0.55 (0. An important point is that the protective effect of ␻–3 PUFA on SCD was greater in the groups of patients who complied more strictly with the Mediterranean diet (consistent with a modified diet of Crete).40–0.30 (0. 18.87) 0. the results obtained in this randomized trial are consistent with previous controlled trials [3. cardiovascular (CV) mortality and SCD.87–1. However.5 years. Treatment with ␻–3 PUFA significantly lowered the risk of the primary endpoint (the relative risk decreased by 15%). There was no difference across the treatment groups for nonfatal CV events.85 g daily). Thus. Secondary analyses included overall mortality. Regarding the other dietary fatty acids. animal experiments have clearly indicated that a diet rich in saturated fatty acids is associated with a high de Lorgeril/Salen 106 . If animal data. this has been done in randomized dietary trials and. the first thing to do in order to prevent SCD in humans would be to drastically reduce the intake of saturated fats. which would be an argument against such diets because lipoprotein oxidation is a major step in the inflammatory process that renders atherosclerotic lesions unstable and prone to rupture [29–31]. demonstrating a proarrhythmic effect of saturated fatty acids. which is not ethically acceptable. In addition. a mixed primary and secondary prevention trial. As a matter of fact. were also modified in these trials. as written above about the same trials [22. are confirmed in humans. because other potentially antiarrhythmic dietary factors. in particular linoleic acid. in the secondary prevention of CHD. in the Dayton study.and reperfusion-induced ventricular arrhythmia. besides the effect of saturated fatty acids on blood cholesterol levels. In fact. Roberts et al have reported that the percentage content of linoleic acid (the dominant ␻–6 PUFA in the diet) in adipose tissue (an indicator of long-term dietary intake) was inversely related to the risk of SCD. the exact mechanism(s) by which saturated fats increase CHD mortality remain unclear. the SCD endpoint is usually not analyzed in these studies. Large (but not all) epidemiological studies have shown consistent associations between the intake of saturated fatty acids and CHD mortality [26]. 23]. which was defined in that study as instantaneous death or death within 24 h of the onset of symptoms [27]. whereas PUFA of either the ␻–6 or ␻–3 family reduce that risk [4–6]. that ␻–3 PUFA were more effective on SCD than ␻–6 PUFA in most animal experiments [4–6]. the beneficial effect cannot be entirely attributed to the reduction of saturated fats. Also. in which the chief characteristic of the experimental diet was the substitution of ␻–6 PUFA for saturated fat. few data have been published so far in humans regarding the effect of ␻–6 PUFA on the risk of SCD. diets high in ␻–6 PUFA increase the linoleic acid content of lipoproteins and render them more susceptible to oxidation [28]. However. a clear demonstration of a causal relationship between dietary saturated fatty acids and SCD would require the organization of a randomized trial. In contrast with ␻–3 PUFA. Erosion and rupture of atherosclerotic lesions were shown to trigger CHD complications (see below.incidence of ischemia. 19]. Let it be mentioned. the rate of SCD decreased in the experimental groups [18. However. however. in the same way as for ␻–3 PUFA. the section on plaque inflammation and rupture) and myocardial ischemia and to considerably enhance the risk of SCD [32–35]. In addition. This is in line with most animal data and may suggest that patients at risk of SCD may benefit from increasing their dietary intake of ␻–6 PUFA. diets high in ␻–6 PUFA failed to improve the overall prognosis of the patients [36]. as expected. Thus. the number of SCD was apparently lower in the experimental group The Lyon Diet Heart Study 107 . including ␻–3 PUFA. the best fatty acid combination to prevent SCD (and the other complications of CHD) and. Thus. results of several trials suggest that it is important to reduce their intake in the secondary prevention of CHD. increasing consumption of ␻–6 PUFA should not be recommended in clinical practice for patients with established CHD. in other words. which could. despite the beneficial effect of ␻–6 PUFA on lipoprotein levels. Thus. would result from the adoption of a diet close to the Mediterranean diet pattern (consistent with a modified diet of Crete) [38. the prevention of CHD (including the prevention of ischemic recurrence after a prior AMI) has focused on the reduction of the traditional risk factors: smoking. linoleic acid (approximately 4–6% of the total energy intake). hypercholesterolemia. reduce SCD in the long term by reducing the development of atherosclerosis. although specific human data on the effect of saturated fatty acids on SCD are lacking. it has not been investigated in experimental models. in particular cancers. to cumulate antiarrhythmic. [41] found that cell membrane trans isomers of linoleic acid (but not of oleic acid) are associated with a large increase in the risk of primary cardiac arrest.than in the control group (18 vs. As a substitute for saturated fat. its effects on blood lipoprotein levels are similar to those of ␻–6 PUFA and it has the great advantage of protecting lipoproteins against oxidation [38]. which are found in the current average Western diet. As for the role of trans fatty acids on ventricular arrhythmias. in theory. it has become clear in secondary prevention that clinical efficiency de Lorgeril/Salen 108 . Priority was given to the prevention (or reversion) of vascular atherosclerotic stenosis. As discussed above. Despite a possible beneficial effect on the risk of SCD. 39]. antioxidant and hypolipidemic effects. Roberts et al. Thus. [40] reported no significant relationship between trans isomers of oleic and linoleic acids in adipose tissue and the risk of SCD whereas Lemaitre et al. HBP. 27) but the number of deaths from other causes. Diets including low intakes in saturated fatty acid (as well as trans isomers of linoleic acid) and ␻–6 PUFA (but enough to provide the essential linoleic acid) and high intakes in ␻–3 PUFA and oleic acid (Mediterranean diet pattern consistent with a modified diet of Crete) appear to be the best option to prevent both SCD and nonfatal AMI recurrence [19. 38]. the best choice is obviously to increase the intake of vegetable monounsaturated fat (oleic acid) in accordance with the Mediterranean diet pattern. If oleic acid has apparently no effect on the risk of SCD (at least by comparison with ␻–3 and ␻–6 PUFA). Finally. For several decades. thus offsetting the potential protective effect of ␻–6 PUFA on SCD and resulting in no effect at all on mortality [37]. it seems preferable not to increase the consumption of ␻–6 PUFA beyond the amounts required to prevent deficiencies in the essential ␻–6 fatty acid. 71). Such negative effects were not reported with ␻–3 PUFA. was higher in the experimental group (85 vs. lipid-rich and leukocyterich lesions and stable. is the erosion or rupture of an atherosclerotic lesion [32. This is thought to be a major step in the initiation and formation of arterial fibrostenotic lesions [29]. It is now accepted that one of the main mechanisms underlying the sudden onset of acute CHD syndromes. we proposed that inflammation and leukocytes play a role in the onset of acute CHD events [42]. and in particular plaque inflammation and rupture. which triggers thrombotic complications and considerably enhances the risk of malignant ventricular arrhythmias [34. however. This does not mean. From a clinical point of view. the most important question is: How and why does plaque rupture occur? Most investigators agree that atherosclerosis is a chronic low grade inflammation disease [29]. Recent progress in the understanding of the cellular and biochemical pathogenesis of atherosclerosis suggests that. which results in alterations of its antiatherosclerotic and antithrombotic properties. Steinberg et al. This has recently been confirmed [32–35]. and they contribute to myocardial damage during both ischemia and reperfusion [45]. hypertension. 35].needs to primarily prevent the fatal complications of CHD such as SCD. 44]. whatever the degree of stenosis and lumen obstruction. Indeed. it is critical to prevent the occurrence of new episodes of myocardial ischemia whose repetition in a recently injured heart can precipitate SCD or CHF. is totally different. In this regard. In 1987. hyperhomocysteinemia. acellular fibrotic lesions poor in lipids. Leukocytes have been also implicated in the occurrence of ventricular arrhythmias in clinical and experimental settings [43. as the propensity of these two types of lesion to rupture into the lumen of the artery. Issues such as local inflammation. in addition of the traditional risk factors of CHD. Pro-inflammatory factors (free radicals produced by cigarette smoking. plaque rupture and attendant acute CHD complications follow. diabetes. Clinical and pathological studies showed the importance of inflammatory cells and immune mediators in the occurrence of acute CHD events and prospective epidemiological studies showed a strong and consistent association between acute CHD and systemic inflammation markers [46]. 33]. [47] proposed in 1989 that oxidation of lipoproteins causes accelerated atherogenesis. there are other very important targets of therapy to prevent plaque inflammation and rupture. peroxidized lipids. that we should not try slowing down the atherosclerotic process. however. myocardial infarction and SCD. Myocardial ischemia is usually the consequence of coronary occlusion caused by plaque rupture and subsequent thrombotic obstruction of the artery. an essential distinction should be made between unstable. Elevated plasma levels of low-density lipoproteins The Lyon Diet Heart Study 109 . A major question is to know why there are macrophages and activated lymphocytes [29] in atherosclerotic lesions and how they get there. elevated and modified blood lipids) contribute to injure the vascular endothelium. including unstable angina. 31. as there is a positive correlation between plasma levels of LDL and markers of lipid peroxidation [52. In the accelerated form of CHD typical of post-transplantation patients. Pharmacological/quantitative (lowering of cholesterol) and nutritional/qualitative (high antioxidant intake) approaches of the prevention of CHD are not mutually exclusive but additive and complementary. higher levels of lipid peroxidation [49–51] and of oxidized LDL [52] were found as compared to the stable form of CHD in non-transplanted patients. and platelet reactivity is significantly higher in transplanted patients than in non-transplanted CHD patients [54]. An alternative way to reduce LDL concentrations is to replace saturated fats with polyunsaturated fats in the diet. diets high in polyunsaturated fatty acids increase the polyunsaturated fatty acid content of LDL particles and render them more susceptible to oxidation (which would argue against use of such diets. when LDL particles become trapped in the artery wall. Two processes have been proposed. oxidized LDL circulates in the plasma for a period sufficiently long to enter and accumulate in the arterial intima. LDL levels can be lowered by drugs or by reducing saturated fats in the diet. and reduction of blood LDL levels (for instance by drugs) results in less CHD. In that context. Elevated plasma levels of oxidized LDL are associated with CHD. such diets failed to improve the prognosis of the patients [for a review. Reactive oxygen metabolites and oxidants influence thrombus formation [see 53 for review]. Reduction of the oxidative susceptibility of LDL was reported when replacing dietary fat with carbohydrates. leading to the formation of typical atherosclerotic foam cells. suggesting that the entry of oxidized lipoproteins within the intima may be another mechanism of lesion inflammation. 48]. the traditional Mediterranean diet. First. 55] and low absolute LDL level results in reduced amounts of LDL available for oxidative modification. Oxidized LDL is chemotactic for other immune and inflammatory cells and up-regulates the expression of monocyte and endothelial cell genes involved in the inflammatory reaction [29. they undergo progressive oxidation and are internalized by macrophages. see 36]. Second. and the plasma level of malondialdehyde-modified LDL is higher in patients with unstable CHD syndromes (usually associated with plaque rupture) than in patients with clinically stable CHD [30]. with low saturated de Lorgeril/Salen 110 . The concept that LDL oxidation is a key characteristic of unstable lesions is supported by many reports [29]. the mechanism(s) behind the effect of high LDL levels is not fully understood. However. 48]. inflammation and further LDL oxidation. As a matter of fact. However. in the secondary prevention of CHD. The inflammatory response itself can have a profound effect on LDL [29]. in particular in patients without hyperlipidemia [30. The oxidized LDL theory is not inconsistent with the well-established lipid-lowering treatment of CHD.(LDL) are a major factor of CHD. creating a vicious circle of LDL oxidation. 23:277–285. it is not surprising to observe that this diet was associated with lower rate of new episodes of CHF in the Lyon Diet Heart Study. Salen P. it is noteworthy that moderate alcohol consumption. a well known cardioprotective factor. Eur Heart J 2002. Finally. This is consistent with what we know about the Mediterranean diet pattern (consistent with a modified diet of Crete) [38. 61]. As both dietary ␻–3 fatty acids and moderate alcohol consumption are major characteristics of the Mediterranean diet. et al: Effects of changes in fat. 63]. oleic acid-rich diets decrease the pro-inflammatory properties of oxidized LDL. or a diet combining reduced fat.2:757–761.fat and polyunsaturated fat intakes. 66] contribute to pacify and stabilize the dangerous lesions. For instance.98:2234–2251. a low intake of omega-6 fatty acids and a high intake of omega–3 fatty acids would logically produce a highly cardioprotective effect. was recently shown to be associated with low blood levels of systemic markers of inflammation [67]. Thus. ␣-tocopherol or vitamin C. In that regard. Paillard F: Dietary prevention of sudden cardiac death. The Lyon Diet Heart Study 111 . any dietary pattern combining a high intake of natural antioxidants. 57] and results in leukocyte inhibition [58]. Circulation 1998. This implies a direct influence of dietary fatty acids on plaque formation and the process of plaque rupture. Wellens HJ: Sudden cardiac death. fish. a high intake of oleic acid. Thus. appears to be the best option. suggesting a new protective mechanism to explain the inverse relationship between alcohol and CHD rate. De Lorgeril M. Defaye P. Lancet 1989. Mabo P. 39] and with the results of the Lyon Diet Heart Study. Various components of the Mediterranean diet may also affect LDL oxidation. Fehily AM. significant correlation was found between certain dietary fatty acids and the fatty acid composition of human atherosclerotic plaques [62. low-fat dairy products and a high intake of fruits and vegetables were shown to favorably affect either LDL oxidation itself or/and the cellular consequences of LDL oxidation [60. Gilbert JF. It is conceivable that fatty acids that stimulate oxidation of LDL (␻–6 fatty acids) induce plaque rupture whereas those that inhibit LDL oxidation (oleic acid). References 1 2 3 Zipes DP. which suggests that dietary fatty acids are rapidly incorporated into the plaques. a low intake of saturated fatty acids. Constituents of olive oil other than oleic acid may also inhibit LDL oxidation [59]. inhibit leukocyte function (␻–3 fatty acids) [64] or prevent ‘endothelial activation’ and the expression of proinflammatory proteins (oleic acid and ␻–3 fatty acids) [65. 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King IB. reperfusion flow. et al: Oxidized LDL and malondialdehyde-modified LDL in patients with acute coronary syndromes and stable coronary artery disease. reflow ventricular fibrillation. Lancet 1995. World Rev Nutr Diet. Hodis HN. Salen P: Modified Mediterranean diet in the prevention of coronary heart disease and cancer.34(suppl II):1–63. Am J Clin Nutr 1996.316:1161. Latour JG: Leukocytes.63:698–703. Avogaro P. Palacios JF.18:100–107. Davies MJ. World Rev Nutr Diet. Steinberg D. Van der Wal AC. Circulation 1994.68:813–817. Vanhaecke J: Correlation between oxidized low density lipoproteins and coronary artery disease in heart transplant patients. Tomiyashu U: A controlled trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. 2000. Am Heart J 1992. Dormandy JA: Leukocytes and the risk of ischemic heart diseases. Khoo JC. Juul K. Van Cleemput J. Holvoet P. Sidossis LS: What is so special about the traditional diet of Greece. et al: Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Simopoulos AP.93:1354–1363. Vanhaecke J. Janssens S. Basel. Parthasarathy S. Eur Heart J 1997. Basel. Perez G. Falk E. et al: Influence of leukopenia on collateral flow.340:115–126. Suzuki K. et al: Oxidation of plasma low-density lipoprotein accelerates its accumulation in the arterial wall in vivo. Nielsen LB. vol 87. Am Heart J 1989. Hoshida S. J Clin Invest 1995. Lemaitre RN. de Lorgeril M. Holvoet P.35:669–677. Pearce ML. Witztum JL: Beyond cholesterol: modifications of low-density lipoproteins that increase its atherogenicity. The Lyon Diet Heart Study 113 . et al: Lipid peroxides and antioxidant defenses in accelerated transplantation-associated arteriosclerosis. Richard MJ. Matrai A. Circulation 1994. Arnaud J. Stassen JM. de Lorgeril M. A frequent cause of coronary thrombosis in sudden coronary death. Zhao Z. et al: Biochemical and cytotoxic characteristics of an in vivo circulating oxidized low density lipoprotein.117: 523–532. de Lorgeril M.90:775–778. Viret R. Moreno PR. et al: The diet heart hypothesis in secondary prevention of coronary heart disease. Circulation 2002. et al: Polymorphonuclear leukocyte activity and ventricular arrhythmia in acute myocardial infarction.62:868–872. Carew TE. Kuzuya T. et al: Trans isomers of oleic and linoleic acids in adipose tissue and sudden cardiac death. Raghunathan TE. thrombosis and unstable angina. Collen D.105:697–701. pp 1–23. Am J Cardiol 1991. N Engl J Med 1999.28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Louheranta AM. Monjaud I. Kramsch DM. Farb A. Wood DA. pp 24–42.89:36–44. Karger. Van der los DS. Tang AL. de Lorgeril M. Hashimoto S.317:1361–1365. Am J Cardiol 1988. Munkholm K.320: 915–924. de Lorgeril M. JAMA 1987.125:974–980. Dixon WJ. Roberts TL.98: 1487–1494. Ernst E. Circulation 1996. Porkkala-Sarataho EK. Chancerelle Y. et al: Malondialdehyde-modified low density lipoproteins in patients with atherosclerotic disease. et al: Coronary plaque erosion without rupture into a lipid core. Commerford PJ. Lavallée M. and infarct size in dogs. Karger. N Engl J Med 1984. Hammerschmidt DE. N Engl J Med 1987. de Lorgeril M. vol 87. The scientific evidence. Bagge U. Becker EC. 2000. Nyyssönen MK. Ross R: Atherosclerosis: An inflammatory disease. Circulation 1998. Thomas A: Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. Circulation 1996. Kruskal JB.18:14–18. Dayton S. Basmadjian A. J Lipid Res 1994.345:278–282. Franks JJ. Riemersma RA.257:2318–2324. N Engl J Med 1989. Salen P. Implications for plaque rupture. et al: Increased lipid peroxidation in cyclosporin-treated heart transplant recipients. et al: Cell membrane trans-fatty acids and the risk of primary cardiac arrest. Circulation 1969. et al: Linoleic acid intake and susceptibility of very-low-density and low-density lipoproteins to oxidation in men.95:2611–2619. N Engl J Med 1987.310:1137–1140. et al: Macrophage infiltration in acute coronary syndromes. Arterioscler Thromb Vasc Biol 1998. Kirsch RE: Fibrin and fibrinogen-related antigens in patients with stable and unstable coronary artery disease.94:1698–1704. Domaine de la Merci La Tronche. Oliver MF: Dietary polyunsaturated fatty acids and composition of human aortic plaques.14:1829–1836. Arterioscler Thromb 1991. Crook D.11:903–911. Mata P. Visioli F. Cybulsky MI. Lee TH. Froehlich M. Felton CV. Appel LJ. Curr Opin Lipidol 1998. Pagnan A. et al: Effect of dietary fat saturation on LDL and monocyte adhesion to human endothelial cells in vitro. Williams JD. Miller III ER. Cardiovasc Res 1997. Brenner H. LDL oxidation and coronary artery disease. Bonamone A. Koenig W: Effect of alcohol consumption on systemic markers of inflammation. Montedoro G. Grenoble. de Lorgeril M.9:301–307. Arterioscl Thromb 1992. Connor WE. Davies MJ.117:25–32.357:763–767. et al: Effect of dietary monounsaturated and polyunsaturated fatty acids on the susceptibility of plasma low density lipoproteins to oxidative modification. et al: Platelet function and composition in heart transplant recipients compared with nontransplanted coronary patients. Alonso R. Clinton SK.16:1347–1355. ascorbate and beta-carotene on low density lipoprotein oxidation. et al: Oleic acid inhibits endothelial cell activation. Imhof A. Risby TH: Effect of dietary patterns on measures of lipid peroxidation. ⫹33 476 63 74 71. Zock PL. Results of a randomized clinical trial. Bonfrate C. Dr. Circulation 1993. FR–38706 (France) Tel.fr de Lorgeril/Salen 114 . Porter JM: Dietary eicosapentanoic acid and docosahexaenoic acid from fish oil: Their incorporation into advanced human atherosclerotic plaques.delorgeril@ujf-grenoble. Fax ⫹33 476 63 71 52.312:1217–1224. Arterioscler Thromb Vasc Biol 1996. Bellomo G. M. Rapp JH.344:1195–1196.98:2390–2395.53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 Ambrosio G. Tsimikas S. Boeing H. Pepys MB. Lin DS. Gimbrone MA. Jialial I. Vieillissement et Maladies Cardiovasculaires (NVMCV) UFR de Médecine et Pharmacie. N Engl J Med 1985. Boissonnat P. Lopez-Farre A. Golino P: Reactive oxygen metabolites and arterial thrombosis.12:222–230. Libby P: The omega–3 fatty acid docosahexaenoate reduces cytokine-induced expression of proatherogenic and proinflammatory proteins in human endothelial cells. Biffanti S. E-Mail michel. Reaven PD: The role of dietary fatty acids in lipoprotein oxidation and atherosclerosis. Lancet 1994.34:445–452. Massaro M. Grundy SM: Effect of combined supplementation with alpha-tocopherol. et al: Effect of dietary enrichment with eisosapentanoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophile function. de Lorgeril Laboratoire Nutrition. Dureau G.19:220–228. Arterioscler Thromb Vasc Biol 1994. Arterioscler Thromb Vasc Biol 1999. Tritto I. Am J Clin Nutr 1998. Katan MB: Diet. Lancet 2001.88:2780–2786. Arterioscler Thromb 1992. et al: Low density lipoprotein oxidation is inhibited in vitro by olive oil constituents.12:529–533. De Caterina R. Hoover RL. Carluccio MA. Atherosclerosis 1995. Circulation 1998.68:759–760. wheat. tomatoes. . Rome. Adalberta Albertia. Because both due to shortage of funds and similarity with the two rural areas of Greece. Aging. is perched on a spot of the Poro Mountain overlooking the Tyrrhenian Sea about 60 km north of Reggio Calabria near the toe of Italy. and Preitoni. a small town in the Calabria Region in Southern Italy. There was no manufacturing industry. The main farm products were olives. World Rev Nutr Diet. transportation was mainly by mule. and hypertension. In the hamlet of Nicotera Marina few families were engaged in fishing. Similar findings were observed in the cohort of men from Corfu (Greece) examined in 1960. The population was relatively poor in comparison to the two rural areas of Italy in the SCS. figs. The total population of the entire survey area was 9. oranges. overweight and obesity were uncommon. Karger. this study was not followed longitudinally. was the third Italian rural area of the Seven Countries Study (SCS) examined in the fall of 1957 as a pilot study. and for local use. but there was a migration of persons under the age of 40. vol 95. Both men and women were engaged in moderate physical activity and only men in some cases in rather heavy physical work. Italy Nicotera. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. Besides the main center of Nicotera and the hamlet of Nicotera Marina there were three more detached hamlets: Comerconi. University of Rome-Tor Vergata. Rome-Tor Vergata and bDepartment of Statistical Sciences.043 inhabitants at the time of the survey. Basel. Perugia. About 80% of the people lived in the centers and went out daily to work in their small fields often as far as several kilometers away. Daniela Fruttinib a Human Nutrition Unit. bergamot for the perfume trade. selected for the quite high olive oil and legumes consumption.Simopoulos AP (ed): Nutrition and Fitness: Mental Health. Badia. pp 115–121 The Nicotera Diet: The Reference Italian Mediterranean Diet Flaminio Fidanzaa. Because of its geography (altitude 0–641 m) and road conditions. grapes. 2005. and WBC Section. pulses. a little meat and poultry. The prevalence of myocardial infarction in men aged 45–64 years was very low (4 cases out of 598 examined in 1957). University of Perugia. CNR Research Center. Nicotera. For the other components of the family the differences in food consumption at meal was quantitative more than qualitative. Meal Patterns and Way of Cooking in Nicotera We report here only the meal patterns of 35 Nicotera heads of families. In the second survey in May–June. Some difficulties occurred with the Nicotera family dietary surveys. salesmen 11. Because of no significant seasonal difference in energy nutrient. this procedure was followed in a sample of 32 families. there are marked differences related to home food production according to the season. 2]. six substitute families were then statistically selected from the roster. the meal patterns of 35 heads of families examined in different seasons. In this way one dietitian could at the same time carry out the survey on two families. cheese and milk were consumed sparingly. craftsmen 26. clerks 17. The final result was that 17 families were surveyed for all three seasons.The Dietary Habits of Subjects from Nicotera The weighed record method for 7 days in three different seasons of 1960 was used for the dietary survey of the Nicotera families. Cereals were well represented and also were vegetables. construction workers 6 and mule drivers 3. so the total number of subjects had to be reduced from 32 to 24. From the roster of all men examined in 1957. clerks and salesmen (n ⫽ 19) and one for farmers and construction workers (n ⫽ 16). with a total of 35 families. six of the families refused to continue to cooperate. sixteen names were chosen at random. The percentage distribution occupation of 35 Nicotera heads of families is as follow: farmers 37. eggs. Meat. Then. because of the differences in food selection. Obviously. legumes and fish. Wine. The procedure of the dietary survey with this method is fully described in previous papers [1. The prevalent foods consumed at each of three main meals are presented in a decreasing order of three season mean frequency. Table 1 shows the three-season mean of food intake expressed in g/day of 328 components of 35 Nicotera families examined in 1960. Virgin olive oil was the most common edible fat. Because this type of dietary survey is time consuming and very expensive. are subdivided in two homogeneous groups: one for craftsmen. For the first survey in January one dietitian became ill and it was impossible to find a replacement. Then for each head of family so selected. Fidanza/Alberti/Fruttini 116 . 11 families for two seasons and seven families for one season. mostly red wine. was used moderately by men. all the families were considered together [3]. the family living closest to him was picked. ml Sugar products Wine. Home-produced goat’s milk cheese or salami were consumed occasionally. or vegetable soup were preferred. fruit and wine was similar to that at lunch. soup with vegetables or legumes and pasta. For lunch. the selection of side dishes was similar to that of the craftsmen group. At breakfast. Fish or meat was followed by side dishes as at lunch.Table 1. coffee. The second course was composed of fish or meat and as side dishes cooked or green vegetables and cured olives. Cheese was preferred to salami occasionally. bread. The consumption of bread. for the first course pasta with tomato sauce. The consumption of bread was similar to that of the craftsmen group. Homemade bread. the vegetable or legume and pasta soup was always The Nicotera Diet 117 . or more often roasted barley hot drink and milk were consumed. Mean daily intake of foods (g) of subjects from Nicotera (Italy) in 1960: mean of three seasons Age group. At dinner. At breakfast. the vegetables or legumes and pasta soup was preferred to pasta with tomato sauce. coffee or more often roasted barley hot drink with less bread and much less milk than the other group was consumed. garden fruit and homemade wine were consumed in reasonable amounts. ml Males Females 13–19 20–39 40–59 ⬎60 13–19 20–39 40–59 ⬎60 35 531 58 68 209 75 26 37 3 36 11 13 48 28 93 43 519 57 117 280 96 37 48 5 62 18 20 11 22 291 64 455 43 73 231 104 44 40 3 50 22 17 38 25 288 18 444 64 134 282 77 35 50 5 30 13 36 26 31 234 45 319 32 60 175 79 20 28 2 25 12 9 15 20 35 50 351 33 73 212 98 30 34 5 37 13 15 41 20 45 63 346 39 68 200 60 22 32 3 24 9 9 35 19 59 10 241 13 44 136 96 43 26 1 35 7 16 24 14 31 The craftsmen group meal pattern was the following. Both cheese and salami were consumed occasionally. years n Cereals Legumes Potatoes Vegetables Fruit Fish Oils Fats Meat Eggs Cheese Milk. The farmer group meal pattern was the following. At lunch. As second course. The dinner was composed of either olive oil or tomato sauce pasta and sometimes vegetable soup. fish was preferred to meat. while the intakes of fruit and wine were lower. garlic. wine. Cured olives were regularly consumed while cheese was preferred to salami as an occasional dish. parsley. cereals. Few people drank some milk in the evening.The MAI is simply obtained by dividing the sum of total energy percentage from those food groups mostly consumed in a healthy Mediterranean Diet (bread.preferred to pasta with tomato sauce. For vegetable soup the variety of vegetables was great so there was a high probability that the recipes included either many different nutrients or an elevated concentration of certain nutrients. The most common fish consumed was: stock fish (air-dried cod). they consumed as snacks bread with fruit or raw vegetables from their garden or farm. a synergy among the properties of the same nutrients was obtained. fish. animal fat and margarines. cakes/pies/cookies. pork and kid. parsley. Bread was made with high extraction flour from homeproduced wheat. red pepper). dried salted cod and blue fish. nuts. rosemary. fresh fruit. The fish recipes included olive oil. the consumption was similar to that at lunch. cheese. legumes. It was roasted over charcoal in special iron containers with continuous rotation until the barley became dark brown. sweet beverages. different nutritional properties of ingredients were combined. eggs. In the second case. When farmers went to their farms far away. meat. For example. For bread. vegetable oils – especially virgin olive oil) by the sum of total energy percentage from those food groups consumed less in a healthy Mediterranean Diet (milk. The roasted barley was grounded in a coffee-mill and then boiled in water and passed through a strainer. cured olives. and cooked vegetables as side dishes were preferred to raw ones. Also. In the first case. the sauce for pasta was prepared with olive oil. parsley. Regarding meat beef. sugar). garlic. milled using stone mills. tomatoes. and red pepper. cured olives. vegetables. onion. potatoes. basil. they were consumed in decreasing order using the same ingredients as in the fish recipes. fish was preferred to meat as a second course. green leafy herbs. vegetables. onions. wild herbs all from the garden. spices (oregano. The majority of recipes were prepared using a great variety of ingredients with important nutritional characteristics: various vegetables from the home garden. and little meat or fish. The home preparation of some foods is interesting as is the way of cooking of some dishes. The Nicotera Diet as the Reference Italian Mediterranean Diet To objectively assess how close a diet is to its Reference Mediterranean Diet we have set up the Mediterranean Adequacy Index (MAI). tomatoes. basil. fruit and wine. Fidanza/Alberti/Fruttini 118 . red pepper. The barley hot drink was prepared at home from barley produced on the farm. we have also computed the MAI of diets consumed by random samples of men from 16 SCS cohorts examined around 1960.0 6.9 in 1965 to 2. 2003.72) with 25-year death rate from coronary heart disease [5].8 8.2 MJ because of differences in energy density of some foods.3 7. The MAI is negatively correlated (R ⫽ ⫺0.In Crevalcore (Northern Italy) the MAI value.2 6. the MAI values were lower than those of the Nicotera subject diet and deteriorated over time. Table 2 shows the median values of MAI computed from energy percentage of food groups consumed by Nicotera subjects examined for three seasons in 1960. changed from 2. in general. thus indicating a progressive abandoning of the traditional Mediterranean diet particularly in Montegiorgio.2 in 1991.9. The Healthy Italian Mediterranean Diet Temple Food Guide On the occasion of the International Conference on European Mediterranean Diets held in Rome at the Medical School at the University of Rome Tor Vergata on January 20.The mean value of MAI can be. In both areas. The corresponding values in Montegiorgio (Central Italy) were 5. higher because of non normal distribution of dietary data. As an example. we presented the Healthy Italian Mediterranean Diet Temple The Nicotera Diet 119 . computed from energy percentage of food groups. Median values of the Mediterranean Adequacy Index computed from energy percentage of food groups consumed by Nicotera subjects examined for three seasons in 1960 Age class 13–19 years 20–39 years 40–59 years ⬎60 years Males Females n subjects MAI n subjects MAI 35 43 64 18 8.5 Each Mediterranean country should have its own Reference Mediterranean Diet and accordingly for Italy we have proposed the diet of Nicotera subjects examined in 1960 [4].9 45 50 63 10 6.Table 2.6 5. we report here the MAI values of diets consumed by the two rural SCS Italian cohorts followed longitudinally from 1965 to 1991.6 and 3. Also different may be the mean values of MAI computed from food groups values expressed as g/day or g/4.5 6. Recently. In the three wide steps at the base of the Temple there are written in upward order the following sentences: most healthy lifestyle. potatoes.000 in 25 years was in the same range of cohorts from Japan. The development of the Greek-Roman Temple was based on the Nicotera diet of heads of families examined in 1960. In Corfu as in Nicotera the prevalence of myocardial infarction in 1960 was low (3 cases out of 529 men) as also hypertension. for this reason it was chosen as the Reference Italian Mediterranean Diet. which was set up as the Reference Italian Mediterranean Diet for adults. virgin olive oil and wine. cereals and in smaller characters. On the tympanum the word ‘Moderation’ which is a basic characteristic of a healthy Mediterranean diet dominates. eggs. sugar) are written. in general. life habits and cultural traditions can be adapted to other populations.Food Guide (HIMDTFG). energy intake ⫽ energy expenditure. On the big left lateral column it is written: brown bread. overweight and obesity. On the Temple. after appropriate modifications related to food availability. to clearly provide the message of the healthy Mediterranean diet essence. nuts. cakes.7. Then. Very high are the intakes of antioxidant vitamins and food components. The idea of the Temple came from the Simopoulos paper on ‘The Mediterranean Food Guide’ [6]. and folate. as we have already said. All nutrients meet. The HIMDFG. In the two smaller central columns the words legumes and fish are written. meats. The MAI of men examined in Nicotera computed in the same way is 8. Consequently. Crete. All the above food groups are prevalently consumed in a healthy Mediterranean diet. hypertension and obesity observed in Nicotera men can be considered the biological answer to their diet. with the following MAI values: Fidanza/Alberti/Fruttini 120 .2. the MAI of the Nicotera diet can be considered an advisable value. Conclusions The Nicotera diet of heads of families is a well balanced diet. The ratios of various classes of fatty acids are more than satisfactory. we preferred to indicate food groups using words instead of misleading figures or drawings as in the overly used and misleading Pyramid. fats. The very low prevalence of myocardial infarction. the words of food groups less prevalently consumed in a healthy Mediterranean diet (milk and dairy products.The MAI value of the Corfu diet computed from food groups expressed as g/day is 10. fresh fruit and in smaller characters. the national reference values. and Dalmatia. In Corfu the coronary heart disease death rate per 1. On the metopes in a progressive order. the Nicotera diet is practically similar to the diet of SCS cohort of men examined in Corfu (Greece) in 1960. While on the big right column it is written: vegetables. Chiuchiù MP. Flaminio Fidanza Via S. Alberti-Fidanza A. 11.53:854–860. Fidanza F. Ferro-Luzzi G.25:502–509. sources of variation and other data from nine surveys in Italy. Simopoulos AP: The Mediterranean Food Guide. Eur J Clin Nutr 1999. Nutr Today 1995. Menotti A: Mediterranean Adequacy Index: Correlation with 25-year mortality from coronary heart disease in the Seven Countries Study. In the above populations the sociocultural meanings related to foods have changed considerably over the past generation. 5.14:254–258. Fidanza F. Verducci G. Fidanza-Alberti A. Quaderni Nutr 1971.4 (Crete cohort). 8. 3. ⫹39 075 31363. Voeding 1967.28: 244–252. Voeding 1964. Alberti A. Fidanza F.3 (Ushibuka-Japan cohort).4. Lanti M. but they should be set into the life style context of those populations at that time. Fidanza-Alberti A: Rilevamento dei consumi alimentari di alcune famiglie in tre zone agricole d’Italia.2 (Dalmatia cohort). Nutr Metab Cardiovas 2004. the Mediterranean diets followed by the SCS cohorts and retained healthy from epidemiological confirmation have not to be considered as food suppliers only. However. appropriate adaptations taking into account these new socioeconomic realities are needed. Accordingly. Trend of food and nutrient intake from 1960 to 1991. Fax ⫹39 075 5839294 E-Mail fidanzaflaminio@libero. Prof.6 (Tanushimaru-Japan cohort). References 1 2 3 4 5 6 Fidanza F. Proja M: Dietary surveys in connection with the epidemiology of heart disease: Results in Italy.it The Nicotera Diet 121 . Fidanza-Alberti A: Dietary surveys in connection with the epidemiology of heart disease: Reliability.30:54–61.31:139–188. Vetturino 4/B I–06126 Perugia (Italy) Tel. Fidanza F. Fruttini D: Dietary studies on two rural Italian population groups of the Seven Countries Study. whereas heavy drinkers have an increased risk of infarction and stroke. pp 122–139 Wine and Health: Evidence and Mechanisms Inés Urquiaga. Renaud and Ruf [10] show that the correlation .Simopoulos AP (ed): Nutrition and Fitness: Mental Health. World Rev Nutr Diet. The observations lead to hypotheses which necessarily have to be confronted in the laboratory. On cardiovascular disease a reduction which might reach 60% in morbidity and mortality has been reported [3–8]. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. and a longer life [1. Chile Epidemiological observations provide us valuable insights in the role played by the environment on human health. male or female. is associated with decreased risk in all-cause mortality. It is a characteristic component of the Mediterranean diet and might account for the lower incidence of coronary heart disease among Mediterranean populations [9–10]. especially ischemic heart disease death as well as other chronic diseases. The studies and discussions held on the so called ‘French Paradox’ give wine a special position. The epidemiological work is not finished and much remains to be evaluated experimentally. 2]. Aging. The shape of the correlation is generally described as a J-shaped curve in which moderate drinkers (two drinks per day) of any kind of alcohol have a decreased risk of coronary heart disease relative to non-drinkers. Basel. This sequence is apparent in the development of our present ideas related to wine and health. show a 30–40% decrease in risk of coronary heart disease mortality. Moderate drinkers. Santiago. Federico Leighton Molecular Nutrition Laboratory. Epidemiological Evidence Epidemiological studies show that moderate alcohol consumption. 2005. particularly wine. Catholic University of Chile. vol 95. Faculty of Biological Sciences. and 10–20% decrease in mortality from all causes. Karger. 14].51–1. The specificity of wine for lowering the risk of all-cause mortality and cancer has been confirmed by Gronbaek and collaborators [15].234 women. was associated with a decrease in cardiovascular. some studies showed a difference according to the type of alcohol. also rich in antioxidants.78. This work is in contrast to others in which not only wine. p ⬍ 0.001) than for other components like vegetables or vegetable fats. A more recent work by Renaud and collaborators on 34. In this study.among coronary deaths and various foods. In addition. the risk was lower in wine drinkers (odds ratio (OD) 0. Gronbaek and collaborators have already shown that wine drinking does not increase the risk of upper digestive tract cancer as compared to beer or spirits [16]. in 21 countries. In the Canadian Study of Health and Aging.84. 30–79 years old. but also other alcoholic beverages are considered to be responsible for the beneficial effects [13]. attributed to cardiovascular disease and cancer [6. 18]. but not beer or spirits. cerebrovascular. However. 3 to 5 drinks per day led to reduction in cardiovascular mortality by 47% in the wine drinkers.52–1. 95% CI 0. 95% confidence interval (CI) 0. As for cancer. and all causes mortality [12].19). They also found that it was only wine but not spirits or beer that reduced cancer mortality by up to 20% (3 glasses of wine/day). and also mortality by other causes was 50% lower.001). led to the conclusion that moderate consumers (2–5 glasses per day) have a 24–31% reduction in all-cause mortality. The same general conclusions were reached for alcohol. Gronbaek and collaborators in the Copenhagen City Heart Study on 6. in a study which involved countries with similar economic development [11]. the follow up of 4. found that wine. the alcohol consumption recorded in 1976 in a cohort initially designed to study cardiovascular Wine and Health 123 . respectively.014 middle-aged men from eastern France. at the same time they found a positive correlation with milk-fat products (0. 77% of them wine drinkers.051 men and 7. Moderate wine or alcohol consumption is also beneficial for conditions associated with aging. p ⬍ 0. Thus.41 and OR 0.49. wine would exert a more marked effect than that of fruits and vegetables.87. and a better cognitive performance and lower risk of dementia have been described [17. It was only in wine drinkers that the all-cause mortality was lowered by more than 20% for an intake of up to 3 drinks per day. the subsequent question was to evaluate on what types of cancer wine may have protective effects. is stronger for wine (⫺0.088 persons for 5 years showed a 31% reduction in the risk of developing dementia in alcohol drinkers compared to non drinkers [19].66.28–0.88) than in beer or spirit drinkers (OR 0. most particularly wine. The results also showed that the protective effect of a moderate intake of wine on all-cause mortality is observed at all levels of blood pressure and serum cholesterol. In another cohort study (the Copenhagen City Heart Study). 95% CI 0. In Bordeaux (France). and other alcoholic beverages.92 in daily drinkers).03).60 in occasional drinkers. education. Type II diabetes mellitus (NIDDM) is another condition that correlates with aging and in which oxidative stress plays a pathogenic role. baseline cognitive performances and other possible confounders.98–4. 95% CI 1.diseases has been linked to the risk of getting dementia in the period 1990–1994 [20]. This study suggests that a person who prefers beer is more likely to become a heavy or an Urquiaga/Leighton 124 .11). and total alcohol was not associated with a lower risk of AD.55. beer.34–0. a population-based prospective study found that subjects drinking 3–4 standard glasses of wine per day (⬎250 and up to 500 ml).01) and 0.81. Moderate alcohol consumers have a decreased risk of diabetes [24].78 in weekly drinkers and OR 1. the ORs were.74–3. In the 922 mild drinkers (⬍1–2 glasses per day) there was a negative association only with AD.15–2. categorized as moderate drinkers. after adjustment (OR 0. education.82).25 for Alzheimer’s disease (AD)(p ⬍ 0.05).28.01) and 0. OR 2.12. 95% CI 0.05).73. the crude OR was 0.57.33. 95% CI 0. Compared to non drinkers.55.15. 95% CI 0.89). 95% CI 0.43–2. 27]. 95% CI 0. an increased risk was observed for beer (OR 2.43. only intake of up to three daily servings of wine was associated with a lower risk of AD (OD 0. The subjects were recruited between 1991 and 1996 and followed annually. respectively. occupation. However. Moderate wine consumption correlates with decreased risk of macular degeneration. psychological or sociofamilial factors [21–22].28 (p ⬍ 0. as compared with the non-drinkers. in weekly drinkers (OR 0.19 (p ⬍ 0. Moderate wine drinkers appear to be at lower risk of becoming heavy and excessive drinkers as well as developing alcoholic cirrhosis [26. but nonsignificant in daily drinkers (OR 0. The inverse relationship between moderate wine drinking and incident dementia was explained neither by known predictors of dementia nor by medical. sex.69 in weekly drinkers and OR 1.86).13–0. 95% CI 0.75–3. After adjusting for age. apolipoprotein E (APOE)-epsilon 4 status. sex.57 in occasional drinkers. 260 individuals developed dementia (199 AD.23–0. the risk of developing dementia was significantly lower among occasional wine drinkers (OR 0. 95% CI 0.99 in daily drinkers) or for spirits (OR 0.42–1. A recent cohort of elderly persons from New York City included 980 community-dwelling individuals aged 65 and older without dementia at baseline and with data on alcohol intake. p ⬍ 0. Intake of liquor. After 4 years of follow-up. 0.18 for the incidence of dementia (p ⬍ 0. After adjusting for age. 95% CI 0. 61 dementia associated with stroke).13–4. 95% CI 0. an agerelated disorder [25]. OR 1. Stratified analyses by the APOE-epsilon 4 allele revealed that the association between wine consumption and lower risk of AD was confined to individuals without the APOE-epsilon 4 allele [23].65. Wine and Health 125 . 1. moderate drinkers who included wine in their weekly alcohol intake had significantly lower risks of becoming heavy or excessive drinkers as compared to those who did not drink any wine.HDL Alcohol Wine (nitric oxide) eNOS Fibrinogen Factor VII (nitric oxide) eNOS Thrombosis Platelet aggregation LDL oxidation Phenolics Endothelial function (nitric oxide) eNOS DNA damage Plasma lipid peroxides Fig. The risk of kidney stones also decreases in moderate wine consumers. excessive drinker than a person who prefers wine. Favorable changes in CV risk factors shown in moderate wine drinkers. it does not favor an increase in the waist-to-hip ratio. Wine has been described as a healthy beverage for centuries. Further they found that the risk of developing cirrhosis in wine drinkers (more than 30% wine in their total alcohol intake) was less than 50% of the risk in non-wine drinkers for any given level of total alcohol intake. increase the risk [33]. in studies that simultaneously show that fruit juices. A particularly intriguing property of wine is that in contrast to beer and hard liquor. This has been observed for many bacteria and there is an interesting report on the capacity of wine to control oyster-borne hepatitis A [31]. Women who included beer in their alcohol intake showed increased risk of heavy and excessive drinking compared to non-beer drinking women. Among men. There is a large variety of other positive phenomena associated with moderate wine consumption. particularly grapefruit juice. a parameter strongly associated with cardiovascular risk [32]. while beer and spirits drinking did not modify the relation between total alcohol intake and risk of developing cirrhosis. Other studies have reported relations between beer drinking and high-risk behaviors such as frequent heavy drinking and other alcohol-related problems. a property mainly associated with its capacity of killing or stopping the growth of microorganisms. while wine drinking seems to be considered ‘the beverage of moderation’ [28–30]. and do not show increased frequency in light-to-moderate drinkers. On the whole. For lung cancer. however. Further research is required to examine the hypothesis that genetically predisposed people might become addict to alcohol through moderate consumption [38]. to cancer. moderate drinkers are not at increased risk of any type of cancer [37]. esophagus. Yet. and sometimes stomach and liver. to birth defects. in three prospective Danish studies. In an editorial commentary. There are a number of cancers that are referred to as alcohol-related. it was found that a high consumption of beer and spirits is associated to an increased risk of lung cancer. a doubling in the frequency of women drinking two to three glasses per day has been found [36]. Gronbaek and collaborators in a population cohort study observed the association between alcohol intake and cancer of the upper digestive tract [16]. Indeed. Urquiaga/Leighton 126 .Deleterious Effects of Alcohol Consumption When dealing with the negative effects of alcoholic beverage consumption it is necessary to establish very clearly the levels of consumption that correspond to a statement such as ‘alcohol consumption leads to cardiovascular morbidity. generally. this effect has to be confronted with the higher frequency of obstructive events that do benefit from moderate consumption [1]. moderate wine consumption should be considered as safe. the possible role of nitrosamines is emphasized. and to migraine’. cancers of the mouth. whereas moderate intake of beer or spirits increases the risk considerably. with the sole exception of activities requiring a maximum degree of alertness. Their conclusion was that a moderate intake of wine probably does not increase the risk. to cirrhosis. a significant correlation for women drinking 3 or more glasses per day has been described [4] and in Mediterranean populations. with the evidence available. but often forgotten by those who stress cirrhosis as the consequence of excessive drinking. pharynx. with a much lower breast cancer incidence than in USA. larynx. whereas wine intake apparently protects [34]. they correlate with heavy smoking and heavy drinking. There have been discussions on the meaning of the increased cardiovascular risk of non-drinkers. among others. They are associated with very heavy drinking. the very concept of moderate consumption stems. For mammary cancer no clear demonstration of alcohol beverages as a risk factor was found [35]. The conclusion is that with the possible exception of breast cancer. with alcohol abuse. Wine should be considered as a healthy component of the diet in many cultures. from studies that identify the consumption levels associated with minimal risk. A positive correlation has been observed for hemorrhagic stroke and drinking. to hypertension. yet the meaning of the increased risk for heavy drinkers is straight forward. Wine and Health 127 . but the potential negative consequences associated with moderate drinking. Additionally. the challenge was to find the biological basis of the phenomena.Epidemiological Conclusions Today the main concern for most epidemiologists is not the benefits. So far the research has focused on alcohol and on phenolics as constituents of wine. This risk is mediated through the major cholesterol-carrying lipoprotein of serum. drinking patterns or associated traits [39]. Drinkers of any type of wine have a lower mortality risk than do beer or liquor drinkers. The health related biological effects observed in response to ethanol consumption are: increased high density lipoprotein (HDL) cholesterol levels. low-density lipoprotein (LDL). some epidemiologists reject a difference among wine and other alcoholic beverages. and a direct cardioprotective effect on the heart. The differences are attributed to lifestyle differences among those who prefer one type of alcoholic beverage over another thus making it exceedingly difficult to determine whether the differences in apparent health effects are actually related to the beverage itself. decreased fibrinogen. decreased HDL cholesterol levels constitute a central risk factor for CHD [40]. recognized as cardiovascular risk factors. which are not contested. that would be modified in the alcohol consumers. Alcohol Alcohol intake modifies plasma lipids and hemostatics factors. endothelial nitric oxide synthase (eNOS) stimulation. yet it remains unclear whether this reduced risk is due to nonalcoholic wine ingredients. increased plasminogen and tissue-type plasminogen activator (t-PA). Additionally. and on several biological targets. Mechanisms Biology of Wine Constituents: Effects of Alcohol and Polyphenols After the epidemiologists recognized the potential beneficial role of wine. Lipid Factors A high concentration of serum cholesterol is a major risk factor for coronary heart disease (CHD). or ‘free’ cholesterol from peripheral tissues. relative to wild-type control animals. is associated with HDL and has been shown to reduce the susceptibility of LDL to lipid peroxidation [46]. HDL structure. whereas heavy drinking downregulates paraoxonase activity and its expression. and utilization of cholesterol by steroid hormone-producing cells [49]. Subsequently. biliary cholesterol concentrations. One of the main antiatherogenic functions of HDL is reverse cholesterol transport. Rimm et al. lung and brain but not in the liver. [41] in a meta-analysis reported that an experimental dose of 30 of ethanol a day increased HDL cholesterol by 3. Exercise also increases serum HDL cholesterol level as improves reverse cholesterol transport [45]. an esterase. As a consequence. These data show that SR-BI plays an important role in transferring ␣-tocopherol from plasma lipoproteins to specific tissues. From some studies it is estimated that half of the beneficial effects of moderate alcohol intake are due to an increased HDL cholesterol concentration. Moderate alcohol intake increases serum HDL cholesterol level and stimulates cellular cholesterol efflux [44]. testis. HDL cholesterol is efficiently delivered directly to the liver and steroidogenic tissues via a selective uptake pathway [43]. after which much of the cholesterol is esterified by the plasma enzyme lecithin:cholesterol acyltransferase. storage.and time-dependent manner and the ability of oxLDL to decrease SR-BI expression was dependent on the degree of Urquiaga/Leighton 128 .At present there is consensus on the positive association between alcohol intake and plasma HDL cholesterol level. oxidized LDL (oxLDL) decreased SR-BI expression in a dose. HDL removes unesterified.73). There is evidence that light drinking upregulates. increased serum levels of paraoxonase in HDL diminish the atherogenic effect of LDL [47]. kidney or white fat. Defective tissue uptake of lipoprotein ␣-tocopherol in SR-BI-deficient mice may contribute to the reproductive and cardiovascular pathologies exhibited by these animals [50]. irrespective of its genetic polymorphism in rats and humans [48].99 g/dl (95% CI 3. This receptor also facilitates efficient transfer of vitamin E (␣-tocopherol) from HDL to cultured cells. This increase in plasma ␣-tocopherol was accompanied by a significant decrease (65–80%) in the ␣-tocopherol concentrations in bile and several tissues including ovary. In SR-BI-deficient mutant mice. As the oxidative modification of LDL plays a central role in the initiation and acceleration of atherosclerosis. There is also evidence that alcohol dehydrogenase genotype and alcohol metabolic rate do not modify the effects of alcohol on plasma HDL concentration [42]. SR-BI can influence plasma HDL cholesterol levels. The HDL receptor SR-BI (scavenger receptor class B type I) mediates the selective uptake of plasma HDL cholesterol by the liver and steroidogenic tissues.25–4. and the uptake. spleen. there was a significant increase in plasma ␣-tocopherol levels. Oxidative stress regulates the expression of SR-BI receptor. Human serum paraoxonase. and a 1. OxLDL decreased both [14C]cholesteryl oleate/HDL uptake and efflux of [14C]cholesterol to HDL in a time-dependent manner [51]. Numerous studies have investigated the effect of alcohol on platelet aggregation. like collagen. collagen. HDL and estrogen stimulate eNOS and the production of nitric oxide (NO) which has numerous protective effects in the vascular system. and anti-inflammatory effects [52]. In general. Therefore. for the explanation of the cardiovascular effects of HDL and estrogens.25-ng/dl increase in t-PA antigen concentration. reported that 30 g of alcohol a day was associated with a 7. epinephrine and ADP [54].LDL oxidation. or postmenopausal women receiving estradiol replacement therapy. reduced leukocyte adhesion.47% increase in plasminogen concentration [41]. HDL-associated estradiol is capable of stimulating eNOS in an SR-BI-dependent manner [53] leading to a new paradigm that involves eNOS. in a meta-analysis. in others this inhibition was not found [55–57]. ADP and platelet-activating factor. Hemostasis Factors The effects of alcohol on the coagulation and thrombolytic processes are not sufficiently studied. aggregation studies are not consistent. stimulated eNOS. HDL isolated from premenopausal women. Wine and Health 129 . together with elevated HDL levels. Rimm and collaborators reported that 30 g of alcohol a day was associated with a 1. a finding attributed to the difference on assay methods used in vitro or ex vivo to measure platelet aggregation [41]. haemostatic factors in moderate alcohol drinkers show a more thrombolytic profile. Rimm and collaborators. This rebound phenomenon could explain the ischemic strokes or sudden deaths known to occur after episodes of drunkenness [58]. thrombin. The apparent protection afforded by wine has been replicated in animals with grape phenolics added to alcohol. Some human studies have shown that physiological concentrations of ethanol inhibit platelet aggregation in humans as well as in animals in response to several agonists. Sex is another factor associated with decreased risk of developing cardiovascular disease. Fibrinolysis is increased in alcohol drinkers. Decreased risk is found in premenopausal women. whereas HDL isolated from postmenopausal women or men had minimal activity. Consistent evidence has been provided linking moderate alcohol intake with lower fibrinogen levels. A rebound phenomenon of hyperaggregability is observed after acute alcohol consumption but not after wine consumption.5-mg/dl decrease in fibrinogen concentration [41]. All tend to demonstrate that alcohol added in vitro leads to a significant decrease of platelet aggregation induced by thrombin. including vasodilation. an Occidental diet (OD) and their supplementation with red wine. Red wine was also associated with an increase in antithrombin III (ATIII) but only in individuals on MD. physiological and clinical parameters related to atherosclerosis and other chronic diseases. Red wine supplementation of both diets resulted in further decrease in plasma fibrinogen and factor VIIc. on biochemical. two groups of 21 male volunteers each received either a MD or an OD. So alcohol by itself imparts cardioprotection by adapting the heart to oxidative stress. but mainly to wine phenols [62]. 240 ml/day. Alcohol and polyphenols are both involved. compared with OD. higher levels of protein S and longer bleeding time. We found that MD. 61]. with a reduction of myocardial ischemic reperfusion injury. ethanol induces a significative increase in clot lysis. 30. clinical. Other Alcohol Effects In rats. during the second month. moderate alcohol consumption induced significant oxidative stress in the heart which was then reflected into induction of the expression of several cardioprotective oxidative stress-inducible proteins including heat-shock protein (HSP) 70. We carried out an intervention study in humans to evaluate the effect of a Mediterranean diet (MD). For 3 months. The antithrombotic effect of red wine is attributed in part to alcohol. Overall.Preincubation of human monocytes with low alcohol followed by incubation in the absence of alcohol resulted in an increase in t-PA and urokinase-type plasminogen activator (u-PA) expression [59]. And in mice. these findings provide evidence that both MD and red wine have independent but complementary benefits with regard to cardiovascular risk. and in increases in PAI-1 and t-PA antigen. red wine was added isocalorically. They decrease thrombosis [57. as discussed below. physiological and biochemical evaluations were made. 60 and 90 days. Polyphenols Polyphenol Bioavailability The total amount of phenols found in a glass of red wine is on the order of 200 mg versus about 40 mg in a glass of white wine. Wine contains many Urquiaga/Leighton 130 . increases expression for t-PA and u-PA and decreases expression for PAI-1 (plasminogen activator inhibitor) [60]. At 0. was associated with an improvement in hemostatic cardiovascular risk factors: lower plasma fibrinogen and factors VIIc and VIIIc. myocardial infarct size and cardiomyocyte apoptosis [63–64]. antithrombotic. anti-inflammatory and anticarcinogenic properties. In an acute ingestion study in humans. On the contrary. metabolized in the intestinal cells and in the liver and excreted by the urine [66. While polymeric condensed tannins and pigmented tannins constitute the majority of wine phenolics. 80]. Also the experimental meal taken with wine provoked a significant increase in the total plasma antioxidant capacity and in the plasma concentration of ␣-tocopherol and SH groups. and the anthocyanins [65]. 75]. Some of these effects are the following: Antioxidant Polyphenols are recognized as strong antioxidant and oxygen free radical scavengers [74. The health effects of dietary polyphenols might be explained by both intact compounds and their metabolites formed either in the tissues or in the colon by the microflora [70–73]. Wine phenolics include the non-flavonoids: hydroxycinnamates. most of which originate in the grape berry. hydroxybenzoates and the stilbenes. Their mechanism of action can be explained by a direct antioxidant effect and by modification of some protein properties than produce changes in enzymes activities (inhibition or activation) and gene expression. was as resistant as or more resistant to lipid peroxidation than fasting LDL [81]. postprandial LDL obtained after a meal consumed with wine. other studies report that red wine and a phenolic extract from red wine do not affect LDL oxidizability [79. postprandial LDL obtained after a meal consumed with ethanol was more susceptible to metal-catalyzed oxidation than the homologous baseline LDL. Polyphenol Effects Polyphenols and their metabolites have many biological activities. Metabolites are glucuronide or sulfate conjugates and methylated conjugates [68]. Several studies report an increased resistance to oxidative modification of human LDL after longterm consumption of red wine and red wine polyphenols [77. Red wine and red wine phenols increase in vitro the resistance of human LDL against oxidative modification [76]. They present antioxidant. the supplementation of a meal with grape seed Wine and Health 131 .phenolic substances. 67]. the flavonols. In another study. In contrast. 78]. These phenols are partly absorbed from the gastrointestinal tract in animals and humans. plus the flavonoids: flavan-3-ols. their large size precludes absorption so their health effects are likely restricted to the gut [69]. In these studies. polyphenols enhance the generation of NO. L-NAME. The results presented support the following conclusions: an OD induces oxidative stress. without affecting the increased cholesterol and triglyceride levels [62]. alcohol-free red wine supplementation for one month reversed the prothrombotic effect of the diet. Plasma antioxidant capacity measure as TRAP values. The effects of red wine were prevented by the NO inhibitor. NO was evaluated as a possible mediator of the effects [87]. we found that the total antioxidant reactivity (TAR) was significantly higher in volunteers on MD compared to those on OD and wine intake increased TAR significantly in both groups.01) and a reduction in thrombus weight (1. where the 8-OHdG levels decreased to values similar to those in the MD plus wine group.27 ⫾ 0. p ⬍ 0. 3. In our intervention study in humans described earlier. an OD and their supplementation with red wine.0 vs. p ⬍ 0. p ⬍ 0.33 vs. These studies provide evidence that red wine modulates primary hemostasis and prevents experimental thrombosis in rats. The OD group showed higher levels of oxidative DNA damage.3%.45 ⫾ 0. Antithrombosis In in vitro and ex vivo experiments. Supplementation for 10 days with red wine or alcohol-free red wine. 86].2 ⫾ 1. In rats with diet-induced hyperlipidemia. 32. enhancing the resistance to oxidative modification of LDL [82]. independent of its alcohol content. measured as delay in the thrombotic occlusion of an artificial prosthesis inserted into the abdominal aorta. by a NO-mediated mechanism. when compared with the MD group. wine supplementation to an OD or a MD improved antioxidant defenses in both groups and counteracted the oxidative damage produced by the OD [83. 132 ⫾ 13 s in controls. a diet rich in fruits and vegetables enhances antioxidant defenses.01). 84].001) a decrease in platelet adhesion to fibrillar collagen (11. but not white wine or alcohol.39 mg. were significantly higher in animals receiving alcohol-free wine. induced a marked prolongation of bleeding time (BT) (258 ⫾ 13 vs.extract reduced the postprandial oxidative stress by decreasing the oxidants and increasing the antioxidant levels in plasma and. Urquiaga/Leighton 132 . as a consequence. measured as 8-hydroxydeoxyguanosine (8-OHdG) levels in blood leukocyte DNA and elevated protein damage markers. Some studies were also performed to investigate the effect of wine polyphenols on experimental thrombosis in rats. to evaluate the effect of a MD.6 ⫾ 1. a platelet inhibitor and vasodilator [85. particularly in the OD. Wine intake significantly decreased 8-OHdG in both diets. Wine intake induced an increase in plasma and urinary polyphenols. Flavonoids and their in vivo metabolites may exert modulatory actions in cells through actions at protein kinase and lipid kinase signalling pathways. Other studies have shown that red wine contains phytochemicals that inhibit aromatase activity in vitro and suppress aromatasemediated breast tumor formation in vivo [93.Anti-Inflammation Chemotaxis and accumulation of leukocytes in the arterial wall are considered to be critical events in the inflammation associated with atherosclerosis. Endothelial Function Normal endothelium-dependent vasomotor function or endothelial function (EF) is a physiological response. protein kinase C (PKC). Inhibitory or stimulatory actions at these pathways are likely to affect cellular function by altering the phosphorylation state of target molecules and by modulating gene expression [97]. tyrosine kinases. Akt/protein kinase B (Akt/PKB). an enzyme associated with longevity [96]. They downregulate gene expression of inflammatory mediators [88. 89]. and mitogen-activated protein kinase (MAP kinase) signaling cascades. especially flavonoids. Middleton and collaborators reviewed the mammalian enzyme systems that are target of flavonoids [89]. Some Protein Polyphenol Interactions Polyphenols. They have been reported to act on phosphoinositide 3-kinase (PI 3-kinase). Particular phenol components of wine such as resveratrol and quercetin have shown an inhibitory effect on carcinoma cell proliferation [91. have numerous effects caused by their interaction with different proteins. 94]. Endothelial Wine and Health 133 . mediated by NO. 92]. Recent examples of these are the inhibition of aromatase activity [94] and angiotensin-converting enzyme (ACE) [95] and activation of sirtuin. Anticarcinogenesis It has been reported that dehydrated-dealcoholized red wine (wine solids) when consumed as part of a precisely defined complete diet. Flavonoids were reported to inhibit adhesion of immune cells to endothelial cells. which appears to play a key role in the prevention or reduction of the risk of atherosclerosis. delays tumor onset in transgenic mice that spontaneously develop externally visible tumors without carcinogen pretreatment [90]. there is a reduction of endothelial function with OD when compared to the MD (p ⫽ 0. effects such as those shown for hemostasis. Red wine polyphenol extract enhances eNOS expression and increases NO production in human umbilical vein endothelial cells (HUVECs) [101. are related to polyphenols or to an efficient antioxidant system. These effects are attributed to oxidative stress associated with an OD. This loss of endothelial function is not seen when both diets are supplemented with wine (p ⫽ 0. and to the elevated plasma antioxidant capacity associated with wine consumption and the MD. ET-1 release induced by oxLDL is inhibited by quercetin [104]. when considering the biological consequences of moderate alcoholic beverage consumption. Urquiaga/Leighton 134 . Quite clearly. Equally. Recalling our study on diets and wine supplementation we showed that in the absence of wine. independent of antioxidants. Moderate red wine intake improves endothelial function evaluated as flowmediated dilation of the brachial artery [99]. cigarette smoking. Red wine polyphenols activate tyrosine kinases. hyperhomocysteinemia and diabetes mellitus. For example. Red wines strongly inhibit the synthesis of endothelin-1 (ET-1).dysfunction is associated with risk factors for coronary heart disease such as hypercholesterolemia. if the new paradigm to explain the protective role of elevated HDL levels requires the participation of eNOS.001). respectively. would be biologically safer than drinking alone. a vasoconstrictor peptide that decreases endothelial function. increase cytosolic free calcium and stimulate a Ca2⫹-dependent release of NO in bovine aortic endothelial cells [98]. in particular the type. as well as pro-oxidant food consumption. Wine polyphenols protect NO from oxidation. a well-known requirement for NO-mediated effects. hypertension. it is obvious that antioxidants will be necessary to protect the NO generated. quantity and opportunity of antioxidant-rich food consumption. Conclusion The experimental results presented in this review do not support the frequently held conclusion that ethanol is the main active component. or those to be expected when HDL levels increase. This finding suggests that some polyphenols may have potent vasorelaxing effects on coronary microvessels during hyperemia [100]. This consideration could also lead to the idea that ethanol.014). the different results obtained in epidemiological studies that consider alcohol consumption could well be related to the dietary habits of those populations. which wine could provide. 102]. Wine polyphenols decreased ET-1 release and transcription in bovine aortic endothelial cells [103]. Acute red wine consumption produces an increase in coronary flowvelocity reserve in human volunteers. consumed together with antioxidant-rich foods. Gaziano JM. de Lorgeril M: Wine. Wheatley K.Acknowledgement Work supported by PUC-PBMEC/2003. Fuchs CS. or spirits. Sesso HD. Stampfer MJ. 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Vollmar AM.414:863–864. Bills ND. Douthwaite JA. Wood EG. Pharmacol Rev 2000. Pontificia Universidad Católica de Chile Alameda 340. Andriambeloson E.275:218–220. Lamming DW. Keen CL. Eng ET: Structure-function studies of aromatase and its inhibitors: A progress report. Andriantsitohaina R: Red wine polyphenols increase calcium in bovine aortic endothelial cells: A basis to elucidate signalling pathways leading to nitric oxide production.135:1579–1587.36:838–849. and cancer. Hinrichs SH.64:748–756. Farnsworth NR. 90 Clifford AJ.52:673–751. and medical foods for use under the supervision of a physician for management of specific diseases. Karger. There is no current legal definition for ‘functional food’ in most countries and foods of this type are regulated under existing food or related legislation in countries where functional claims are made. Mass. Both from the public point of view. dietary supplements. In some countries well-founded claims for such effects have been allowed. and as a result of science-based experimental test systems. In many countries regulations exist for conventional foods.What Are They? Novel or functional foods have been difficult to define in a legal sense. pp 140–150 Implications of Food Regulations for Novel Foods Safety and Labeling John R. The European Union has published regulations for novel foods. proteins. University of Massachusetts. Each of these categories have regulations which govern which claims can be made. while in other countries no claims have been permitted. and either specific rules or guidelines for the types of data which are needed to establish . USA Novel Foods. 2005. the concept of novel or functional foods or components is that such foods or components can have a beneficial effect on bodily functions and structures. Lupien Adjunct Professor of Food Science. Amherst. foods for special dietary use. fats.The Role of Government in Implementing a Healthy Diet and Physical Activity Lifestyle Simopoulos AP (ed): Nutrition and Fitness: Mental Health. Despite the difficulty of precise definitions. vol 95. Aging. In the European Union there are regulations for ‘novel foods’ which in some cases could also be considered as functional foods. World Rev Nutr Diet.. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. but the main thrust of these rules is to control newer foods derived from present biotechnology developments. and essential vitamins and minerals. there appears to be a common public understanding of the concept that many foods may contain beneficial (or harmful) substances in addition to the common nutrients of digestible carbohydrates. Basel. ethanol. As discussed below. or in advertising. research into the possible beneficial or protective effects of foods Food Regulations for Novel Foods 141 . The FAO/WHO Codex Alimentarius Commission has adopted a General Standard for the Labeling and Claims for Prepackaged Foods for Special Dietary Use. while they are separate in Australia and New Zealand. This has meant up to now that if the nutritional and other quality and safety aspects were substantially equivalent to similar foods that were not produced using recombinant DNA techniques that specific labeling was not required. developments in several countries and at the international level have tended to take into account newer features of foods and how they are produced and processed. and a number of FAO/WHO Expert Consultations have been held to better define basic concepts. and the nature of the claim [26–28]. and Nutrition Claims.the validity of any claims on the labels of foods. there are rules in the European Union. At the Codex international level foods derived from biotechnology are being actively discussed. even if that was not intended by the promoter making the claim for a food. The FAO/WHO Expert Consultations have endorsed the approach used in the USA of ‘substantial equivalence’ for foods derived from biotechnology. The Codex Committee on Food Labeling and the Codex Task Force on Foods Derived from Biotechnology are actively discussing international aspects of labeling and a general standard for foods derived from biotechnology. However. In most countries there are also clear legislative provisions for drugs. and General Guidelines on Claims. and certain claims for disease treatment can make a food product a drug in the legal sense and lead to severe regulatory consequences. At the international level there has been discussion about functional foods. novel foods. or prevention of disease. Nutrition Labeling. examine the quality and safety aspects of these foods. In the past there was no middle ground between foods and drugs. and related topics. including possible problems of allergenicity. while drugs are usually defined as articles intended for use in the diagnosis. but no final recommendations have been made for adoption by the 165 member country members that comprise the Codex Alimentarius Commission. and all of these should be taken into consideration in determining if a claim can be made. treatment. and labeling and claims for these types of foods and foods for special dietary use. cure. Australia and New Zealand that cover novel foods and foods derived from recombinant DNA techniques that are somewhat overlapping in the EU. Novel or Functional Food Claims Foods are usually defined as articles for food and drink. and health-related claims were not permitted on foods. also called neutriceuticals. Table 1 includes a list of some examples of foods or food ingredients that have shown possible benefits. since a disproved or doubtful claim can lead to regulatory problems or loss of market share for the product in question. osteoporosis. in addition to foods sold as such. and medical foods. and to maintain a good and constantly stronger scientific database to support claims. which may be instrumental in modifying the risks on intestinal disorders. considerable additional research is underway. Research into phytochemicals. one of the first claims on a food product was on an all bran cereal product stating that increased intake of wheat fiber could reduce the risk of colon cancer. in particular with the concept of ‘novel foods’ and ‘functional foods’. allium compounds. Lupien 142 . thiocyanates. there are also foods for special dietary use for the general public. and the regulation of their marketing is more structured in many countries. cancer and heart disease. probiotics and prebiotic substances that do not have traditional nutritive value has shown a wide range of possible functions for foods. This is an evolving area. novel foods. which can modify the bacterial flora in the intestine and enhance certain immune functions. Claims about increased intake of Vitamin A and cancer protection have also been put in doubt due to a trial of smokers in Finland where results showed that higher intakes of vitamin A actually increased the incidence of lung cancer. Phytochemicals such as indoles. and it has been a difficult task to substantiate claims.and their ingredients. sulfur containing compounds. Probiotics are microorganisms such as lactobacilli and bifidobacteria. in making claims about the functionality of foods or their ingredients. Therefore. and protect against some diseases of the intestine and colon. In the United States. and firmly establishing the beneficial effects of any of these substances has been shown to be difficult. possible promote absorption of certain essential minerals. Subsequent nutritional and dietary research has not fully supported this claim. Because of this. In each of these areas. and citing the US National Cancer Institute as the authority for this claim. Other Product Classifications and Their Regulation As mentioned above. isoflavones and phenols have been shown to have some possible beneficial or protective effects. Each of these product classes has a more specific definition than do ‘functional foods’. it is necessary to use caution. Prebiotics are oligosaccharides. regulatory authorities and new legislation in some countries have opened up the possibility of properly substantiated health-related claims for foods and their ingredients. dietary supplements. and other products of the same company. kale). visual functions • May improve body composition.) Eggs. Examples of functional components* [taken from ref. horseradish Phenols Caffeic acid Ferulic acid Fruits. may reduce risk of degenerative diseases. may reduce Catechins Tea • Neutralize free radicals. may decrease risk of certain cancers Flavonoids Anthocyanidins Fruits • Neutralizes free radicals. may reduce Flavanones Citrus • Neutralize free radicals. citrus. eye disease Food Regulations for Novel Foods 143 . etc. may reduce Flavones Fruits/vegetables • Neutralizes free radicals. vegetables. sauces. may reduce risk of cancer risk of cancer risk of cancer risk of cancer Glucosinolates.Table 1. may reduce risk of cancer • Antioxidant-like activities. 21] Class/components Source* Potential benefit Carotenoids Alpha-carotene Carrots • Neutralizes free radicals which may cause Beta-carotene Lutein Various fruits. Indoles. citrus • Neutralizes free radicals. Isothiocyanates Sulphoraphane Cruciferous vegetables (broccoli. heart disease. fish and marine oils Cheese. vegetables green vegetables • Neutralizes free radicals • Contributes to maintenance of Lycopene • May reduce risk of prostate cancer Zeaxanthin Tomatoes and tomato products (ketchup. corn Collagen hydrolysate Collagen hydrolysate Gelatin • May help improve some symptoms damage to cells health vision • Contributes to maintenance of health vision associated with osteoarthritis Dietary fiber Insoluble fiber Beta-glucan** Soluble fiber** Whole grains** Fatty acids Omega–3 fatty acids – DHA/EPA Conjugated linoleic acid (CLA) Wheat bran Oats Psyllium Cereal grains • May reduce risk of breast and/or colon cancer • Resuces risk of cardiovascular disease (CVD) • Reduces risk of CVD • Reduces risk of CVD Tuna. meat products • May reduce risk of CVD and improve mental. The Codex describes foods for special dietary uses as ‘foods which are specially processed or formulated to satisfy particular dietary requirements which exist because of a particular physical or physiological condition and/or specific diseases and disorders and which are presented as such. soy protein-containing foods • May lower LDL cholesterol. scallions Cruciferous vegetables • Lowers LDL cholesterol. December 1999. cocoa. contains Soybeans and soy-based foods • 25 g per day may reduce risk of Soybeans and soy-based foods Flax. chocolate • May improve urinary tract health • May reduce risk of CVD health immune system • Lowers LDL cholesterol.Table 1 (continued) Class/components Plant sterols Stanol ester Prebiotic/probiotics Fructooligosaccharides (FOS) Lactobacillus Saponins Saponins Soy protein Soy protein** Phytoestrogens Isoflavones – daidzein. the specific nature of such products Lupien 144 . The composition of these foodstuffs must differ significantly from the composition of ordinary foods of comparable nature. vegetables • May reduce menopause symptoms. garlic. if such ordinary foods exist’. Dithiolthiones Tannins Proanthocyanidins Onions. genistein Lignans Source* Potential benefit Corn. wood oils • Lowers blood cholesterol levels by Jerusalem artichokes. inhibiting cholesterol absorption anti-cancer enzymes heart disease such as hot flashes • May protect against heart disease and some cancers. lowers LDL cholesterol. maintains Cranberries. **FDA-approved health claim established for component. shallots. leeks. total cholesterol and triglycerides Sulfides/thiols Diallyl sulfide Allyl methyl trisulfide. cranberry products. soy. maintains healthy immune system *Examples are not an all-inclusive list. While foods of this nature are obviously intended to be ‘functional’. other dairy • May improve gastrointestinal health Soybeans. olives. rye. wheat. soy foods. onion powder • May improve gastrointestinal health Yogurt. there is specific legislation that exempts these products from many of the restrictions for foods or drugs contained in the US Food. except for foods and food ingredients obtained from plants or animals by traditional propagating or breeding practices and having a history of safe food use [4]. The European Union regulation on novel foods and novel food ingredients (Regulation EC No. and even foods that are labeled as dietary supplements have become increasingly popular. As with foods for special dietary use. products of this type must bear a label statement that these products have not been approved by the US Food and Drug Administration (FDA) and that the product is not intended for use as a drug [9–11]. Medical foods or neutriceuticals are specially formulated products intended for use under the supervision of a physician for the specific dietary management of a disease or condition. medical foods are also intended to be functional and have a direct and beneficial influence on a specific medical condition. foods and food ingredients isolated from microorganisms. flavorings. and are regulated under the EU novel food regulation at present. These foods meet distinctive nutritional requirements that are based on recognized scientific principles and are established by medical evaluation. and a wide array of other products such as herbal remedies. In the USA. The EU novel foods regulations are mainly concerned with food safety. In the United States. Food Regulations for Novel Foods 145 . Many of the novel foods regulated by EU rules have been developed to fit into the concept of functional foods. However. and extraction solvents are exempted from the EU novel food regulation since they are regulated under other EU rules. Food additives. In the USA. and possibly false or misleading. Many of these dietary supplement products. particularly with regard to health claims. are not specific about label claims. Drug and Cosmetics Act [1]. have label claims that are considered by many food regulators as somewhat exuberant. Dietary supplements such as vitamin and mineral capsules or tablets. The Codex description also implies that newly discovered beneficial effects of traditional foods would not be covered by the Codex description of foods for special dietary uses [26–28]. medical foods do not require pre-market clearance by FDA and there have been some concerns about the quality and efficacy of some of the products that are being marketed as medical foods [12–14]. and plants or animals. 258/97) applies to genetically modified products. a lively level of discussion on the concept of functional foods is also underway in Europe and elsewhere and could lead to additional regulation. fungi. and have the thrust of having been prepared to regulate foods and food ingredients derived from biotechnology. and equivalent products sold over the counter in pharmacies in Europe. algae. and perhaps elsewhere.and the restriction on their uses appear to clearly separate them from other types of possible ‘novel foods’ or ‘functional foods’. The FDA can regulate materials that advertise foods and dietary supplements if the advertising is used in association with the sale of a product and is considered ‘labeling’. the control of claims is more strict that in the USA. and that these products were not intended for use as a drug. this process has not been very effective. In either case false or misleading claims are not allowed. In practice. With regard to health claims. The NLEA also allowed for properly substantiated nutrition and health claim on the labels of foods. In general. but FDA regulation of claims under NLEA was restrictive enough to lead to new legislation called the Dietary Supplement Health and Education Act (DSHEA) [3. In the United States many products that are being sold as traditional foods have label claims about their beneficial effects when consumed as a part of a varied and balance diet. and to have evidence that any information provided is truthful and not misleading.National Regulatory Systems and Requirements and International Considerations Since ‘novel foods’ and ‘functional foods’ are not defined or set aside as a specific class of product in most countries. and under EU regulations. 22]. but differences exist between various EU member countries with regard to claims allowed under national law. The DSHEA further loosened control on products that are ingested and allowed claims for pills. special dietary foods. These differences can lead to EU wide marketing of products with hard to substantiate claims. In the European Union countries foods are regulated under national food laws. or as drugs. since approval Lupien 146 . 16. The 1990 Nutrition Labeling and Education Act (NLEA) [2] required additional labeling about the nutritional content of foods beyond that previously required or recommended under the Food. FDA tended to require that marketers of foods with health claims obtain prior approval of the claim and present evidence of ‘significant scientific agreement’ among qualified experts showing that any claims were justified. 18. marketers of such products are required to notify of FDA of such products and label claims. tablets. or in advertising. and the claims that are made for the products in their labeling. 21]. capsules. 15. depending on how they are marketed. medical foods. but the enforcement of these regulations has not been particularly vigorous and products with questionable claims and possible safety problems continue to be marketed in the USA [20. Drug and Cosmetic Act. novel foods. they are regulated under existing law as foods. or even food-like products that were labeled as dietary supplements and included a label statement declaring that the products and claims were not approved by FDA. While no pre-marketing approval is required from FDA. while other advertising is regulated by the US Federal Trade Commission. As an example of European control of claims. In June 2000. Nestle was fined GBP 7. information of previous human exposure to the product. labeling. and also present information on proposed labeling. local level Trading Standards Officers in the UK have taken Nestle and other food marketers to court over certain label claims.500 for making an illegal medical claim. anticipated intake or extent of use. 17]. Over 200 FOSHU-approved products are currently on the Food Regulations for Novel Foods 147 . but this had practical difficulties when central government is not fully involved in regulating products. and also had to pay GBP 13. Australia and New Zealand. If the government authorities are satisfied that the dossier supports quality and safety requirements. effects of production processes. the Shropshire County Council successfully sued Nestle for marketing a shredded wheat product with label claims that eating this cereal would reduce the risk of coronary heart disease.600 costs involved in holding the court proceedings [6]. history of any organism used as a source of the novel food. and health effects of each FOSHU product. but some consideration of labeling is also possible [4.of a product in one or two countries can lead to EU wide distribution of these products under existing EU rules [5. In Japan regulations for Foods for Special Health Uses (FOSHU) have been in force for over two years. Food and related rules which govern claims for functional foods also are in effect in Japan. 28]. safety. quality. processing. Information provided should include product specifications. and nutrition. In the EU novel food regulation. In the UK. The Japanese rules require that a manufacturer or marketer of a FOSHU product present a dossier to the Japanese government with pertinent information on the ingredients. In many cases it would appear necessary to liaise with regulatory authorities prior to marketing products. and will have significance to all food marketers about making future claims unless they have adequate scientific data to back up claims. companies wishing to market a product which is considered a novel food must present information to authorities in a Member State where a product will first be marketed to demonstrate product safety. As noted above. other European countries. and there are differences between procedures and products allowed in each of these countries. Developing countries also have some legislation in place. approval of the FOSHU product can be given. toxicological and microbiological information. and substantiates the health effects to be put on the label or used in advertising. 8. Marketers of functional food products in these markets must carefully assess existing rules that apply because of the differences that exist in each of these markets. 23]. 25. this court decision is considered as a test case. the main concern is the safety of the novel food. and at the same time allows local authorities to take legal action which has nationwide or EU-wide significance [7. 1 covers Novel Foods. the Codex Alimentarius Commission has not held extensive discussions on functional foods. on any undesirable substances that may be present. and claims for foods for special dietary use.2 covers Foods Produced using Gene Technology [29]. on nutrition claims and nutrition labeling. For such foods specific labeling in required which states that the food or certain ingredients have been genetically modified.5. while Food Standard 1. In previous discussions on functional foods three sequential steps have been suggested: Lupien 148 . pesticide residues. on traditional preparation or cooking. In general these Codex standards and guidelines state that packaged food should not be described or presented on any label or labeling in a manner that is false. or chemical contaminants which are used in or can occur in food production and processing.1 describes non-traditional foods as foods with no history of significant human consumption in Australia or New Zealand. ANZFA Standard 1. Similar procedures are also in place in China. with somewhat different procedures and results. ANZFA Standard 1. This will involve several steps in building an adequate level of data. and appear to be freely accepted by Japanese consumers. Food Standard 1. It requires premarket approval of novel foods on the basis of a dossier that includes information on the composition of a product.5 for Foods Requiring Pre-market Clearance. In Australia and New Zealand. on any known adverse effects from consumption of the product.2 covers food produced using gene technology and limits the technology to foods where recombinant DNA techniques have been used. and on patterns and levels of consumption. and must be done with the realization that data to establish the safety and efficacy of foods and food ingredients is considerably more difficult than is the case with food additives. At the international level. It can be seen from the above paragraphs on current ANZFA rules that the concepts defined in the EU rules on ‘novel foods’ have been divided into two separate ANZFA Standards.5. the Australia New Zealand Food Authority (ANZFA) has published rules under Part 1.5. it is clear that marketers of foods which fit the profile of novel foods or functional foods must be prepared to have in their possession adequate scientific data to substantiate any claims that they wish to make on products [24]. and ‘novel foods’ as non-traditional foods with safety concerns. Work has been done on basic labeling rules. misleading or deceptive or is likely to create an erroneous impression regarding its character in any respect. Supporting Data for Novel Food or Functional Food Claims and Future Perspectives Based on the discussion above.market in Japan.5. Consumers are willing to accept the concept of functional foods and want to know more about them. 14/2/1997. Drug. 2 Development of models and methodologies including possible biomarkers to demonstrate through studies on human nutrition possible functional effects and the consequences thereof to justify specific functional or physiological claims. Washington. US Government Printing Office. to demonstrate functional effects and benefits to health including reduction to disease where pertinent to justify structure/function or health claims. The potential for novel or functional foods is great. Regulation (EC) no 258/97 of the European Parliament and of the Council of 27 January 1997 concerning novel foods and novel food ingredients. 1994. US Nutrition Labeling and Education Act. novel foods. marketers of novel or functional foods or ingredients that can increase the functionality of foods must conduct careful and adequate basic studies and human trials to justify the claims that may be made for functional food products. l990. EU Official Journal L 403. potential marketers of these foods must be prepared to fully understand the regulatory requirements which apply in each marketing area. 1938. Given the differences in regulation of foods. the future for novel foods or functional foods appears to be very positive. Those meeting the challenges of successful development of scientific data so that products can be marketed should meet with great success. foods for special dietary use. special dietary foods..1 Basic research and experimentation: identification and understanding of the mechanisms of interaction between the food or ingredient and modification of gene expression or cellular biochemical function in order to demonstrate potential functional effects. pp 1–7. Washington. References 1 2 3 4 US Federal Food. and Cosmetic Act. 3 Design and carrying out of appropriate human nutrition studies. Food Regulations for Novel Foods 149 . US Government Printing Office. Consumer studies in the USA have shown that 95% of consumers believe that certain foods can provide health promotion of disease prevention benefits beyond basic nutritional benefits [19]. and be ready to meet these requirements both before marketing a product. However. and medical foods in different countries and regions. US Dietary Supplement Health and Education Act. US Government Printing Office. Therefore. which may have to be done on a large scale. Washington. original Act. and after a product has been placed on the market through adequate post marketing surveillance. amended periodically. It is likely that consumers in Europe and other parts of the world have similar attitudes and desires. as amended. FAO. Centaur Publishing/Gale Group. Canella C. Paris. EUFIC. Functionality. Philadelphia. Pape S: Functional Foods: Lots of action. New York. Rome. FDA Finalizes Rules for Claims on Dietary Supplements: Food & Drink Weekly.it Lupien 150 . 1999. 2000. Lippincott/Williams & Wilkins. Report of the 22nd Session of the Codex Committee on Nutrition and Foods for Special Dietary Uses. FAO.21. McCawley I: Industry Unveils Code to Rein in False Food Claims. 2000. Gastroenterol 1998. Pape SM: Is FDA’s food labelling enforcement policy unhealthy? Prepared Foods. Schnell Publishing Company. IFIC. International Food Information Council Functional Foods Attitudinal Research. EUFIC. little guidance. Marketing Week. New Claims for Soya: Food Today. Cahners Publishing Group. Nutrition Today. 2000. Food Insight. 2001 (see website http//www. Supercalifragilistic-Oligofructose(s). Safety Evaluation of Novel Foods: A European and international perspective.5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Canella C. Haymarket Publishing. EUFIC. 2000. IFIC. Washington. Paris. Claim or ‘anti-claim. E-Mail lupien@srd. Pariza MW: Functional Foods: Technology.gov. 2000. FAO. 2000. IFIC.11(suppl):40–41. Glinsman WH: Functional Foods: An Overview of Regulatory Status. Gale Group. John R. Cahners Publishing Group. CRN News. London. and Health Benefits. MA 01003 (USA) Fax ⫹1 508 888 6779. Pinto A: Alimenti Funzionali: Alimentazione tradizionale e nuove tecnolgie di produzione. 2000. Rome. 2000. Functional Foods: Food Today. Report of the 28th Session of the Codex Committee on Food Labelling. 2000. London. Canella C. 2000. Challener C: Medical Foods Fill a Niche. Med Estetica 1997. BiotechnologyEUFIC reviews. Med Estetica 1998.au). Marketing. McCawley I: Nestle Lawsuit Sets Precedent. 1999. Washington. Washington. 2000. New York. Centaur Publishing/Gale Group. 1998. Abrahams B: Difficult to swallow (medical foods). ANZFA Food Standards: Canberra.’ FDA permits a qualified claim for omega–3 fatty acids. Pinto A: Functional foods and neutriceuticals. 1999. London. Do You Know Where Your Functional Foods Are? Food Insight. Marketing Week. 1999. Lupien Adjunct Professor of Food Science University of Massachusetts Amherst. Codex Alimentarius Food Labelling Complete Texts: Rome. Pinto A: Integratori alimentary. IFIC. Nutrition Today. 2000. Washington. 2000. Background on Functional Foods. Washington. 2000. Lippincott/Williams & Wilkins.anzfa. Washington. Chemical Market Reporter. 1998. Philadelphia. 1999. London. Paris. Prepared Foods. IFIC. FDA Approves Soy Health Claim for Food Labels: Food Insigh. Tapsell. Aging. Food is also referred to in Australia’s research priorities. Craig S. In Australia. Gillen Smart Foods Centre. It is part of our social. economic and population health fabric. Lynda S. vol 95. Australia. with business. The National Centre of Excellence in Functional Foods (NCEFF) was funded through the innovation platform to provide leadership for functional foods in Australia. Food can be described from so many perspectives. The National Food Industry Strategy. pp 151–161 A New Look at Intersectoral Partnerships Supporting a Healthy Diet and Active Lifestyle:The Centre of Excellence in Functional Foods. Basel. Fisheries and Forestry. Karger. The food industry employs 17% of the total manufacturing workforce and Australia’s food exports account for around 22% of overseas trade [1].Simopoulos AP (ed): Nutrition and Fitness: Mental Health. Science and Practice Linda C. This review starts with food. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. Wollongong. a part of the Preventive Healthcare priority goal [2]. with an emphasis on integrating science and business interests. underpins the significance of food to Australia’s economic health. argues that to establish effective health promoting partnerships we must be prepared to genuinely address competing imperatives and find a space for co-operative activity. with nutrition and/or food positioned along the way as an element of concern. Combining Industry. 2005. Patch. innovation and environmental platforms. and with reference to the Centre of Excellence in Functional Foods. food has special significance in all these domains. with the development of new health-promoting foods. The food supply is noted as a key ‘settings strategy’ in the framework for . World Rev Nutr Diet. an initiative of the Department of Agriculture. Australia Reviews on healthy lifestyles normally begin with a picture of health problems. University of Wollongong. but the amount and type of Tapsell/Patch/Gillen 152 . and alternative sweeteners [6]. may well have different meaning or weight depending on the context in which it is being discussed. There is a wide range of studies that can address certain health outcomes.the national obesity prevention strategy. Nutrition Perspective There is no universal definition of functional foods. The concept of functional foods has a number of origins. In this section. This implies an understanding of foods and food components and the link between their consumption and specific health outcomes. including meals consumed outside the home. these were seen as the nutrition (science). lutein-enriched eggs. Healthy Weight 2008 [3]. The American Dietetic Association position statement on Functional Foods [7] lists foods and components in terms of potential health benefits and associated scientific evidence. increased proportions of manufactured foods and meals with reduced energy density and increased proportions of meals with reduced portion size. but there are clear links with advances in nutrition science and in particular food science and technology. in particular whole foods and bioactive components of foods. The path. must navigate through a number of ambiguities underpinning the need for an effective knowledge management strategy. would also fit this way of thinking. and regulatory perspectives. These issues will now be explored. There are many different ways in which information on food is communicated and positioned. anti-oxidants obtained from grapes and apples. marketing. positioning the National Centre of Excellence in Functional Foods within the analysis. for example. From the Centre of Excellence perspective. displaying the disparity that often lies between the food category and the science to support its position. These represent different categories in which the functional food concept may be examined. The concept of functional foods. The identification of whole dietary patterns and their potential relationship to improved health outcomes [5]. however. outcomes sought include increased choices and local availability of lower energy density and healthy foods and drinks. but there is a common reference to foods that provide benefits beyond basic nutrition [4]. citrus fruits. Functional Food:An Intersectoral View One of the essential attributes in developing effective intersectoral partnerships is adequate communication. Thus. the scene is set for intersectoral activity that can use any number of starting points or organising principles to make it happen. however. A recent edition of the journal of the Australian Institute of Food Science and Technology provides information (under the heading of functional foods) on pecan nuts. The development of a model for substantiation will underpin the system for approval of health claims.1A2 describes heath claims as those that relate to intrinsic weight-reducing properties • a therapeutic or prophylactic action or equivalent • • the word ‘health’ or equivalents with the name of the food • any expression or implication of advice of a medical nature • the name or reference to a disease or physiological condition. that of regulation. European and Japanese frameworks. Data in this literature refer to sales and consumer surveys. Functional foods are constructed as responding to a consumer demand for more ‘hands on’ responsibility for their own health.2). General level claims will require the industry to provide evidence on request for conditions that do not refer to serious diseases. The policy includes 26 broad principles and refers to criteria for general and high level claims. and this brings us to the market place. Market Perspective The literature on functional foods in the marketing domain is widespread. Australia has a long-standing history of food regulation. a policy guideline on health claims was announced by the Australia New Zealand Food Regulation Ministerial Council [10] to guide the development of a system of health claims. which currently includes a description of health claims (Standard 1. Regulatory Perspective Around the globe. Standard 1. the term has a defined space in this context. referring to serious diseases. but prohibits them on food. This will necessitate effective problem solving between the scientific and regulatory sectors. the way in which information on food can be legally presented to consumers is an interesting line of investigation in its own right. There are clear differences in the American. including food standards legislation that dates back into the early part of the last century. In the last decade. Australia and New Zealand formed a joint Food Standards Code.research required to justify a health claim is open to debate. This then creates another perspective for functional foods.1A. resulting in substantial A New Look at Intersectoral Partnerships 153 . In December 2003. The only authorised health claim is the link between folate and a reduced risk of neural tube defects [9]. High level claims. bearing in mind the implications for regional and world trade. Like the nutrition and regulatory sectors. bearing in mind that the output from this exercise concerns communication between the food industry and consumers. but also there are efforts to gain some synergy [8]. where it appears relatively unconstrained to describe market trends. will require pre-approval by Food Standards Australia New Zealand (FSANZ). and takes many forms. age and ethnic positioning 1 First 5 foods listed in table 1 of ADA position statement on functional foods. Here. drawing on any number of concepts and disciplines.Table 1. While the issue is identified and Tapsell/Patch/Gillen 154 . the language used in reference to functional foods alone can be seen to display the disparity between groups and the challenges facing intersectoral partnerships in which food has a primary position. 3 First 5 categories of functional foods listed by Sloan [11]. warrants consideration. however. including reference to a role of giving medical advice. and indeed there are sectors other than the three mentioned here. Understanding the differences between groups. 2 growth in sales of this food category. There are many other examples. Descriptors used in Standard 1. which all add to the complexity of the task. The language describing functional foods is in contrast to that of the nutrition and regulatory contexts (table 1). a less formal approach. particularly in the US. and developing frameworks that enable genuine sharing of the central issues. Regulatory and Marketing context Nutrition1 Regulatory2 Marketing3 Low fat foods Slimming food. with intrinsic weight reducing properties Therapeutic or prophylactic action ‘Health’ in the name Broader nutrient and specialty ingredient fortification Condition-specific marketing Lifestyle enhancers Medical advice Referent to a disease or physiological conditions Sports market crossover Kid’s health Foods containing sugar alcohol in place of sugar Oatmeal/oat bran/whole oat products Milk-low fat Vegetables and fruit Cereal with added folic acid Gender. Terms used to describe functional foods in the Nutrition. The marketing language has an appearance of confabulation. Intersectoral Partnerships in Food If there is one issue in the world today that is linking food with a vast range of intersectoral components it is obesity. Japan and Europe [11]. The nutrition perspective refers to foods and food components. while the regulatory descriptors identify broad domains of action or implications of actions.1A2 of the Australia and New Zealand Food Standards Code. In Australia. This knowledge base is substantially greater than many areas referred to in the traditional domains of nutrition and health. and cordials/drinks brought from home. packaged snacks and confectionery bought at the canteen be replaced by fruit and water. Technological advances from this domain are closely aligned to new product development and lie behind the emergence of the functional food market. and one that has implications for all forms of food and nutrition communications. One review of this area suggests that risk perceptions and concerns relating to technology. drawing on aspects of the chemical. resulting from a decline in physical activity and rise in energy intake [13]. the need for intersectoral approaches to addressing the problem is well recognised [12]. Fourteen percent of the children purchased food from the canteen. A recent study of food consumption patterns of Australian children 5–15 years of age found on average 37% of energy was consumed at school. The missing element in the discussion is of course the consumer. scientific innovation and personal health issues should form the basis of these communications [18]. This leads to the issue of the technological know-how to produce new products. snack bars. A study of Finnish consumers found that functional foods were not seen as a separate category. not least because there have been obesity prevention strategies in place for some time and they seem to have had little impact [14]. The authors recommended that biscuits. their sustained acceptance of this range is a complex matter. This simple solution lies in stark contrast to the information provided on consumer food purchasing trends in the marketing literature [11]. over 60% of the adult population (25 years and over) are overweight and 20% obese. but rather as a secondary category within a food A New Look at Intersectoral Partnerships 155 . energy dense foods and beverages were over-represented in foods consumed at school whether brought from home or purchased at school [16]. While the marketing literature would suggest that consumers are adopting functional foods. physical and structural analyses of foods to links between biology and engineering [17]. and fast food. a more innovative solution may be developed that addresses the need for less energy-dense foods and which will be adopted by children and their parents. It will be important for those working in the nutrition and health field to appreciate this sector if new solutions to well-described problems such as obesity are to be found. but overall. In New South Wales a school canteen policy has been put in place through an intersectoral partnership between Health and Education which outlines a number of resolutions including a statement that foods regarded as ‘extras’ in the Australian Guide to Healthy Eating can only be sold on two occasions per term [15]. It seems that if we could combine this latter knowledge with the nutrition concerns. The situation is causing concern.prioritised by the health sector. A recent review of research trends indicates the extent of this knowledge and the capacity it brings to improve the food supply [17]. The rate of childhood obesity is one of the worst on record. There are limitations. industry and related stakeholders. The generic stream funds independent precompetitive research and activities. and consumers become much more conscious of their management of energy intake and energy expenditure. a generic stream funded by the National Food Industry Strategy and the four partner organisations. bringing together science. the Department of Primary Industries. The Centre itself is based on intersectoral collaboration. Australia The Australian National Centre of Excellence in Functional Foods (NCEFF) was established in July 2003 to support the Australian food industry in the development of a functional foods market. food is an essential part of life [20]. The food and nutrition sector itself. obesity is well recognised as a serious health problem requiring an intersectoral approach. then developing frameworks to enable full participation needs to be on the agenda. It is likely. Food is implicated in the problem by virtue of its contribution to energy intake. that we need some paradigm shifts in our relationships with food. and a separate industry-funded stream. food regulation. however. marketing and innovation management. This enables the generation of new knowledge available to all and a framework for building concepts for a functional food market generally. the strategies developed for influencing consumers’ food intake would seem to benefit from a deeper understanding of this psychology. technology. The collaboration between the four partner organisations creates additionality by combining capacities in food technology. where the strategic uptake of nutrition knowledge becomes an imperative in food product development. but if the capacity of this sector is to be maximally enhanced in helping to solve the problem. for example in comparing tobacco control to food control. however. The Centre has two main streams of operation. a joint venture between the Commonwealth Scientific and Industrial Organisation (CSIRO) – Division of Health Sciences and Nutrition. nutrition and consumer sciences (from basic sciences through to human trials). In summary. Projects are organised under clusters of substantiation research and development (nutrition perspective). while the industry-specific stream works closer to the market on projects sponsored by industry. when unlike tobacco. and market intelligence/innovation Tapsell/Patch/Gillen 156 . with reasons for selecting these foods varying depending on that category [19]. In this respect. regulation. Food Science Australia and the Australian Research Council Key Centre for Smart Foods at the University of Wollongong.group. and disciplines in public health. The task of the Centre is to provide leadership in the functional food area. has many parts. Victoria. The National Centre of Excellence in Functional Foods. marketing and distribution addresses the question of energy delivered to the target population. the example that follows is based on research conducted at the Smart Foods Centre prior to the formation of NCEFF.management. NPY and A New Look at Intersectoral Partnerships 157 . while there is strong evidence implicating dietary saturated fat (SFA) in the development of type 2 diabetes mellitus (T2DM) [22]. In marketing terms this would relate to foods for healthy aging. will produce knowledge that is relevant to new food formulations that support optimal metabolic responses under various conditions. It demonstrates how whole foods can have a functional label. The achievement of this aim. There are a number of ways in which PUFA may protect against insulin resistance and T2DM. As the Centre develops new linkages will be formed with other research providers and organisations as part of the consolidation of effort. A Case Study of Functional Food Research:Walnuts in the Dietary Management of Type 2 Diabetes mellitus The role of dietary fat in insulin resistance has been well researched at a number of levels [21]. but one interesting mechanism is the effect on body fatness. The functional foods platform is aimed toward improved nutrition and carries with it a view to a healthy lifestyle. and facilitating communication between stakeholders on nutrition related issues. Thus. keeping up with developments in the regulatory environment. To finish. has many dimensions. energy expenditure and oxidative capacity. research undertaken is considered in the light of the types of nutrition communications that might lead from the research. However. including physical activity. why dietary methodology is relevant in substantiating effects and what consumers think of the consequences of the area under research. Arc receptor. In animal model studies Huang and colleagues have demonstrated the effect of type of fat on obesity via an impact on body fatness and various measures of hormonal systems regulating food intake and energy balance (leptin. a whole of diet approach lies at the centre of the research strategy. Projects in the regulatory and market intelligence clusters relates to the strategic research program. the potentially protective role of dietary polyunsaturated fats (PUFA). identifying business opportunities. and is relatively under-researched in diabetes management [22]. it is possible to see how these dimensions can be systematically and productively linked. This set of studies. however. weight control. The first stage of the strategic (generic) research program focuses on the impact of types and amounts of macronutrients and of anti-oxidants on energy balance. appears to have been forgotten. currently underway. first observed many years ago. healthy lifestyle and child and adolescent health. In keeping with the direction Australian legislation is taking on health claims. as well as the likely market for any emerging products. but starting with food. or through the impact of these fatty acids (or foods) on health indicators such as body fat. normative and control factors.01) and was able to predict intention 55% of the time. but after 6 months the walnut group was the only group to achieve all dietary targets (table 2). p ⬍ 0.54. LF inclusive of PUFA-rich foods. Overall the odds of intending to use n⫺3 enriched functional foods doubled for each one-unit increase in attitude score. LF. and LFP with the inclusion of 30 g walnut supplied). Xyris. Attitude was a significant determinant of intention whereas subjective normative beliefs and control beliefs were not related. such that foods that deliver these fatty acids could be seen as having a functional role in the diet. The nature of this evidence relates to the effects of macronutrients on metabolic control and other health variables. it would also be helpful to know if patients were able to consume these foods regularly and whether they perceived the foods to have a functional role.01. If this were the case. Dietary intakes were assessed by validated diet history interview at baseline.AgRPmRNA expression). To gain insights into consumer perceptions here and with another group of patients in a similar trial (n ⫽ 126) [29]. 24]. their functionality in this regard was of interest. There were significant correlations Tapsell/Patch/Gillen 158 . In particular. we applied a questionnaire derived from focus group interviews to elucidate the three determinants of intention to consume these foods in the Theory of Planned Behaviour [30] attitude. In this study. In this study walnuts could be seen as n⫺3 enriched functional foods. In this sense the walnuts provided a functional role in meeting target intakes of nutrients that stands to be limiting if high fat foods are excluded from the diet. Nutrition principles for the management of type 2 diabetes mellitus are based on a systematic review of the scientific evidence [22]. something that could be assessed in human studies. This study demonstrated the significance of including 30 g walnuts per day in the diet [27] to deliver the required amounts of essential fatty acids [see 28]. There was no significant difference in nutrient intakes between groups at baseline. but the effect could be reversed by changing the SFA for PUFA (notably – n⫺3) with a much less effective response by changing to a low-fat diet [23. 3 and 6 months and nutrient intake analysis was done using Foodworks (v. Using regression analysis we were able to show that the TPB provided a significant explanation of intention (R2 ⫽ 0. Because walnuts have a unique composition providing high amounts of n⫺6 and n⫺3 fatty acids. LFP. This functionality could be defined in terms of delivering the essential fatty acids. the evidence in support of the inclusion of polyunsaturated fats is quite strong [26].3. A higher PUFA diet (and with attention to the type of PUFA) resulted in a lower energy intake and a low food efficiency ratio (weight gain/intake) [25]. Brisbane). a high SFA diet induces obesity without hyperphagia. 55 adult men and women with type 2 diabetes mellitus were randomly allocated to three dietary advice strategies (low fat. In obesity prone mice. 39 ⫾ 2. kcal Saturated fat.22b 0. these were not determinants of intention.56 11. The concept of functional foods unites health.16 ⫾ 4.977.07 5. if functional foods are to be adopted by consumers.19.36 ⫾ 0. industry and regulatory groups in a move towards providing healthy food products.95⫾431. immediate prospects for modifying behaviour come through a change in attitude.05) and income (r ⫽ ⫺0.4 ⫾ 0.Table 2.84 1. The National Centre of Excellence in A New Look at Intersectoral Partnerships 159 ⬍0.71 0.003 .001 2.12 3.8 10.001 0.004 ⬍0. The above case study outlines how animal model research can inform food based research with humans. This has implications for the communication of science.75 2.76⫾500.19 6.67⫾1.05) with intention.65b 1.77 ⫾ 1. Dietary intakes by group after 6 months intervention Dietary variable Energy.84 NS 0. On top of this.55 a Recommended by American Diabetes Association.145.90 0. b between age (r ⫽ 0.81 ⫾ 0.35 ⫾ 1. Recommended by ISSFAL based on 2. %E Polyunsaturated fat.000 cal intake.88 ⫾ 1. These are some of the aspects of the research program of the National Centre of Excellence in Functional Foods. and how this in turn may provide evidence of the functionality of specific foods in the diet. g LF (n ⫽ 20) LF-P (n ⫽ 19) Walnut (n ⫽ 16) p value1 ⬍10a ⬃10a 2. 1 One-way analysis of variance for differences between groups. however. and clearly the food industry is a major one.006. Thus. p ⬍ 0. a number of stakeholders may be identified. consumer research provides information on how nutrition knowledge needs to be communicated and the potential acceptance of related products in the marketplace.59⫾376. another important string to the bow of intersectoral collaboration.29 9.19 Goal 1.21. then their attitudes towards functional foods warrants attention.69 ⫾ 1. g EPA⫹DHA. p ⬍ 0. Conclusions Where food is seen as the starting point for developing healthier lifestyles.14 7. %E ␣-Linolenic acid. With attitude having the greatest influence on intentions. but effective communication of this concept and of approaches to its development is central to its successful adoption by consumers.44 1.72 ⫾ 2.19 ⫾ 1. NSW Department of Health. Other researchers acknowledged in this study were Dr. Ball K. Accessed 30 March. Sloan A: The top 10 functional food trends: The next generation. Br Food J 2003. Marijka Batterham. Accessed 30 March. Trichopoulos D. Accessed 9 December. Trichopoulou A: Tracing the Mediterranean diet through principal components and cluster analyses in the Greek population. 2004.56:82.pdf. References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 NFIS. 2003. NFIS Market Data: National Food Industry Strategy.au/obesity/adult/canteens. and an initiative of backing Australia’s ability.htm.au/ resources. Australia New Zealand Food Authority: Process evaluation of the management framework for the folate-neural tube defect health claims pilot.56:30–49. 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What are the key food groups to target for preventing obesity and improving nutrition in schools? Eur J Clin Nutr 2004.57:S12–S17. 2002. Acknowledgements The Smart Foods Centre is supported by the Australian Research Council. 2004. 2003.foodsecretariat. Med J Aust 2003. Accessed 22 December. has taken all these aspects on board in developing an infrastructure to support this process. Bell AC. Available at: http://www.au/_srcfiles/Part_2_process_eval. Ms Marian Bare and Ms Meredith Kennedy. Shimizu T: Health claims on functional foods: The Japanese regulations and an international comparison. Dr. Accessed 30 March. Anonymous: Pecans confirmed low GI. Geneva. Available at: http://www. Tapsell/Patch/Gillen 160 .nfis.179:577–579. Nutr Res Rev 2003. Food Technol 2003.58:258–263.16:241–252.gov. Australia New Zealand Food Regulation Ministerial Council: Policy guidelines for the management of health claims. Eur J Clin Nutr 2003. 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J Am Diet Assoc 2005: in press. Han M. NPY. Ajzen I.6:35–44. Available at: http//www. Accessed 30 March. leptin. pp 148–154. National Centre of Excellence in Functional Foods Northfields Avenue. Storlien LH. Rosenthal A. Wld Rev Nutr Diet. Huang XF. Diab Care 2003. Prof. Karger.au A New Look at Intersectoral Partnerships 161 . Mercer SGL. Xin X. Wheeler M: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. 2001. Patch CS. Fishbein M: Understanding Attitudes and Predicting Social Behavior.282: E1352–E1359. vol 88. NSW 2522 (Australia) Tel. Lähteenmäki L: Reasons behind consumers’ functional food choices. neuropeptide Y and pro-opiomelanocortin mRNA expression. Storlien LH: The level of NPY receptor mRNA expression in diet-induced obese and resistant mice. New Jersey. Storlien LH. Gillen LJ. Patch CS. Molec Brain Res 2003. Linda C. Nutr Food Sci 2003. Holzmeister LA. Else PL: Dietary fat subtypes and obesity.19 20 21 22 23 24 25 26 27 28 29 30 Urala N. Tapsell LC. Bantle JP.edu.org. J Nutr Educ Behav 2005: in press. Mayer-Davis E.33:148–158. Simopoulos AP. E-Mail ltapsell@uow. Beebe CA. Xin X. Basel. Purnell JQ.issfal. Batterham M: Structured dietary advice incorporating walnuts achieves optimal fat and energy balance in patients with type 2 diabetes mellitus. Wang H. Mooradian AD. Dietz W: possible lessons from the tobacco experience for obesity control. Am J Physiol Endocrinol Metab 2002. 2004. Prentice-Hall. Huang XF: Effects of dietary fat types on body fatness. Hoogwerf B. University of Wollongong Wollongong.26:S51–S61. Tapsell LC. McLennan P. Fax ⫹61 2 4221 4844. Salem N: Workshop on the essentiality of and recommended dietary intakes for omega⫺6 and omega⫺3 fatty acids. ⫹61 2 4221 3152. Am J Clin Nutr 2003. and AgRP mRNA expression. and ARC leptin receptor. Diabetes Obes Metab 2004. Leaf A. American Diabetes Association: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Brunzell JD.77:S1073–S1082. Owen A. Tapsell.115:21–28. the Western Pacific. 2005. In China’s rural areas – and that’s still more than 800 million people – NCDs account for more than 80% of deaths.000 deaths were attributed to communicable diseases and 2. World Rev Nutr Diet. One example comes from China. Switzerland The Growing Burden of Noncommunicable Diseases In January of 2004. Karger. In 2002. in South-East Asia 5. In the Eastern Mediterranean 1. Low.000 to noncommunicable diseases. the World Health Organization’s (WHO) Executive Board agreed to forward the WHO Global Strategy on Diet.701. Aging. both in high. 9. Geneva.000 deaths were attributed in 2002 to communicable diseases and 7. among the key risk factors.730. which was prompted by Member States’ concern at the explosion in noncommunicable diseases (NCDs). For example. NCDs accounted for 60% of total mortality worldwide and 46% of the global burden of disease [1].Simopoulos AP (ed): Nutrition and Fitness: Mental Health. less than 3% [2. Physical Activity and Health? Amalia Waxman World Health Organization. together with tobacco use. after allowing countries an extended period.000 to noncommunicable diseases and.and middle-income countries account for the increase in burden of disease from NCDs. The burden of NCDs in developing countries already outweighs that of communicable diseases.746.423. communicable diseases. 3]. in this region.000 deaths were attributed to NCDs with 1. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. for comments. Noncommunicable diseases are increasing at alarming rates globally. vol 95.000 to communicable diseases [1].030. The strategy was endorsed by the WHO member states at the 56th World Health Assembly in May 2004.000. The strategy is an important global public health initiative. Only in Africa do deaths from communicable diseases outweigh those from noncommunicable diseases. pp 162–166 Why a Global Strategy on Diet. until 29 February. for which unhealthy diet and physical inactivity are. Basel. .and low-income countries. Physical Activity and Health to its World Health Assembly. The Causes of Noncommunicable Diseases Noncommunicable diseases are increasing for several key reasons. There are globally more than 1 billion overweight people and at least 300 million of them are clinically obese. These demographic changes can be explained by significant improvements in both medical science. In some Pacific Island states as much as 70% of women and about 60% of men in urban areas are obese (BMI ⬎30). and often in combination. The increased prevalence of modifiable risk factors is closely linked to economic development. Obesity is now also a global epidemic [4]. Urbanization is key to understanding lifestyle changes [5]. 16. Of these. high cholesterol.This disease burden is expected to increase to 60% by the year 2020. Global Strategy on Diet. One consequence of this change in world demographics is increased rates of chronic diseases. and most of this growth is projected to occur in Asia. Close to 800 million people are suffering from malnutrition. cancer and mental disorders are expected to be the largest contributors. life expectancy is increasing and populations are aging. birth rates are declining. The number of people with type two diabetes is expected to increase threefold by 2020. physical activity and tobacco use. Food is clearly a major factor in all this. a slow decline over the past decade. Physical Activity and Health 163 . stroke. Countries have not yet been able to successfully defeat the burden of infectious diseases and they are already faced with a double burden of noncommunicable diseases. are the major causes of these diseases. low intake of fruit and vegetables. and successful public health and other development efforts over the last 100 years.7 million are attributed to cardiovascular diseases (CVDs). 33. especially ischemic heart disease and cerebrovascular diseases. These risk factors are indicators of future health status [4]. The world population exposure to the modifiable risk factors for cardiovascular diseases. in most parts of the world. Rapid growth of urban centers results. high body mass index and physical inactivity – independently. Twice as many die from CVDs in developing countries than in developed countries. Five of the top 10 global disease burden risk factors identified by the World Health Report 2002 – high blood pressure. But current risk levels predict major increases in chronic diseases. diabetes and other NCDs is also increasing at a very rapid pace. cancer. Throughout the world. technology. Of the estimated 57 million deaths which occur each year. Heart diseases. Lifestyle and consumption patterns are key determinants of such diseases and include changes in diets.4 million are attributed to NCDs. This report reflects the impact of risk factors over the last decade or so. in deficiencies in housing. multi-stakeholder approach. Upon request by its Member States. therefore. and from the private sector. In addition. The strategy also reflects the expertise and advice of several United Nations organizations. in particular the food and non-alcoholic drinks industry. lifestyles become sedentary with a rapid shift from energyexpenditure-intensive to automated occupations. both developed and developing. Need for a New Approach This is. in particular the Food and Agriculture Organization (FAO). in the etiology of NCDs is robust. representing several fields and disciplines. The strategy builds upon the vast evidence. and experience from countries taught us that we know enough to act and change the current trends. changes in transportation and the increased use of motorized vehicles [6. One of the strategy’s most important conclusions is that reducing the burden of NCDs requires a multi-sectoral. WHO has also received significant input from representatives of civil society and nongovernmental organizations. sugar and salt – but reduced access and affordability of fruits and vegetables. industrialization and expansion of food markets. Waxman 164 . It also draws on the experience and knowledge of health. infrastructure. These involved more than 80 countries in formal meetings. Physical Activity and Health. Populations are exposed to increased availability and aggressive promotion of processed cheap food – generally high in fat. 7]. WHO has over the past 2 years developed the Global Strategy on Diet. Consistent with an approach in which countries participated from the outset. An increase of 82% of caloric sweetener has been recorded due to higher income levels and urbanization. as well as sport manufacturing organizations. Countries need to act now to ensure that developing countries do not experience the high peak in NCD prevalence that has occurred in the developed world. nutrition and physical activity experts from a wide range of disciplines and countries. This trend is accompanied by influences of global trade. All lead to a decrease in energy expenditure. a global epidemic and requires a global response. six regional consultations with Member States were completed between March and June 2003. The evidence for the disease burden is strong. This group provided scientific and policy input and advice for the development of the strategy throughout the process. The science behind the role of the two risk factors. diet and physical activity. best practices and experience in countries in tackling and preventing NCDs. WHO has been supported in this process by a reference group of prominent experts from all over the world. and basic services. The document also elaborates on the role of surveillance and the importance of continued research and evaluation at a national. Many countries are already developing their own national strategies. Key principles are set to guide the development of strategies to address unhealthy diets and physical inactivity: best available scientific evidence. comprehensiveness. nutrition and health claims. addressing issues related to marketing of foods. NGOs. and the accountability of all stakeholders to achieving success. For the private sector the strategy highlights the importance of improving the nutrition profiles of products. The strategy pays much attention to the role of health services and health professionals in primary prevention and urges that diet and physical activity recommendations and follow up are built into health services. especially to children. and agriculture polices can have a great effect on national diets. it suggests that countries provide incentives to promote a healthy diet. The strategy recommends that countries review and evaluate their food and agriculture policies to be consistent with healthy diet. The strategy advocates for policies to change social norms to increase physical activity and incorporate it into daily life. provides WHO Member States with a comprehensive range of policy options from which to choose. a life course perspective. addressing poverty.The strategy is not prescriptive but. level to monitoring progress and trends. provide accurate and balanced information to consumers. The main policy recommendations of the strategy are: for countries to develop national dietary and physical activity guidelines. Member States. especially among the poor. in particular with regard to nutrition labelling. the strategy reiterates the importance of providing clear messages about the benefits and amounts of physical activity levels needed to reduce risks for NCDs. Further. fat (and type of fat) and sugar. as well as a global. Food programmes need to take note of the growing burden of NCDs and their risk factors. multisectoral and multidisciplinary approaches. It stresses the importance of building on existing structures and national mechanisms rather then creating new ones. Many public policies such as transport and urban planning play a huge role in levels of physical activity. What are the policy options the strategy is recommending? The strategy suggests recommendations for action by all stakeholders: WHO. School policies and supportive school environments for healthy diet and physical activity are also recommended. Global Strategy on Diet. In particular. The strategy sees governments assuming a steering role in changing the environment to support their populations and individuals improve their lifestyle. the private sector and UN agencies. like a toolbox. It also advocates for a review of current marketing practices. to reduce salt. gender and culture sensitivities. It suggests that national effective legislation and appropriate infrastructure are critical for introducing effective policies. Physical Activity and Health 165 . Price policies are important as prices determine food choices. No 894.27: 1905–1916.10:277–283. influencing consumers. Lifestyle Changes and the Nutrition Transition. Physical Activity and Health. Sino-America Medical Conference. The World Health Report. Project Manager Global Strategy on Diet. 2003. multi-level involvement with all relevant stakeholders worldwide. Popkin B: The road to obesity or the path for prevention: Motorized transportation and obesity in China. Bell AC. Report of a WHO consultation. Office of the Assistant Director-General Noncommunicable Diseases and Mental Health. Ge K. sustained political commitment. Ms. Finally the strategy appreciates the important role of the United Nations and other intergovernmental organizations in assisting WHO and its Member States in addressing issues which are crucial for implementing the strategy but which are often outside the health sector. The WHO’s goals to advance public health worldwide – and perhaps as importantly. WHO: Obesity: Preventing and managing the global epidemic. BMJ 1995. agriculture policies. Obes Res 2002. to set new public health priorities – can only be met through decisive and coherent action by countries. 2001. and broader. promoting availability of healthy foods and advocating and supporting health promoting programmes. Urbanization. WHO Technical Report Series. Jebb SA: Obesity in Britain: Gluttony or Sloth. Prentice AM.Civil society has a major role to play. Ruitai S: Epidemiology transition in China. East meets West for 21st Century. Ruitai S: The challenge of epidemiology transition in China. Popkin BM:. World Health Organization Avenue Appia 20 CH-1211 Geneva 27 (Switzerland) Tel. World Dev 1999. development programmes.int Waxman 166 . Amalia Waxman. such as: economic analysis. ⫹41 22 791 3353. Chin Prev Med 2001. Boston. But independent action is not enough in an increasingly globalized and interdependent world. E-Mail waxmana@who. National action can be effective – it has provided much of our evidence base for effective interventions. 2000. References 1 2 3 4 5 6 7 WHO: Shaping the Future. The strategy acknowledges its role and describes how NGOs can assist governments in disseminating information.311:437–439. vol 95. I will draw on various federal government documents.000 or so annual deaths in the United States. particularly in the past decade. Obesity in the United States has been increasing steadily over the past several decades. Stanford. Stanford University. According to the Healthy People 2000 review in 1999.000 of the 2. 2005. Aging. The picture with respect to physical activity and fitness is hardly any better. It is now considered to be an epidemic. How did this happen? How did the United States become an overweight. p 7]. eight million children ages 6–19 years are overweight. Moreover. World Rev Nutr Diet. a number that has tripled in the past 20 years. unfit population? In order to provide some perspective on these developments and what is described as the ‘obesity epidemic’ in the United States. pp 167–176 Nutrition and Fitness Policies in the United States Philip R. The costs in terms of the health of the population are enormous.Simopoulos AP (ed): Nutrition and Fitness: Mental Health. Calif. their sedentary lifestyle and their excess alcohol consumption contributes to about 400. Karger. I will review the evolution of public policies related to nutrition. particularly during the past 40 years.. Reports from the US Department of Health and Human Services [1–4]. RAND [5–7] and a growing number of scholars attest to this fact [8–11]. obesity can play a major role in the disability. This amount is the same as the toll from cigarette smoking [11. including those of the . USA Nutrition and fitness policies in the United States must be considered a failure from a public health perspective. sedentary. and the health of the population. fitness. physical activity. Basel. It is now linked to higher health care costs than cigarette smoking or problem drinking. down from 22% in 1985 [12]. Lee School of Humanities and Sciences. In this review. In fact. It has been estimated that the poor diets of Americans.000. only 15% of adults aged 18 years and older engaged in 30 min of moderate physical activity 5 days per week. and the Implementation of a Healthy Diet and Physical Activity Lifestyle. particularly among adults from 30 to 70 years of age. such as eat habits and physical activity. Federal policies on physical fitness during the past 40 years have had little effect. scholarly work with colleagues at UCSF. Commercial interests have had a far greater influence on nutrition policies than the public interest [11]. particularly after the publication in 1974 of the report A New Perspective on the Health of Canadians [14] that health behaviors. Education and Welfare (DHEW). particularly the behavior of the individual. and local level [13]. the Department of Agriculture (USDA). and schools. Finally. insurance companies. It was not until the 1970s. Throughout I will stress the tensions between a population health perspective and a focus on individual behavior or lifestyle. President Clinton transferred the support for the Council to DHHS to achieve greater integration with the work of the Office of Disease Prevention and Health Promotion in the Office of the Assistant Secretary for Health. prior to 1980. Historical Perspective Physical Fitness and Physical Activity Physical fitness was of little interest to federal policymakers. as an important factor in health. particularly at the federal level. except those in the armed forces until President Eisenhower created the President’s Council on Youth Fitness and Sports by Executive Order in 1956 after the President learned that American children were less fit than European children. After my historical review. The bad habits Lee 168 . A great deal of attention was paid to health promotion. Over the decades. I will examine some of the forces that have influenced and continue to influence the public policy process. the President’s Council devoted relatively little attention to health-related fitness activities for the whole population and concentrated primarily on working with private industry. as well as contributions by the Institute of Medicine and Professor Marion Nestle of New York University.Department of Health and Human Services (DHHS). Many of America’s health problems were labeled ‘behavioral’ or ‘lifestyle’ problems. the Department of Health. Over the years. state. and the US Congress. began to attract the attention of policymakers. Presidents have expanded the Council’s mandate to include all Americans and changed its name to the President’s Council on Physical Fitness and Sports. I will discuss some recent policy developments that may affect current trends. on my service as Assistant Secretary for Health and Scientific Affairs in DHEW during the Johnson Administration (1965–1969) and the Assistant Secretary for Health in DHHS during the first Clinton Administration (1993–1997). President Bush has continued the emphasis on linking the Council’s activities to health promotion efforts at the national. g.’ three key variables were stressed: nutrition. The 25 years between these two clear statements has seen more words than effective action. there were a number of important developments in the DHEW. too much drinking. This point of view was expressed succinctly in 1977 by the late Dr. driving too fast. listed Physical Activity and Fitness as the first priority and nutrition as second [23]. In the late 1970s. released in 1990. staying up at night. engaging in promiscuous sex. While legislation enacted in the mid-1970s included an emphasis on health promotion and disease prevention. He also initiated what has become known as the Healthy People process. In 1978. The potential role of employee health programs and school physical education programs in promoting exercise were noted. and exercise. convened a national health summit in 2003 ‘to call on Americans to take the steps that will lead to a healthier nation’ [22]. chronic disease. taking pills. under the leadership of Dr. and smoking cigarettes’ [15]. California demonstrated the importance of seven health-related behaviors (e. the Secretary of DHHS. population-based studies in Alameda County. Healthy People 2000: National Health Promotion and Disease Prevention Objectives. John Knowles. maintaining normal body weight. the Assistant Secretary for Health/Surgeon General. Twenty-five years and eight Secretaries of DHEW and DHHS later. ‘Enhance General Physical and Emotional Well Being. He began to shift the focus of federal health policy from health services and financing medical care to health promotion and disease prevention. ‘The Responsibility of the Individual’: ‘Prevention of disease means forsaking the bad habits which many people enjoy – overeating.were said to contribute to the growing burden of chronic illness. In the goal. communicable disease).g. Beginning in the 1960s. the DHEW Task Force on Disease Prevention and Health Promotion identified strategy targets in 12 categories of health-related goals (e. the figures for black females had risen from 44 to 52%. Tommy Thompson. engaging in regular physical activity) in increasing life expectancy among those who maintained these behaviors compared to those who did not engage in at least four of these healthy behaviors [16–18]. Julius Richmond. The Task Force stated a theme that was to be repeated over the years: ‘A strong national commitment to disease prevention and health promotion is needed to ensure that Americans will be a truly healthy population’ [21]. 20]. the percentage of overweight adults (age 20–74 years) had risen from 26% in 1976–1980 to 35% in 1994. the legislation had little impact on health promotion and disease prevention policies at the state or local levels [19. unwanted fertility/family planning. increasing demand for health care and contributing to the rising costs of health care. who was then President of the Rockefeller Foundation in an essay entitled. for Hispanic females from 33% in 1990 to 35% in 1995 and for Nutrition and Fitness Policies in the US 169 . At the Healthy People 2000 Review in 1998–1999. This broader perspective was evident in the breadth of actions needed to achieve equity: ‘Healthy People 2010 recognizes that communities. The actual causes of death identified by McGinnis and Foege [24] are headed by tobacco (19%) and poor diet/lack of exercise (14%). headed by diseases of the heart (29. The focus shifted from an emphasis on intensive. We do not seem to have made much progress since 1979 when Dr. During recent decades overweight prevalence has increased significantly and levels of light to moderate physical activity and vigorous activity have changed little. and national organizations will need to take a multidisciplinary approach to achieving health equity – an approach that involves improving health.9%). all cancers (22. Vigorous physical activity for children and adolescents (age 10–17 years) was stable at 64 percent. released in January 2000. the method of calculating the cause of death differed sharply from the usual listing of the most common causes of death. African Americans and Hispanics.9%).5%). the picture is not a good one. The importance of health-related behavior. agriculture and the environment. ‘Actual Causes of Death in the United States. Lee 170 . For example. represented a significant shift from past Healthy People publications in the goal to ‘eliminate health disparities’ and its greater consideration of the relationship of education and household income to health status. for adults (18 years and older). Healthy People 2010. and stroke (6. The report noted low levels of physical activity among the majority of adults including 25% who are not active at all. In this paper.low-income females aged 20–74 from 37% in 1976–1980 to 47% in 1991. education. many suburbs lack sidewalks and in many inner city areas the sidewalks are not safe for the elderly walking alone or for children walking to school. was stressed by McGinnis and Foege in their famous paper. only 27% of students in grades 9–12 were engaged daily in physical education at school. states. among older adults and among the less affluent. justice.’ published in 1993. regular aerobic physical exercise to a wide range of health enhancing physical activities. or lifestyle. as I noted at the outset of this paper. However. housing. as well as data collection itself’ [26]. transportation. The 1996 Surgeon General’s Report on Physical Activity and Health reflected a major change in thinking about physical activity at the federal level [25]. labor. the figure was only 16% engaged in vigorous physical activity [12]. The population reporting no leisure time physical activity was higher among women. lack of access to convenient facilities and lack of a safe environment in which to be active. Physical activity is now considered a leading health indicator and. Richmond issued his first health objectives for the nation. It is important to note that the barriers most adults face when trying to increase physical activity are lack of time. and the Child Nutrition Program. How to Select Food. but the nutrition program for the elderly was administered by the Administration on Aging/DHHS. related to the harm done to our health by the excessive consumption of sugar and large quantities of fat meats. The establishment of the Food and Nutrition Board. and (2) to provide information to the public on ‘subjects connected to agriculture in the most general way. While establishing precedents with respect to food groups and dietary advice. the Select Committee began to address broader nutrition policies [28]. and (2) expansion of the Food Stamp Program in order to protect the poor from food price inflation. revealed serious problems of malnutrition among the poor. President Johnson outlined the Food for Freedom Program. the US Department of Agriculture (USDA) had two functions: (1) to assure a reliable and adequate food supply. the School Lunch Program. In 1917.’ which has been interpreted as giving dietary advice [11. by the Citizen’s Board of Inquiry. Atwater. chaired by Senator McGovern. The DHEW began nutrition surveys after the report. From its foundation in 1862. became a key player in the development of federal policies for food assistance for the poor in the late 1960s and early 1970s. also called the ‘war on hunger’. Hunger USA [27]. The period from the turn of the century to the 1960s has been described by Professor Marion Nestle as ‘Eat More – Preventing Dietary Deficiencies 1890 to 1960s’ [11]. By the mid1970s. In the mid-1960s. W.O. While domestic issues initially attracted the Select Committee’s attention. the USDA issued its first set of dietary recommendations in a 14page pamphlet. Most of these programs were administered by the USDA. In addition. permitting all foods to be recommended. it ignored the analysis of the USDAs first director of research. The Senate Select Committee on Nutrition and Human Needs. The Child Nutrition Act established the School Breakfast Program. Nutrition and Fitness Policies in the US 171 . a number of food assistance programs were expanded in the 1970s – including the Food Stamp Program. there were two modest expansions of nutrition policies: the Food Stamp Program in 1965 and the Child Nutrition Act of 1966. In addition. a nutrition program for the elderly was launched. p 33]. National Research Council. Based on the survey results. it was the grain shortage in the Soviet Union and the inflation produced by the Arab oil embargo in the early 1970s that led Congress to take broader measures to ensure adequate food supply that have continued to this day: (1) income support for farmers to assure adequate food production. National Academy of Sciences in 1941 and the enactment of the School Lunch Program by Congress in 1946 were early developments in nutrition policy.Nutrition Policy A sound nutrition policy is fundamental to any effort to improve our nation’s health. especially animal fats. sugar. after years in preparation. The report described the magnitude of the problem as follows: ‘As the diseases of nutritional deficiency have diminished. The campaign included specific advice regarding the intake of fat. The Dietary Guidelines for Americans were first issued jointly by the USDA and DHHS in February 1980 as the consensus about the relationship of diet to a variety of chronic diseases grew. Although many areas of agriculture policy that are germane to the consideration of this conference remain controversial. and generate substantial health care costs’ [31]. and calories. and Congress gave added nutrition responsibilities to the USDA to be shared with DHEW. touch the lives of most Americans. saturated fat. the Surgeon General’s Report on Nutrition and Health gave special emphasis to the importance of obesity as a public health problem and on the need to reduce the intake of total fats. which generated a great deal of controversy because of its recommendations to eat less fat. I will focus on dietary recommendations and nutrition policy – an area of continuing conflict. In 1988. the DHHS issued the Surgeon General’s Report on Nutrition and Health [31]. The Task Force recommended. especially saturated fat. particularly coronary heart disease. In 1977. The shift in policies from eat more to eat less was also reflected in the DHEW Task Force Report on Disease Prevention and Health Promotion [21] and in the Surgeon General’s Report Healthy People [30] in 1979. especially saturated fats [31]. Dietary Goals for the United States [29]. The Dietary Goals represented a fundamental shift in federal dietary advice from ‘eat more’ to ‘eat less’ [11]. Lee 172 . The controversy and intense pressure by the food industry interest groups led the Select Committee to modify its recommendations regarding salt. In the mid-1980s. While providing support for the Dietary Guidelines for Americans. cholesterol. and Blood Institute/National Institutes of Health launched a major nationwide campaign to lower blood cholesterol across the entire population. cholesterol and meat consumption. the National Heart. nutrition policymakers began to pay attention to the research that elucidated the relationship between diet and chronic illness. including dietary advice to the public.Regulation of food labeling was stepped up by the Food and Drug Administration (FDA). and salt should be reduced as part of a prudent diet’ [21]. they have been replaced by diseases of dietary excess and imbalance – problems that now rank among the leading causes of illness and death in the United States. refined carbohydrates. in the Food and Agriculture Act of 1977 [11]. Just as the advances in research related to exercise and other determinants of health began to shift health policies in the DHEW toward health promotion and disease prevention. the Senate Select Committee on Nutrition and Human Needs issued its report. Lung. ‘total fat intake. Some policies. The Policy Process Why.’ Policy learning is a fairly subtle and gradual process. According to Paul Sabatier and Hank Jenkins-Smith. This has been described by Kingdon as a ‘window of opportunity’ [32]. Other analysts have focused on the reasons why certain policies are so resistant to change. would benefit from a lifestyle that includes more physical activity and a diet containing fewer calories’ [31]. even with a major shift in political power or other external circumstances. change their ‘nearcore’ policy-oriented beliefs and a variety of ‘secondary’ beliefs when new information successfully challenges their claims about the nature of a problem Nutrition and Fitness Policies in the US 173 . but reflect the public policy process more broadly. economic. In the absence of changes in broader. when policy options had been developed and when the political stream was aligned with the problem and the policy streams. it is often difficult for government to respond to even serious problems because an effective response would violate the core values of an advocacy coalition. was it so difficult during the past 25 years to reach agreement on dietary advice and to implement programs that dealt more effectively with the increasingly obese population? In part. it would also have a negative economic impact on all those who raise. longterm policy change depends on the competition among two or more ‘advocacy coalitions’ whose members monitor and actively try to influence specific policy issues. process. Altering dietary advice to advise people to eat less red meat would not only violate the core values of some about the proper role of government. when the research related to diet and exercise was so consistent. were initiated when there was agreement on the problem. the answer is politics and the policy process. however. Sabatier and Jenkins-Smith observe that policy can still change if partisan positions are modified through a process of ‘policy learning. In their view.In the section on Implications for Public Health Policy. food companies exerted significant influence on dietary guidelines and nutrition policy. or political conditions. which dictate their basic orientation to an issue and the role of government. and market beef. such as Food Stamps and agricultural subsidies. The practice of the food companies and the response of government are not unique. Professor John Kingdon has been a longtime student of Congress and how an issue becomes a priority for policymakers and is enacted into law. contextual conditions. in general. They effectively lobbied Congress and members of the executive branch as well as co-opted nutrition experts as allies. However. slaughter. The members of an advocacy coalition almost never change their deep-core values and beliefs. During this period. most policy change is the product of shifts in large-scale social. They may. the report noted: ‘Americans. Because dietary advice affects food sales. and local governments. The struggle in terms of policy and politics is over the way the government balances corporate interests and the public interest. p 28]. current policies may become indefensible and a coalition may accept new methods of governmental intervention [33]. we have seen in the case of cigarette smoking and the tobacco companies that a combination of grass roots organizations and legal challenges can dramatically change the landscape. In short. ‘Lawyers Shift Focus From Big Tobacco to Big Food’ [35]. Will the next 20 years be any different? Will the growing efforts to stimulate action at the grassroots with respect to obesity. and because companies demand a favorable regulatory environment for their products. by health professionals themselves. by community organizations. if the health of Americans is to improve. To date.or the effectiveness of a solution. p 146]. dietary practices raise political issues that cut to the heart of democratic institutions’ [11. In tobacco suits. Twenty-three years ago. more complex. The New York Times has reported changes in the landscape of food politics in a recent article. Some of these efforts seem to be bearing fruit. the lawyers became successful when they focused on deceptive marketing rather than personal injury. Professor Nestle astutely summarized the issue when she wrote: ‘Diet is a political issue. However. chronic disease and disability is growing. however. The process is. The record of the past 23 years has not been a good one in achieving national health objectives related to physical activity and nutrition. and physical activity now be successful when they have had so little impact in the past? The evidence about physical activity and diet in relation to health status. lawyers have settled five cases out of court. Time will tell whether a broad-based movement can be initiated and sustained. This appears to be the focus in the current food cases. Thomas and coworkers wrote: ‘The health prospects of Americans during the last two decades of the twentieth century will depend on the quality of decisions made by federal. Efforts by the Surgeon General of the US Public Health Service in collaboration with nonprofit and professional organizations and several major foundations have initiated national efforts to increase physical activity among adults. and by families and individuals acting on their own behalf. the balance has favored the corporate interests. one with McDonalds. and one with the New York City school system. Lee 174 . overweight. by voluntary and professional health associations. To date. Given a new understanding of the problem and potential remedies. state. by business and industry. three with major food companies. both individual and collective actions will be necessary’ [34. Evans J. Centers for Disease Control and Prevention.347: 305–313. 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With Understanding and Improving Health and Objectives for Improving Health. Harper-Collins College Publishers. Philips BW. Healthy People 2000: National Health Promotion and Disease Prevention Objectives. US Government Printing Office.gov/steps/. Washington. Health Resources Administration: Papers on the National Health Guidelines: Baseline for Setting Health Goals and Standards. Available from: http://www. Senate Select Committee on Nutrition and Human Needs: Dietary Goals for the United States. Alternatives. US Government Printing Office. Office of the Assistant Secretary for Health and Surgeon General: Healthy People: The Surgeon General’s Report on Health Promotion and Disease Prevention. New York. National Nutrition Consortium Guidelines for a National Nutrition Policy. U. US Government Printing Office. and Public Policies. Office of Disease Prevention and Health Promotion. Washington. Senate Select Committee on Nutrition and Human Needs. Sect.edu Lee 176 . US Department of Health and Human Services. Inner Quad. DHEW Publication No (HRA) 76–640. Kingdon J: Agendas. Washington. Public Health Service. Washington. Oliver T. Prevent Med 1980. E-Mail prl@stanford. April 8. Fax ⫹1 650 725 5451.healthierus. DHEW (PHS) Publication No 79–55071B. The New York Times. Available from: www. US Department of Health and Human Services. Washington. Lee Program in Human Biology Bldg. ed 2. US Government Printing Office. Lipton HL: A Political History of Medicare and Prescription Drug Coverage. US Congress. DHHS: The Surgeon General’s Report on Nutrition and Health. Philip R. Higgins WC. and Welfare. Washington.in press. A. 1995. Public Health Service. 2000. 1978.32:153].healthypeople. DHEW Publication No PHS 79–55071. Education. 2004. Gunn & Hain. Physical Activity and Health: A Report of the Surgeon General. 1977. M.R. L. 115 Fruttini. C. 52 Ito. 115 Gillen. de 103 Lupien. F.E. 162 Yamada.P. 1 Kang.L. 62 Waxman.J. D.S. P. 93 Dubnov. P. G. R. M. 151 Berry. 17 Salen. M. 73 Ichikawa. A.Author Index Alberti. A.S. 115 Fujii. J. XXXIII Fidanza. M. F.C. Y. F. XIV. S. A. 122 Wahlqvist. 52 Okuyama. 151 Peet.M. E. 103 Simopoulos. S.X. 29 Booth. A. 52 177 .R.L. 52 Casper. 29 Lee. 140 Patch.C. J. 52 Urquiaga. H. K. 73 Leighton. 151 Ferrari. L. 122 Lorgeril. Y. 35 Ferris. 80 Tapsell. 167 Lees. I.W. Subject Index Aggression monoamine oxidase polymorphisms in type A gene 2 omega–3 fatty acid treatment trials 9 Alzheimer disease benefits of moderate alcohol consumption 124 cognitive function effects of nutrients 9, 10 Apolipoprotein E, gene polymorphisms and schizophrenia 2, 3 Atherosclerosis dietary fatty acids and plaque composition 111 epidemiological benefits of moderate alcohol consumption 122–125 inflammation role 109 oxidized low-density lipoproteins 109–111 prevention 108, 109 risk factors 163, 164 Australia food industry 151 intersectoral partnerships in food 154–156 National Centre of Excellence in Functional Foods diabetes type 2 case study of walnuts 157–159 market perspective 153, 154 nutrition perspective 152, 153 organizations and partnerships 156, 157 prospects 159, 160 regulatory perspective 153 novel food regulation 148 obesity rates 155 Bipolar disorder, omega–3 fatty acid treatment trials 7 Bone mineral density, see Osteoporosis Brain-derived neurotrophic factor (BDNF), schizophrenia neuropathology 23 Cancer alcohol benefits of moderate alcohol consumption 123, 133 deleterious effects 126 fat-1 omega–3 fatty acid desaturase gene transfer effects in breast cancer cell line 95, 97 mortality trends 52, 53 omega–3 fatty acids in prevention 57, 58 Cardiomyocytes, fat-1 omega–3 fatty acid desaturase gene transfer effects 94, 95 Collagen 1␣1, osteoporosis gene polymorphisms 41 Cooking Greek diet 86, 87 Nicotera diet 118 Coronary heart disease, see Atherosclerosis 178 Declaration of Olympia on Nutrition and Fitness XXV–XXXI Depression, omega–3 fatty acid studies clinical trials of treatment 5, 6, 12 deficiency in patients 5 postpartum depression treatment 6, 7 Diabetes type 2 benefits of moderate alcohol consumption 124 National Centre of Excellence in Functional Foods case study of walnuts 157–159 Diet and Reinfarction Trial (DART), omega–3 fatty acid protection 103, 105 Dietary Guidelines for Americans, establishment 172 Disease definition 73 physical inactivity as disease 73–78 Docosahexaenoic acid, see Omega–3 fatty acids Eicosapentaenoic acid, see Omega–3 fatty acids Energy density, calculation 66 Estrogen, cardioprotective mechanisms 129 Estrogen receptor, osteoporosis gene polymorphisms 40 European Union, novel food regulation 144–147 Exercise, see Physical activity fat-1, omega–3 fatty acid desaturase gene transfer studies cultured cell studies breast cancer cell line 95, 97 cardiomyocytes 94, 95 fatty acid composition effects 94, 95 human umbilical vein endothelial cells 97 neuronal apoptosis 97, 98 rationale 93, 94 transgenic mice diet study prospects 100, 101 fatty acid profile 99, 100 production 98 Subject Index Free radical theory of aging, overview 55, 56 Functional food, see National Centre of Excellence in Functional Foods; Novel food Global Strategy on Diet, Physical Activity, and Health, implementation 164–166 GLUT4, physical activity effects on muscle levels 76 Greek diet bioprotective nutrients compared with other Mediterranean diets 86 characteristics 87, 88 Crete death rates 80, 81 fatty acid composition and protective effects 82–85 food preparation considerations 86, 87 Lyon Heart Study 88, 111 Healthy Italian Mediterranean Diet Temple Food Guide (HIMDTFG), development 119, 120 Healthy People 2000, overview 169, 170 Healthy People 2010, overview 170 High-density lipoprotein (HDL), wine induction 127–129 HIMDTFG, see Healthy Italian Mediterranean Diet Temple Food Guide Human umbilical vein endothelial cell (HUVEC), fat-1 omega–3 fatty acid desaturase gene transfer effects 97 Interleukin-6, osteoporosis gene polymorphisms 41, 42 Intrauterine growth retardation antenatal exercise effects on birth weight 11, 12 health risks later in life 3 Japan dietary fatty acids and disease 52–54 novel food regulation 147, 148 Leptin, derangements in physical inactivity 75, 76 ␣-Linolenic acid, cooking effects 59 179 LRP5, osteoporosis gene polymorphisms 42, 43 Lyon Heart Study, cardioprotective effect of Crete diet 88, 111 Mediterranean Adequacy Index (MAI), comparison of Mediterranean diets 118–121 Mediterranean diet, see Greek diet; Nicotera diet Menopause, physical activity and exercise prescription in postmenopausal weight loss 31, 32 Monoamine oxidase (MAO), polymorphisms in type A gene and aggression 2 National Centre of Excellence in Functional Foods (NCEFF), see Australia Neurons, fat-1 omega–3 fatty acid desaturase gene transfer effects on apoptosis 97, 98 Neutriceuticals, European Union regulation 144, 145 Nicotera diet dietary habits 116, 117 food preparation 118 Healthy Italian Mediterranean Diet Temple Food Guide development 119, 120 meal patterns 116–118 Mediterranean Adequacy Index for comparison with other Mediterranean diets 118–121 overview of lifestyle 115 Nitric oxide (NO), polyphenol induction 133, 134 Noncommunicable diseases causes 163, 164 global burden 162, 163 global strategy for prevention 164–166 Novel food, see also Australia claims 141, 142, 148, 149 definition 140, 141, 146 examples and potential benefits 143, 144 prospects for study 148, 149 Subject Index regulation European Union 144–147 Japan 147, 148 United States 146 Nutrient density, calculation 66 Obesity Australia 155 complications 30 energy throughput vs intake importance 64, 65 etiology 29, 30 lifestyle modification for weight loss 30, 31 pathways to abdominal obesity 66 physical activity and exercise prescription in postmenopausal weight loss 31, 32 prevalence 29, 64, 163 United States 167, 175 Olive oil, composition and health benefits 87 Olympics, history and positive health parameters XXXIII–XXXVI Omega–3 fatty acids aggression treatment trials 9 Alzheimer disease cognitive function effects 9, 10 anti-inflammatory activity 56, 57 benefits in aging 59, 60 bipolar disorder treatment trials 7 cancer prevention studies 57, 58 depression studies clinical trials of treatment 5, 6, 12 deficiency in patients 5 postpartum depression treatment 6, 7 desaturase gene, see fat-1 gene expression regulation 54 metabolic competition with other fatty acids 53, 54 prenatal deficiency and cognitive development disorders 4, 55 schizophrenia treatment trials 7–9, 12, 24, 25 sudden cardiac death protection 103–108 180 Omega–6 fatty acids gene expression regulation 54 inflammation promotion and peroxidative injury 56, 57 metabolic competition with other fatty acids 53, 54 sudden cardiac death studies 107, 108 Omega–6/omega–3 fatty acid ratio fat-1 omega–3 fatty acid desaturase gene transfer studies cultured cell studies breast cancer cell line 95, 97 cardiomyocytes 94, 95 fatty acid composition effects 94, 95 human umbilical vein endothelial cells 97 neuronal apoptosis 97, 98 rationale 93, 94 transgenic mice diet study prospects 100, 101 fatty acid profile 99, 100 production 98 geographic differences 80, 81 Greek diet 84, 85 trends 80 Western diet 93 Osteoporosis bone mineral density genome screening for quantitative trait loci 37 measurement 35, 36 epidemiology 35, 36 fracture risk 35 gene polymorphisms collagen 1␣1 41 estrogen receptor 40 interleukin-6 promoter 41, 42 LRP5 42, 43 screening guidelines 44 vitamin D receptor 38–40 heritability of bone mass and strength 36, 37, 43 Physical activity antenatal exercise effects on birth weight 11, 12 decline 62 Subject Index eco-nutritional disease prevention 69, 70 emotional health benefits 10, 11 exercise prescription in postmenopausal weight loss 31, 32 goals 63, 64 inactivity as disease 73–78 optima 63 overview of benefits, XXXVII–XL, 67 preventive medicine 67, 68 public policy in United States 168–170 therapeutic physical activity 69 Platelet aggregation, inhibition by wine 129 Polyphenols anti-inflammatory activity 133 anticarcinogenesis activity 1333 antioxidant activity 131, 132 antithrombotic activity 132 bioavailability in wine 130, 131 nitric oxide induction 133, 134 protein interactions 133 President’s Council on Physical Fitness and Sports, historical perspective 168 Schizophrenia apolipoprotein E gene polymorphisms 2, 3 clinical features 17 intrauterine growth retardation as risk factor 3 nutrition interactions case-control studies 20 cross-national ecological studies 18, 19 historical studies of diet 20–22 intervention studies 23–25 neuropathology 22, 23 omega–3 fatty acid treatment trials 7–9, 12, 24, 25 outcomes in developing vs developed countries 17, 18 Seven Countries Study, cardiovascular disease rates 81, 82 Sudden cardiac death (SCD) epidemiology 102 omega–3 fatty acid protection 103–108 omega–6 fatty acid studies 107, 108 181 osteoporosis gene polymorphisms 38–40 Vitamin E. Alzheimer disease cognitive function effects 9. 130 United States economic impact of poor lifestyle 167 novel food regulation 146 obesity rates 167. cooking effects 59 Vitamin C. Alzheimer disease cognitive function effects 9. 174 Urokinase plasminogen activator (u-PA). and Health 164–166 Wine cardioprotective mechanisms fibrinolytic activity 129 Subject Index 182 . 10 heat shock protein induction 130 high-density lipoprotein induction 127–129 platelet aggregation inhibition 129 polyphenols anti-inflammatory activity 133 antioxidant activity 131. 131 nitric oxide induction 133. 175 public policy and trends nutrition 170–173 physical fitness and physical activity 168–170 policy process 173. wine effects 129. 132 antithrombotic activity 132 bioavailability 130. Global Strategy on Diet. 125 deleterious effects of alcohol consumption 126 epidemiological benefits of moderate alcohol consumption 122–125 French paradox 122 World Health Organization (WHO). wine effects 130 Vegetable oils.Tissue plasminogen activator (t-PA). 134 protein interactions 133 cirrhosis risks compared with other alcoholic beverages 124. 10 Vitamin D receptor (VDR). Physical Activity.