Calorie Restriction, Aging and Longevity

Arthur V. Everitt · Suresh I.S. Rattan ·David G. Le Couteur · Rafael de CaboEditors

Calorie Restriction, Agingand Longevity

123

EditorsArthur V. EverittCERA C22, The University of Sydney,Sydney 2006Australiaarthureveritt42@bigpond.com

Suresh I.S. RattanUniversity of Aarhus8000 AarhusDenmarkrattan@mb.au.dk

David G. Le CouteurCERA C22, The University of Sydney,Sydney 2006Australiadavid.lecouteur@sydney.edu.au

Rafael de CaboNational Institute of HealthNational Institute on AgingGerontology Research CenterBaltimore MD 21224USAdecabora@mail.nih.gov

ISBN 978-90-481-8555-9 e-ISBN 978-90-481-8556-6DOI 10.1007/978-90-481-8556-6Springer Dordrecht Heidelberg London New York

Library of Congress Control Number: 2010922314

© Springer Science+Business Media B.V. 2010No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or byany means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without writtenpermission from the Publisher, with the exception of any material supplied specifically for the purposeof being entered and executed on a computer system, for exclusive use by the purchaser of the work.

Printed on acid-free paper

Springer is part of Springer Science+Business Media (www.springer.com)

To my wife, Joyce, with love, and my son Michael,my daughter Sue, and their familiesWishing everyone healthy, happy and long lives

Arthur

Preface

Food or calorie restriction has been shown in many short-lived animals and therhesus monkey to prolong life-span. Life-long nutrition studies are not possiblein humans because of their long survival. Studies over 2–6 years in healthy adulthumans have, however, shown that a 20% reduction in food or calorie intake slowsmany indices of normal and disease-related aging. Thus, it is widely believed thatlong-term reduction in calorie or food intake will delay the onset of age-relateddiseases such as heart disease, diabetes and cancer, and so prolong life.

Over the last 20 or more years there has been a progressive rise in food intakein many countries of the world, accompanied by a rising incidence of overweightand obesity. Thus our increasing food and calorie intake has been linked to the risingincidence of cardiovascular disease and diabetes in early adult life. It is accepted thatovereating, accompanied by reduced physical exercise, will lead to more age-relateddiseases and shortening of life-span. What can be done? Put simply, the answeris to reduce our calorie intake, improve our diet, and exercise more. But calorierestriction is extremely difficult to maintain for long periods. How then can we solvethis problem? This book provides the latest information on the beneficial effects ofcalorie restriction on health and life-span and brings us closer to an understandingat the molecular, cellular and whole organism level of the way forward.

Sydney, Australia Arthur V. EverittAarhus, Denmark Suresh I.S. RattanSydney, Australia David G. Le CouteurBaltimore, Maryland, USA Rafael de Cabo

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Acknowledgments

It was a great pleasure to accept the invitation of Dr Max Haring from SpringerPublishing to prepare this volume on Calorie Restriction, Aging and Longevity. Iam indebted to Professor Suresh Rattan, Professor David Le Couteur and Dr Rafaelde Cabo who kindly agreed to help with editing and arranging authors for certainchapters. I am deeply grateful to all our numerous contributors who have workedso hard to produce the latest reviews on calorie restriction and aging in their specialareas. This has been a long haul and many of our authors have worked under consid-erable stress to produce their manuscripts on time. I am especially grateful to DavidLe Couteur, Brian Morris and Joe Stewart for their help in solving certain problemsin preparing manuscripts and again to David and Joe and also Marisa Wright forhelp with final changes before submission to Springer. The advice of Max Haringwas invaluable in guiding our preparation of the final manuscript. I wish to thankProfessor Holly Brown-Borg and Professor Andrzej Bartke personally for helpingme to continue my 45year link of calorie restriction with pituitary hormones in theregulation of aging.

Financial support for the editing and writing of these reviews at the Centre forEducation and Research on Ageing at Concord RG Hospital and The University ofSydney comes from the Ageing & Alzheimers Research Foundation, a division ofthe Medical Foundation of The University of Sydney.

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Contents

Part I Calorie Restriction in Different Species

1 History of Caloric Restriction, Aging and Longevity . . . . . . . . 3Edward J. Masoro

2 Food Intake, Life Style, Aging and Human Longevity . . . . . . . 15Arthur V. Everitt, Leonie K. Heilbronn, and David G. Le Couteur

3 Okinawa: A Naturally Calorie Restricted Population . . . . . . . 43Matthew W. Rosenbaum, Bradley J. Willcox, D. CraigWillcox, and Makoto Suzuki

4 Aging and the Effect of Calorie Restriction in RhesusMonkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55Ilhem Messaoudi, Jennifer E. Young, Ricki J. Colman,April M. Handy, George S. Roth, Donald K. Ingram,and Julie A. Mattison

5 Dietary Restriction and Aging in Drosophila Melanogaster . . . . 79Luc Poirier, Rafael de Cabo, and Sige Zou

6 Aging and Dietary Restriction: The Yeast Paradigm . . . . . . . . 97Min Wei, Federica Madia, Rafael de Cabo,and Valter D. Longo

7 The Nutritional Geometry of Aging . . . . . . . . . . . . . . . . . 111Stephen J. Simpson and David Raubenheimer

Part II Biochemical and Metabolic Mechanismsof Calorie Restriction

8 Oxidative Stress, Dietary Restriction and Aging . . . . . . . . . . 125Brian J. Merry and Catherine E. Ash

9 Calorie Restriction Mimetics and Aging . . . . . . . . . . . . . . . 141Brian J. Morris

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xii Contents

10 Will Calorie Restriction Stave Off Age-Related BrainDysfunction, Specifically to Learning and Memory?A Review and Critique of the Rodent Literature . . . . . . . . . . 177Edward L. Spangler, Jeffrey Long, Bennett Kelley-Bell,Marshall Miller, Robin K. Minor, and Rafael de Cabo

11 The Aging Liver and the Effects of Long Term CaloricRestriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191David G. Le Couteur, David A. Sinclair, Victoria C. Cogger,Aisling C. McMahon, Alessandra Warren, Arthur V. Everitt,Michel Lebel, and Rafael de Cabo

12 Food Restriction, Hormones, Genes and Aging . . . . . . . . . . . 217Arthur V. Everitt, Holly M. Brown-Borg,David G. Le Couteur, and Andrzej Bartke

13 Hormesis as a Mechanism for the Anti-Aging Effects ofCalorie Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . 233Suresh I.S. Rattan and Dino Demirovic

Part III Calorie Restriction in the Clinical Setting

14 Calorie Restriction and Obesity . . . . . . . . . . . . . . . . . . . 249Krista A. Varady

15 Caloric Restriction and Cardiovascular Disease . . . . . . . . . . 263Anna Csiszar, Rafael de Cabo, and Zoltan Ungvari

16 The Effect of Caloric Restriction on Physiological,Psychological and Behavioral Outcomes in Humans:Results from CALERIE . . . . . . . . . . . . . . . . . . . . . . . . 279Leanne M. Redman and Eric Ravussin

17 Calorie Restriction and Cancer: An Update . . . . . . . . . . . . 301Robin K. Minor, R. Michael Anson, and Rafael de Cabo

18 Conclusion: Human Calorie Restriction and Anti-agingTherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311Arthur V. Everitt, Leonie K. Heilbronn, Brian J. Morris,Holly M. Brown-Borg, Brian J. Merry, Stephen J. Simpson,Krista A. Varady, Edward J. Masoro, Leanne M. Redman,and David G. Le Couteur

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319

Contributors

R. Michael Anson Aging, Metabolism and Nutrition Unit, Laboratory ofExperimental Gerontology, National Institute on Aging, National Institutes ofHealth, Baltimore, MD 21224, USA

Catherine E. Ash School of Biological Sciences, Biosciences Building,University of Liverpool, Liverpool, L69 7ZB, UK

Andrzej Bartke Geriatrics Research, Departments of Internal Medicine andPhysiology, School of Medicine, Southern Illinois University, Springfield, IL62794, USA

Holly M. Brown-Borg Department of Pharmacology, Physiology andTherapeutics, School of Medicine and Health Sciences, University of NorthDakota, Grand Forks, ND 58203, USA

Victoria C. Cogger ANZAC Research Institute, Centre for Education andResearch on Ageing, Concord RG Hospital, The University of Sydney, Sydney,Australia

Ricki J. Colman Wisconsin National Primate Research Center, University ofWisconsin, Madison, WI 53715, USA

Anna Csiszar Department of Geriatric Medicine, Reynolds Oklahoma Center onAging, University of Oklahoma Health Science Center, Oklahoma City, OK73104, USA

Rafael de Cabo Laboratory of Experimental Gerontology, National Institute onAging, National Institutes of Health, Baltimore, MD 21224, USA

Dino Demirovic Laboratory of Cellular Ageing, Department of MolecularBiology, Aarhus University, Aarhus, Denmark

Arthur V. Everitt Centre for Education and Research on Ageing, Concord RGHospital, University of Sydney, Concord, NSW 2139, Australia; Discipline ofPhysiology, School of Medical Sciences, The University of Sydney, NSW 2006,Australia

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xiv Contributors

April M. Handy Intramural Research Program, Laboratory of ExperimentalGerontology, National Institute on Aging, National Institutes of Health,Poolesville, MD 20837, USA; SoBran Inc., Fairfax, VA 22031, USA

Leonie K. Heilbronn Diabetes and Obesity Program, Garvan Institute of MedicalResearch, Darlinghurst, NSW 2010, Australia

Donald K. Ingram Nutritional Neuroscience and Aging Laboratory, PenningtonBiomedical Research Center, Louisiana State University, Baton Rouge, LA70808, USA

Bennett Kelley-Bell Laboratory of Experimental Gerontology, National Instituteon Aging, National Institutes of Health, Baltimore, MD 21224, USA

David G. Le Couteur ANZAC Research Institute, Centre for Education andResearch on Ageing, Concord RG Hospital, The University of Sydney, Sydney,Australia

Michel Lebel Centre de Recherche en Cancérologie de l’Université Laval,Hôpital Hôtel-Dieu de Québec, Québec, Canada

Jeffrey Long Laboratory of Experimental Gerontology, National Institute onAging, National Institutes of Health, Baltimore, MD 21224, USA

Valter D. Longo Ethel Percy Andrus Gerontology Center, Davis School ofGerontology, University of Southern California, Los Angeles, CA 90089, USA

Federica Madia Ethel Percy Andrus Gerontology Center, Davis School ofGerontology, University of Southern California, Los Angeles, CA 90089, USA

Edward J. Masoro Department of Physiology and Barshop, Institute forLongevity and Aging Studies, University of Texas Health Science Center, SanAntonio, TX 78229-3900, USA; Charleston, SC 29401, USA

Julie A. Mattison Intramural Research Program, Laboratory of ExperimentalGerontology, National Institute on Aging, National Institutes of Health,Poolesville, MD 20837, USA

Aisling C. Mcmahon ANZAC Research Institute, Centre for Education andResearch on Ageing, Concord RG Hospital, University of Sydney, Sydney,Australia

Brian J. Merry School of Biological Sciences, Biosciences Building, Universityof Liverpool, Liverpool, L69 7ZB, UK

Ilhem Messaoudi Division of Pathobiology and Immunology, Vaccine and GeneTherapy Institute, Oregon National Primate Research Center, Beaverton, OR97006, USA

Marshall Miller Laboratory of Experimental Gerontology, National Institute onAging, National Institutes of Health, Baltimore, MD 21224, USA

Contributors xv

Robin K. Minor Aging, Metabolism and Nutrition Unit, Laboratory ofExperimental Gerontology, National Institute on Aging, National Institutes ofHealth, Baltimore, MD 21224, USA

Brian J. Morris School of Medical Sciences and Bosch Institute, The Universityof Sydney, Sydney, NSW 2006, Australia

Luc Poirier Laboratory of Experimental Gerontology, National Institute onAging, Baltimore, MD 21224, USA

Suresh I.S. Rattan Laboratory of Cellular Ageing, Department of MolecularBiology, Aarhus University, Aarhus, Denmark

David Raubenheimer Institute of Natural Sciences, Massey University, Albany,New Zealand

Eric Ravussin Pennington Biomedical Research Center, Baton Rouge, LA70808, USA

Leanne M. Redman Pennington Biomedical Research Center, Baton Rouge, LA70808, USA

Matthew W. Rosenbaum Department of Human Welfare, Okinawa InternationalUniversity, Ginowan, Okinawa, Japan; Okinawa Research Center for LongevityScience, Urasoe, Okinawa, Japan

George S. Roth GeroScience, Pylesville, MD 21132, USA

Stephen J. Simpson School of Biological Sciences, The University of Sydney,Sydney, NSW 2006, Australia

David A. Sinclair Glenn Laboratories for Aging Research, Department ofPathology, Harvard Medical School, Boston, MA, USA

Edward L. Spangler Laboratory of Experimental Gerontology, National Instituteon Aging, National Institutes of Health, Baltimore, MD 21224, USA

Makoto Suzuki Okinawa Research Center for Longevity Science, Urasoe,Okinawa, Japan; Faculty of Medicine, University of the Ryukyus, Nishihara,Okinawa, Japan

Zoltan Ungvari Department of Geriatric Medicine, Reynolds Oklahoma Centeron Aging, University of Oklahoma Health Science Center, Oklahoma City, OK73104, USA

Krista A. Varady Kinesiology and Nutrition, University of Illinois at Chicago,Chicago, IL 60612, USA

Alessandra Warren ANZAC Research Institute, Centre for Education andResearch on Ageing, Concord RG Hospital, The University of Sydney, Sydney,Australia

xvi Contributors

Min Wei Ethel Percy Andrus Gerontology Center, Davis School of Gerontology,University of Southern California, Los Angeles, CA 90089, USA

Bradley J. Willcox Okinawa Research Center for Longevity Science, Urasoe,Okinawa, Japan; Department of Geriatric Medicine, John A. Burns School ofMedicine, University of Hawaii; Department of Research Planning andDevelopment, Queen’s Medical Center, Honolulu, HI, USA

D. Craig Willcox Department of Human Welfare, Okinawa InternationalUniversity, Ginowan, Okinawa, Japan; Okinawa Research Center for LongevityScience, Urasoe, Okinawa, Japan; Pacific Health Research Institute, Honolulu,HI, USA

Jennifer E. Young Intramural Research Program, Laboratory of ExperimentalGerontology, National Institute on Aging, National Institutes of Health,Poolesville, MD 20837, USA

Sige Zou Laboratory of Experimental Gerontology, National Institute on Aging,Baltimore, MD 21224, USA

Part ICalorie Restriction in Different Species

Chapter 1History of Caloric Restriction, Agingand Longevity

Edward J. Masoro

Abbreviations

CR Caloric restrictionDNA Deoxyribonucleic acidDR Dietary restrictionIGF-1 Insulin-like growth factor-1mRNA Messenger Ribonucleic AcidNCTR National Center for Toxicological ResearchNIA National Institute on Aging

1.1 Introduction

Sustained research on caloric restriction began in 1930 with a study by McCay andhis colleagues at Cornell University, which resulted in their seminal publicationsome 5 years later (McCay et al. 1935). In that study, white rats were used to deter-mine the effect of retarded growth on life span. The protocol of this study involvedthe following three groups of rats: one group was allowed to grow to maturity atwhat the investigators considered to be a normal rate; the other two groups weremaintained on a reduced energy intake for about 700 and 900 days respectively. Asexpected the latter two groups grew slowly; however, they lived much longer thanthose allowed to grow at the normal rate. The authors concluded that retarding thegrowth of rats extended their life. This finding was in accord with an earlier study bythe Cornell group in which the longevity of brook trout was increased when growthwas slowed by restricting protein intake (McCay et al. 1929). It should be noted thatMcCay and associates believed that it was the retarded growth and not the reductionin energy intake per se that was the factor responsible for the life extension. Indeed,

E.J. Masoro (B)Department of Physiology and Barshop, Institute for Longevity and Aging Studies,University of Texas Health Science Center, San Antonio,TX 78229-3900, USA; Charleston, SC 29401, USAe-mail: e.masoro@att.net

3A.V. Everitt et al. (eds.), Calorie Restriction, Aging and Longevity,DOI 10.1007/978-90-481-8556-6_1, C© Springer Science+Business Media B.V. 2010

4 E.J. Masoro

this hypothesis was the one held by most biological gerontologists for next 40 ormore years.

However, it should not be concluded that restricting energy intake had not beenexplored earlier. In 1914, Francis Peyton Rous, a 1966 Nobel laureate, reported thatreducing food intake inhibited the occurrence of spontaneous cancers in rodents(Rous 1914). Since most cancers occur late in life, this finding had gerontologicalsignificance. A few years later, Osborne and Mendel, distinguished Yale nutrition-ists, reported that blunting the growth of female rats by decreasing their food intakeled to life extension and the ability to reproduce at older ages than the rats that didnot undergo a period of slow growth (Osborne et al. 1917). In the same year, it wasreported that reducing food availability extends the life of Drosophila (Loeb andNorthrop 1917). One might have expected that these findings would have fomentedresearch on the gerontological actions of energy restriction, but such was not thecase partly because of the 1920 paper of Robertson and Ray. These workers reportedin the prestigious Journal of Biological Chemistry that the rate of growth of mice ispositively correlated with the length of life (Robertson and Ray 1920).

Two other important findings were reported in the late 1930s. One was theincreased longevity of Daphnia longispina induced by the reduction of food intake(Ingle et al. 1937). The other was the further work by the McCay group providingstrong evidence that the responsible dietary factor underlying the slow growth wasmost likely the reduction in caloric intake (McCay et al. 1939). Indeed, in the ensu-ing years, the term caloric restriction (CR) has been widely used when referring toglobal food restriction and CR will be the acronym used in this paper.

1.2 The 1940s

Its effects on age-associated diseases dominated CR research in the 1940s. Startingin 1941, John Saxton and his colleagues at Cornell Medical School published paperson the attenuation of age-associated diseases in rats by CR: kidney disease (Saxtonand Kimball 1941); and a broad array of solid tumors (Saxton et al. 1948). CliveMcCay was a co-author of the 1948 paper; moreover, his group had published anearlier paper on the ability of CR to retard a broad spectrum of spontaneous age-associated diseases in rats (McCay et al. 1943). In 1946, it was reported that thefasting of rats one out of every 4 days extends their lives (Carlson and Hoetzel1946); A. J. Carlson of the University of Chicago was a leading physiologist ofhis day. This finding was a forerunner of the every-other-day feeding method ofinducing food restriction in use today.

CR was also found to retard age-associated diseases in mice. It inhibited theoccurrence of spontaneous tumors (Tannenbaum 1940) and the induction of tumorsby chemical carcinogens in mice (Tannenbaum 1944). It was also reported thatCR inhibits the development of leukemia in mice (Saxton et al. 1944). The labo-ratory of Maurice Visscher, the distinguished University of Minnesota physiologist,reported that spontaneous mammary tumors are retarded in mice by CR (Visscher

1 History of Caloric Restriction, Aging and Longevity 5

et al. 1942). The ability of methylcholanthrene to induce mammary tumors in micewas also found to be inhibited by CR (White et al. 1944). In addition to the cancerwork, Visscher’s group showed that CR maintains fertility of female mice to veryadvanced ages (Ball et al. 1947); thus, the early findings on rats of Osborne andMendel were expanded to include mice.

1.3 The 1950s

Publications on CR were sparse during this decade. The Tannenbaum group contin-ued to publish its work on the effect of CR on carcinogenesis in mice (Tannenbaumand Silverstone 1953) as did the Visscher group (Lee et al. 1952). The Visschergroup also further explored the effects of CR in retarding reproductive senescencein mice (Visscher et al. 1952).

The report (Rudzinka 1951) that food restriction enhances the longevity of theprotozoan (Tokophrya infusionum) and the study (Chvapil and Hruza 1959) showingthat CR retards the age-associated increase in rat tail collagen cross-linking werethe only truly significant new advances in the 1950s. Also, in the late1950s, MorrisRoss of the Fox Chase Cancer Institute reported on the beginning of his group’smonumental studies on the effects of CR in rats (Ross 1959).

1.4 The 1960s

In 1960, it was hypothesized that CR extends life by reducing body fat content (Bergand Simms 1960); this was the first challenge to the retardation of growth hypoth-esis proposed some 25 years earlier by McCay and colleagues. Although Berg andSimms had not measured body fat content, they assumed that CR would decreaseit, a reasonable assumption. The basis of their hypothesis was the growing evidencethat obesity is a health risk in humans. Most of the gerontological community wasnot impressed with this hypothesis and continued to subscribe to McCay’s view.Although nutritionists did embrace the hypothesis of Berg and Simms, they foundthe life-extending action of CR to be of little conceptual interest since they viewedit as merely a procedure for decreasing body fat content.

It was during the 1960s that the Ross group made their major contributions toCR field. Much of their work on CR such as the retardation of kidney disease (Brasand Ross 1964) and of tumors (Ross and Bras 1965) confirmed findings publishedin earlier years by other investigators. However, the quality of their studies madebelievers out of doubters. Indeed, in 1973, I heard Morris Ross present the findingsof his group at a National Institutes of Health workshop held in Seattle and was soimpressed that I spent most of the remainder of my research career studying CR.This group was also the first to determine the effect of CR on the age-specific deathrate of rats and found that CR decreased it from ages 6 through 24 months (Ross1961).

6 E.J. Masoro

In the 1960s, it was reported that CR extends the life of rotifers (Fanestil andBarrows 1965) and a fish species (Lebistes reticulates) in captivity (Comfort 1963).Also, measurements of enzymatic activities started to be used for the exploration ofthe biochemical basis of the actions of CR (Barrows and Roeder 1969). This wasfirst use of a then cutting edge tool of biochemistry in the study of CR. Althoughenzymatic analyses have often been employed in the ensuing decades, surprisinglythese analyses have provided little understanding of the mechanisms underlying thelife-extending and related actions of CR.

1.5 The 1970s

Based on his extensive studies on the effects in rats of hypophysectomy and/or CR,Arthur Everitt proposed in the early 1970s that pituitary function and CR are linked.In 1970, he considered the link to be the functioning of the pituitary in the regu-lation of food intake (Everitt 1970). However, by 1973, he viewed the link to bea CR-induced decrease in the secretion of an aging factor by the pituitary (Everitt1973). This latter view was a forerunner of the current debate on a possible role ofthe Growth Hormone-IGF-1 axis in the life-extending action of CR. Over the nextthree decades, Arthur Everitt and his colleagues contributed to our knowledge ofCR in the areas of morphology, physiology, and pathology.

In the 1970s, Roy Walford and colleagues began to publish their extensive workon the actions of CR reporting its effects on immune function in mice (Walford et al.1973). The studies of this group continued for the next three decades and covereda range of physiological and biochemical subject areas. Richard Weindruch was aproduct of the Walford laboratory and he has gone on to a distinguished independentcareer in CR research, some of his important findings and concepts will be presentedin the discussion of the 1980s and 1990s.

In the 1970s, Robert A. Good and colleagues published their initial work onthe beneficial effects of CR in mice with autoimmune diseases (Fernandes et al.1976). These studies continued for the next two decades in Good’s laboratory andthen independently in the laboratory of Gabriel Fernandes well into the twenty firstcentury.

In 1977, it was reported that food restriction extends the life of the nema-tode, Caenorhabditis elegans, (Klass 1977). This species has since become a majoranimal model in CR research.

It was in 1977 that George Sacher proposed that CR retards aging by reduc-ing the metabolic rate per unit of body mass (Sacher 1977). Although Sacher hadnot measured the metabolic rate, this hypothesis rapidly gained favor replacingMcCay’s retardation of growth hypothesis as the dominant view held by biologicalgerontologists.

In 1979, Brian Merry and Ann Holehan published the first of their extensive workon the effect of CR in retarding reproductive senescence in the rat model (Merry andHolehan 1979). Merry went on in the 1980s and 1990s to contribute broadly to theknowledge base of CR in several areas of biochemistry.

1 History of Caloric Restriction, Aging and Longevity 7

1.6 The 1980s

The validity of the three major hypotheses on the mechanism underlying the life-extending action of CR was challenged by studies reported early in the 1980s.Walford’s group found that CR initiated at 12 months of age significantly extendsthe life of mice (Weindruch and Walford 1982) and our group reported that maleF344 rats, which have essentially full skeletal growth by 6 months of age, exhibitalmost the same increase in life span when CR is initiated at 6 months of age aswhen started at 6 weeks of age (Yu et al. 1985). These two studies spelled the endof the long period of belief in McCay’s retardation of growth hypothesis.

Data dissociating the life extending action of CR from its ability to decreasebody fat content was reported by our group for rats (Bertrand et al. 1980) and DavidHarrison’s group for mice (Harrison et al. 1984). For a while this spelled the end ofbelief in the reduction of body fat hypothesis of Berg and Simms. However, in thetwenty first century that hypothesis has been resurrected by investigators, who haveignored the findings of the 1980s rather than providing contrary evidence (Bluheret al. 2003).

Our group reported that over most of their life span, food intake per gram bodymass is greater in rats on a CR regimen than in rats fed ad libitum; moreover, whenthe data are expressed per gram lean body mass, there is no difference between thetwo groups (Masoro et al. 1982). These findings are not in accord with Sacher’sreduction of metabolic rate hypothesis. The then many advocates of Sacher’s viewbelieved so strongly in his hypothesis that this contrary evidence was ignored at thetime by most of them.

During the 1980s, our group used semi-synthetic diets to test the validity of theclaim that the dietary factor underlying the life-extending action of global foodrestriction is the reduced intake of energy. We found that the reduced intake of pro-tein (Masoro et al. 1989), fat (Iwasaki et al. 1988), minerals (Iwasaki et al. 1988),and vitamins (Yu et al. 1982) did not underlie the life extending action. These stud-ies provided further strong evidence for the claim of McCay and colleagues thatthe reduced intake of calories is the responsible dietary factor. Surprisingly, thisevidence is frequently ignored by the authors of papers published in the twentyfirst century, who refer to the life extending and anti-aging actions of global foodrestriction by the ambiguous term, dietary restriction (DR) rather than CR.

During the 1980s, George Roth, Donald Ingram, James Joseph, and other col-leagues in the intramural program of the National Institute on Aging (NIA) studiedthe effects of CR on the nervous system function including behavior. One of themost significant of their many studies is the finding that CR delays in rats theage-associated loss of striatal dopamine receptors (Roth et al. 1984).

In 1985, Brian Merry’s group reported that CR increases whole body proteinturnover in rats 1 year of age and older (Lewis et al. 1985). This finding suggestedthat CR may retard aging by decreasing the age-associated cellular accumulation ofdamaged proteins.

During the 1980s, Dike Kalu and his associates intensively studied the effects ofCR on bone. They found that CR prevents senile osteopenia in male F344 rats (Kalu

8 E.J. Masoro

et al. 1984). And Arthur Everitt and coworkers reported that CR markedly decreasesthe prevalence of hind leg paralysis in rats at advanced ages (Everitt et al. 1985).

It was in the 1980s that Arlan Richardson and his colleagues pioneered the useof the technology of molecular biology in CR research reporting studies on theeffects of CR on hepatic mRNA (Birchenall-Sparks et al. 1985), the expression ofthe α2υ-globulin gene (Richardson et al. 1987), and the repair of DNA (Weraarhakulet al. 1989). Since then, Richardson has continued to utilize the developing tools ofmolecular biology in the study of CR. This technology now dominates researchon CR.

In the 1980s, two USA government agencies, the National Institute on Aging(NIA) and the National Center for Toxicological Research (NCTR), jointly estab-lished a program for the generation and study of a number of rat and mouse strainsmaintained on a CR-diet along with animals of the same species and strain thatwere fed ad libitum. This program, directed by Ronald Hart and Angelo Turturrohad two functions: intramural studies and the distribution of animals for researchon CR by investigators at academic and other research institutions. The intramuralstudies were focused on longevity and pathology along with studies in the areas ofexpertise of the NCTR staff: physiology (Phillip Duffy), intermediary metabolism(Ritchie Feuers), and drug metabolism (Julian Leakey). The intramural programprovided a wealth of important information, particularly in regard to comparing theeffects of CR on longevity and pathology in a spectrum of rat and mouse geno-types. Its extramural function of providing animals to investigators with expertisein many different biological areas proved to be even more valuable; by this means,it greatly expanded the participation of leading biologists in CR studies as well asaging research in general.

Late in the 1980s, Richard Weindruch and Roy Walford co-authored an ency-clopedic book on what was known about CR at that time (Weindruch and Walford1988). This book had a major impact in interesting investigators in a variety ofbiological disciplines in the study of aging and, in particular, CR.

In 1989, two concepts were proposed regarding the evolutionary basis of the life-extending action of CR. One was based on the selection of organisms that respondto a scarcity of food by decreasing the rate of reproductive aging (Harrison andArcher 1989) and the other was based on the selection of organisms that divertenergy usage from reproduction to somatic maintenance when food availability islimited (Holliday 1989). The latter view has gained wide acceptance. Also in thatyear, Steven Austad reported that CR extends the life of the bowl and doily spider,Frontinella pyramitela (Austad 1989) and Allen Taylor and colleagues reported thatCR delays cataract formation in the Emory mouse (Taylor et al. 1989).

1.7 The 1990s

In 1990, initial findings were reported from the NIA intramural research programstarted in the late 1980s on the effects of CR on non-human primates (Ingram et al.

1 History of Caloric Restriction, Aging and Longevity 9

1990). In 1993, the initial findings of the University of Wisconsin study on theeffects of CR on rhesus monkeys were published (Kemnitz et al. 1993) and in thatsame year, investigators at the University of Maryland interpreted findings of theirongoing study of rhesus monkeys in terms of CR (Hansen and Bodkin 1993). Thesestudies have continued through the 1990s and into the twenty first century; manyof the findings on physiological processes in these primates are similar to thoseobserved with rodent models. Importantly, CR in the non-human primate modelshas been found to decrease risk factors that have links to age-associated diseases inhumans. As of yet, the longevity data from these studies have not been of a qualityto confidently claim that CR extends the life span of the primate species studied. Inthe 1990s, findings were reported on the effect of CR on another primate species,Homo sapiens (Walford et al. 1992). Roy Walford was a member of the Biosphere 2crew. This crew attempted to grow their own food, which resulted in an unplannedfor CR during most of their time in Biosphere 2; Walford made physiological andbiochemical assessments on the crew and found the effects of a low food intake tobe similar to what occurs in rodent species. These findings were a forerunner to theexcellent research on CR in humans being done in the twenty first century (Fontanaet al. 2004).

It was known that the plasma levels of corticosterone, the major glucocor-ticoid in rodents, are transiently increased upon initiating CR. In 1991, it wasshown that the daily peak concentration of plasma free corticosterone remains ele-vated throughout long-term CR (Sabatino et al. 1991). This is an important findingbecause free corticosterone is the biologically active form of glucocorticoid in therat and glucocorticoids play a key role in enabling mammals to cope with harmfulenvironments.

In 1992, it was reported that the metabolic rate per unit of fat-free mass or perunit of metabolic mass is similar in ad libitum-fed rats and those on a CR regimenover most of the life span (McCarter and Palmer 1992). One might think that thisfinding would have put an end to the belief in the hypothesis that CR retards agingby decreasing the metabolic rate. However, that was not the case. Rather this findingfostered what is still an ongoing debate on how to normalize findings on metabolicrate for differences in body size.

It was also found that daily rate of glucose fuel use per unit of metabolic massis the same for rats on a CR regimen as for rats fed ad libitum; this was some-what surprising finding since the mean 24 h plasma level of glucose is modestlydecreased and plasma insulin level is markedly lower in rats on a CR regimen(Masoro et al. 1992). These findings strongly indicated that CR enhances insulinsensitivity. Indeed, it recently has been claimed that the increase in insulin sensi-tivity plays an important role in the life-extending action of CR (Bonkowski et al.2006). However, it should be noted that the evidence in support of this claim is lessthan robust.

In the 1990s, William Sonntag and his colleagues broadly examined the effects ofCR on the growth hormone-IGF-1 axis; they measured growth hormone secretion,plasma IGF1 levels, and IGF1 receptors and other factors. At the end of the decade,this group published a paper summarizing the gerontological significance of their

10 E.J. Masoro

extensive work (Sonntag et al. 1999). It would be wise for current investigatorsstudying the role of IGF-1 in aging and CR to familiarize themselves with the studiesof the Sonntag group.

Several new hypotheses were posed during the 1990s on the mechanisms under-lying the life extending and related actions of CR. It was proposed that CR retardedaging by enhancing apoptosis thereby retarding the accumulation of damaged cells(Warner et al. 1995). Indeed, there is evidence that dysregulation of apoptosis(inadequate as well as excessive) occurs during aging and that CR mitigates theseproblems.

In 1996, Sohal and Weindruch (1996) and independently Yu (1996) asserted thatCR extends life by attenuating oxidative damage. Currently, this hypothesis is theone favored by most biological gerontologists. Indeed, it is clear that CR retards theage-associated accumulation of cellular oxidative damage. However, it has yet to beestablished that oxidative damage plays a major role in the aging process.

Also in 1996, CR-induced reduction of body temperature was postulated to be amechanism underlying life extension and retardation of aging (Koizumi et al. 1996).This view was supported by mouse studies carried out in the authors’ laboratory andby the fact that in several poikilothermic species reducing the environmental tem-perature extends life (Finch 1990). However, the validity of this view is counteredby the fact that the magnitude of CR-induced life extension is similar in mice andrats even though CR reduces body temperature much more markedly in mice thanin rats.

In 1998, I proposed the hormesis hypothesis (Masoro 1998) and in that sameyear, investigators working on CR at the NCTR independently did, too (Turturroet al. 1998). This hypothesis provides a broad framework for studies aimed at under-standing the complex nature of the processes that underlie the anti-aging actions ofCR. At first, few others embraced this view. However, during the twenty first cen-tury it has gained supporters, probably because it appears increasingly likely that aninteraction of multiple processes underlies the life-extending and anti-aging actionsof CR.

1.8 The Twenty First Century

It does not seem appropriate to discuss twenty first century findings in historicalterms. Of course much of the research in the first decade of the twenty first cen-tury has been a continuation of investigations begun in the twentieth century. Forexample work started in the twentieth century on nonhuman primates is being com-pleted and extended and excellent new studies on the human primate have beenundertaken. The major mechanistic innovation so far in the twenty first century isthe extensive exploration of potential signaling pathways involved in the actionsof CR and the interactions among these pathways. These studies will require thedevelopment of innovative ways of testing hypotheses generated from such com-plex data sets. However, predictions about where science is going are notorious fortheir ineptitude.

1 History of Caloric Restriction, Aging and Longevity 11

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Chapter 2Food Intake, Life Style, Aging and HumanLongevity

Arthur V. Everitt, Leonie K. Heilbronn, and David G. Le Couteur

2.1 Calorie Restriction and Human Survival

Since the 1980s, the prevalence of obesity in the USA has risen steadily (Fig. 2.1).In the fifteenth century an Italian nobleman Luigi Cornaro lived a life of gluttonyuntil middle age. When his health started to fail his physician advised him to eatless, his health improved and he lived to 102 years. Cornaro (Fig. 2.2) argued thatdietary restriction and moderate living lead to good health and long life (Cornaroand Butler 1903; Cornaro and Howell 1987; Howell and Cornaro 1987; Olshansky2006). In was not until the mid-twentieth century that Breslow (1952) in UnitedStates reported that overweight people had higher death rates than those of normalweight.

The classic calorie restriction (CR) studies first performed by McCay (1935),showed that long term 40% CR without malnutrition reduces body weight and pro-longs the life of the laboratory rat. Whether the longevity-enhancing effects of foodrestriction are secondary to reduced intake of calories or some specific nutrient suchas fat or protein is still under discussion and may vary with the species (Masoro1998; Anderson and Moore 2004; Mair et al. 2005; Piper et al. 2005; Simpsonand Raubenheimer 2007; Lee et al. 2008). In CR, the intake of calories is reduced,but sufficient vitamins, minerals and other essential nutrients must be eaten. CRretards many physiological aging processes and delays the onset and progression ofmost diseases of old age in rodents (Berg and Simms 1960; Ross and Bras 1971;Weindruch and Walford 1988; Masoro 2005). Since the maximum life duration ofthe rat is about 3 years, longevity studies may be completed in 5 years. In a primate,the rhesus monkey, 20 years of CR was found to delay disease onset and prolonglife (Colman et al. 2009). However in humans, because the lifespan is more than100 years it has not been possible to carry out well-controlled life-long studies.

A.V. Everitt (B)Centre for Education and Research on Ageing, Concord RG Hospital, The University of Sydney,Concord, NSW 2139, Australia; Discipline of Physiology, School of Medical Sciences, TheUniversity of Sydney, NSW 2006, Australiae-mail: arthureveritt42@bigpond.com

15A.V. Everitt et al. (eds.), Calorie Restriction, Aging and Longevity,DOI 10.1007/978-90-481-8556-6_2, C© Springer Science+Business Media B.V. 2010