A CRITICAL REVIEW

Nutrition and Aging—ACurrent Assessment

EDWARD J. MASORO

Department of Physiology, University of Texas Health ScienceCenter, 7703 Floyd Curl Drive, San Antonio, TX 78284

There are two pressing issues in the fieldof nutrition and aging. One is the questionof whether nutrition influences the agingprocess. This issue, the subject of this review,is particularly important at this time because of its potential for providing basicinformation on the nature of aging processesand of the possibility of developing interventions to retard adverse aspects of aging.The urgency of the latter is great since thedemographic projections for the 21st century(1) indicate marked, progressive increases inthe percentage of elderly in the populationof the developed nations. The second issueaddresses nutritional requirements and statusof the elderly. This issue is also pressingsince the available data base is not adequateto answer the fundamental questions regarding geriatric nutrition (2). Space doesnot permit the second issue to be reviewedhere.

RETARDATION OF AGING BYFOOD RESTRICTION

Historical background

In 1934, McCay and Crowell (3) reportedthat restricting the food intake of ratsmarkedly increased longevity, and this finding has been confirmed by many subsequentstudies (4). It appears to be an inevitableresult of food restriction in rodents if malnutrition is avoided. Indeed it is the onlymanipulation known that reproducibly increases the life span (maximum length oflife) of a mammalian species (5). Food restriction appears to influence longevity by

retarding aging processes thus providing anaffirmative answer to the question: can nutrition influence the aging process? Themajor focus of this paper is to review theevidence indicating that food restrictionretards the aging process, possible mechanisms of its actions and the possibility thatmammalian species other than rodents andincluding humans may be similarly affected.

Retardation of aging processes

Investigations of the effects of food restriction on the survival characteristics of rodentpopulations has provided evidence that itretards aging. Initially it was believed thatfood restriction increased longevity by retarding growth and development (6) ratherthan by slowing the aging processes of mature adults. In support of this view Barrowsand Roeder (7) reported in 1965 that food restriction started at 12 mo of age in rats causeda small but significant decrease in longevity.However, since 1965 several reports haveshown significant increases in length of lifeof rodents when food restriction was startedin adult life (8-12). Most striking in thisregard is the study of Yu et al. (13) whoshowed that food restriction initiated inadult life was as effective in extending thelife span of rats as that started soon afterweaning. They also showed that food restriction limited to the early part of life(from 6 wk to 6 mo of age) had only a small

©1985 American Institute of Nutrition. Received for publication25 January 1985. Acceptance date: 1 April 1985.

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effect on life span. These findings have focused attention on the probability that foodrestriction retards aging processes. This possibility was further assessed by Sacher (5)who utilized a method originally proposedin 1825 by Gompertz for analysis of survivaldata; Sacher concluded that food restrictionincreased longevity by decreasing the rate ofaging.

The effects of food restriction on thephysiological systems of rodents also indicate that it retards aging processes. Manyage-related changes occur in the physiological systems (most of a deteriorative nature),and many can be delayed or prevented byfood restriction (14). An example is theretardation and partial prevention by foodrestriction of the age-related increase inserum cholesterol concentration seen in adlibitum-fed rats (15). Food restriction startedin adult life is as effective as that startedsoon after weaning (16) in preventing thisincrease Similar findings were obtainedwith the age-related increases in the concentrations of serum calcitonin (17) and parathyroid hormone (18). With increasing agethere is typically in rats a decreased responseto insulin and to the lipolytic action in fatcells of glucagon and epinephrine. Thesedecreased responses can be prevented ordelayed by food restriction (19-22). The age-related loss in dopamine receptors in thecorpus striatum of rats is slowed by foodrestriction (23). This effect may be responsible for the fact that dietary restriction slowsthe loss of certain motor-behavioral capabilities that generally occurs with increasingage (24). Senile bone loss in rats is prevented(18) and reproductive senescence is delayedby food restriction (25) as are changes inskeletal muscle (26). Dietary restriction alsodecelerates the age-related loss of soluble y-crystallins from the lens of the eye (27). Theage-related decline in immune function isalso retarded by food restriction (28, 29).This may be due to maintaining the production of or the response to Interleukin-2 orboth (30). The diversity of these effects onthe physiological systems strongly indicatesthat food restriction acts on a basic agingprocess.

A third line of evidence that food restriction retards basic aging processes is the

variety of age-related disease processes alsodelayed or prevented. Many studies in rats(31-36) have shown that food restrictiondecreases the progression of chronic nephrop-athy, a major age-related disease process.Moreover, Yu et al. (13) showed that foodrestriction is as effective in this regardwhether initiated in adult life or soon afterweaning. Food restriction also greatly retards the development of cardiomyopathy,another age-related disease in rats (13).Neoplastic disease occurs at later ages infood-restricted rodents (13, 34, 37-39).Recently, Pollard et al. (40) reported that inrats the development of intestinal tumors,induced by the carcinogen methylazometha-nol, can be inhibited by food restriction.Diseases that shorten the life span of particular genotypes are also retarded by food restriction. The progressive renal disease inNZB x NZW F! mice, a result of autoimmune processes, is slowed by food restriction (29). Spontaneously hypertensive rats(SHR) die of hypertension-related eventswhen fed ad libitum; food restriction increases their longevity, and death no longerresults from hypertension-related events (41).Clearly the variety of effects on age-associated diseases indicates that food restrictionis acting on basic aging processes.

Mechanisms of action

McCay et al. (6) hypothesized that slowing of growth and development was causalfor the increased longevity of food-restrictedrodents. Several subsequent studies (42) provided support for this view. Opposing it arethe several recent studies (9-12), which showthat food restriction even when initiated inadult life increases life span. Moreover, Yu etal. (13) found that food restriction limited tothe period of growth and development wasmuch less effective than food restrictionstarted in adult life in extending life spanand retarding the occurrence of age-relatedphysiological deterioration and disease.Thus it seems unlikely that the effects offood restriction on the aging processes aredue to delaying maturation or slowing andprolonging growth.

In 1960, Berg and Simms (31)hypothesizedthe lack of excess body fat as a major causal

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factor in the increased longevity associatedwith food restriction. This concept is in harmony with the widely held view that thereis a direct relationship between adiposity(indicated by body weight above average)and mortality (43). Several recent studiesprovide evidence against this hypothesis,however. Stuchlíkováet al. (11) found thatrats restricted for the first year of life in foodintake became obese when fed ad libitumbut lived longer than less obese rats fed adlibitum throughout life Bertrand et al. (44)reported that there was no significant correlation in ad libitum-fed rats between fatcontent and longevity but that there was apositive correlation in food-restricted ratsbetween longevity and body fat content.Harrison et al. (45) found that the longevityof obese (ob/ob) mice was so increased byfood restriction that it was significantlygreater than the longevity of ad libitum-fedlean mice of the same strain, even thoughthe former maintained a significantly greaterfat content than the latter. Thus it seemsunlikely that reducing body fat contentplays a major role in the action of food restriction on aging processes.

In 1973, Everitt (46) postulated that theretardation of aging processes by food restriction was due to a reduced secretion by thepituitary gland of an aging factor. Everitt etal. (47) provided experimental support forthis view with their findings in hypophysec-tomized rats (with cortisone replacementtherapy only) of the following actions incommon with food restriction: increase oflife expectancy and life span, inhibition ofthe onset of renal and neoplastic disease andretardation of the aging of collagen. In 1982,Everitt (48) further developed his hypothesiswith the following model: food restrictionproduces changes in neurotransmitter metabolism within the hypothalamus, which decreases the secretion of a hypothalamic-releasing hormone and results in a decreasedsecretion of a pituitary hormone. This hypothesis is intriguing and warrants furtherstudy, but at this time the data are insufficient for a critical analysis. Data on theeffects of life-prolonging food restriction onthe secretion of pituitary hormones are scant.In addition, even if it were established thatfood restriction caused a prolonged reduc

tion of secretion of one or more pituitaryhormones, it would be necessary to establishthat such a reduction is part of a mechanismby which food restriction influences agingprocesses.

Lindell (49) proposed that food restrictionenhances gene expression thus maintainingcellular homeostasis as the organism ages. Adecline in gene expression does occur withincreasing age in a variety of organisms andtissues (50). Sparks et al. (51) showed thatfood restriction retards the age-related decline in protein synthesis in many rat tissues.Richardson and Cheung (50) pointed outthat since there is no significant change inthe cellular content of proteins with increasing age, there must be a reduction in the degradation of proteins equivalent to the reduction in synthesis, i.e., protein turnover declines. They stress that a decline in proteinturnover reduces the ability of the organismto respond to change (e.g., environmentalchallenges). Thus logically food restrictioncould act to retard the aging process by delaying the age-related decline in cellular protein turnover. Clearly, this hypothesis shouldbe the subject of intensive experimentalexploration.

In 1977, Sacher (5) proposed that foodrestriction retards the aging process by reducing the metabolic rate, a hypothesis thatwas well received. Sacher had several reasons for making this proposal. In 1908,Rubner (52) reported that different speciesof domestic animals, which vary in size,utilize a similar number of calories per kilogram body mass per lifetime. This information was formalized by Pearl (53) in his"Rate of Living Theory of Aging," which

can be summarized as follows: the higherthe metabolic rate per unit of body mass,the faster the rate of aging and the shorterthe length of life. Moreover, it is generallybelieved that reducing food intake decreasesthe metabolic rate per unit metabolic mass(54). Sacher supported his hypothesis by ananalysis of a study of Ross (55) in which fivedifferent diets were provided for five different groups of rats to produce a range oflongevity characteristics. Sacher calculatedthat the mean kilocaloric intake per grambody mass per lifetime was the same for alldietary groups, i.e., the mean kilocaloric

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intake per gram body mass per day wasinversely related to the mean length of life ofthe dietary group. Karman (56) linkedSacher's hypothesis to the free radical theory

of aging. He suggested that by reducing therate of electron transport and O2 utilization,food restriction decreases the rate of freeradical generation thereby slowing the agingprocesses. The findings of Chipalkatti et al.(57) that food restriction retards free radical-mediated damage support this view.Although food restriction may modulate theaging process by inhibiting free radical-mediated damage, recent evidence indicatesthat it does not do so by decreasing metabolic rate. Masoro et al. (58) reported thaton a life-prolonging food restriction regimenrats had a greater daily and lifetime intakeof calories per gram body weight than adlibitum-fed rats. Subsequently, McCarter etal. (59) showed that the total metabolicactivity per day per gram lean body mass isthe same for these food-restricted rats as forthe ad libitum-fed rats. Since metabolicrate need not be decreased for food restriction to retard the aging processes, it can beconcluded that Sacher's metabolic rate hy

pothesis is not valid.Of course, the metabolic rate and caloric

intake per rat are reduced by food restriction(58, 59). It is not usual to consider metabolicrate on a total animal basis, eg., in theassessment of the metabolic rate of a 50-kgman compared to a 100-kg man the data areexpressed per unit area of body surface orsome other mode of normalizing the datawith respect to body size Indeed, Sacher's

hypothesis is based on the intensity of metabolism per unit of protoplasmic mass as wasthe connection of this hypothesis to freeradical damage However, it is possible thatthe actions of food restriction on the agingprocess relate to metabolic rate per animal;evidence supporting this has been obtainedby McCarter et al. (60). Although it is notevident mechanistically how metabolic rateper animal relates to the aging process, thislead should be pursued.

The findings of Masoro et al. (58) showthat the lean body mass of rats is rapidlyreadjusted during food restriction so thatcaloric intake and the intake of other nutrients per gram lean body mass are the same

as those of the ad libitum-fed rats. Thus theclassic view (5) that food restriction acts byreducing the input of calories or anothernutrient per unit protoplasmic mass must bereevaluated.

The current state of knowledge of themechanism by which food restriction retardsthe aging processes can be summarized asfollows: the total input of calories or nutrientper animal is the factor influencing the aging processes. This input is probably coupledto the aging processes through endocrinic,intermediary metabolic or endocrine-metabolic events. Currently, promising candidatesfor this coupling are: 1) the hypothalamic-pituitary system, 2) protein turnover and3) free radical damage. However, the available information is so scant that a metabolicprocess yet to be considered may well be thebasis of the profound retardation of agingprocesses brought about by food restriction.

INFLUENCE OF SPECIFIC NUTRIENTS ON AGING

The extent to which the actions of foodrestriction on aging are due to reduced intake of a specific nutrient has been exploredfor protein, fat and carbohydrate The results in regard to longevity are not consistentnor have the effects been great in magnitudeSpace does not permit a detailed account ofthese studies or the citation of many relevantreferences. A brief discussion of severalpertinent references can be found in papersby Stunkard (61) and Davis et al. (62). Also,the reduced intake of protein, fat or carbohydrates has only selective and limited effects on age-related physiological deterioration and disease For example, Yu et al. (13)found that, with rats, restricting protein butnot calories retarded the development ofchronic nephropathy but did not influencethe occurrence of neoplastic disease or thedeterioration of most physiological systems.Thus, the reduced intake of these specificnutrients, unlike food restriction, appearsnot to act on general aging processes butrather to influence selectively specific physiological or pathological processes. Also, thedesign of some food restriction studies (10,12, 13, 36) did not involve the restrictionof minerals or vitamins or both, whichindicates that a decreased intake of these

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elements is not involved in the action of foodrestriction on aging.

RELEVANCE FOR THE HUMAN

The extension of life span and the retardation of aging by food restriction has beenunequivocally demonstrated for only threemammalian species: mice, rats and hamsters. This does not mean that food restriction has no similar influence in other mammalian species; rather because of the resources required, no well-executed study hasbeen carried out on long-lived species.

Most information regarding human populations consuming limited amounts of fooddoes not assess the antiaging actions of foodrestriction since these populations almostalways suffer from malnutrition and poorenvironmental conditions. In contrast, thestudies on food restriction in rodents haveinvolved diets of high quality under good toexcellent environmental circumstances.There is one report on humans that mayhave bearing. Kagawa (63) found a greaterconcentration of centenarians in Okinawathan in the rest of Japan. He reported thatOkinawans have a lower intake of energyand sugar and a higher intake of green-yellow vegetables and meat than the averageJapanese. Of course diet may not be thefactor responsible for longevity since thereare other differences (eg., genetics, climate,physical activity) between Okinawans andother Japanese.

On logical grounds it seems likely thatfood restriction modulates aging in allmammalian species including humans. Thisis based on the fact that rodents, like humans, are complex mammals and that agingis a basic, general biological phenomenon.This does not necessarily mean that foodrestriction will increase human life span. Itis quite possible that humans living inappropriate environmental conditions mayhave already stumbled on dietary practicesthat enable a full expression of the humanlife span. (The Okinawans may be a case inpoint.) If so, it will not be possible to formulate diets that will increase the well-documented 100- to 115-yr human life span.Nevertheless, if humans respond to diet in afashion similar to rodents it should be pos

sible to formulate diets that will result inmany people living past 90 yr of age with asignificant number reaching 100-115 yr ofage Such diets should delay age-relatedphysiological deterioration and retard theonset and progression of age-related diseases.By learning the mechanism by which foodrestriction retards the aging processes, itmay be possible to develop interventionsmore palatable than food restriction thatwill benefit the aging human and reduce thedemographically induced societal problemsposed for the 21st century.

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