Increasing adipocyte number as the basis for perirenal depot growth in adult rats.

The mass of the perirenal adipose depot in male Fischer 344 rats increases between 6 and 18 months of age. This increase is due to an increase in the number of adipocytes in this depot, in contrast with the concept that adipocyte number is constant throughout adult life. The epididymal depot increases in mass between 6 and 18 months of age by adipocyte hypertrophy alone.

Preweaning food intake influences the adiposity of young adult baboons.

The hypothesis that preweaning nutrition influences adult fat cell number and adiposity was tested in baboons. Newborn baboons were fed Similac formulas with caloric densities of 40.5 kcal (underfed), 67.5 kcal (fed normally), and 94.5 kcal (overfed) per 100 g formula. From weaning (16 wk) until necropsy at 5 yr of age all baboons were fed the same diet. At necropsy, fat cell number and fat cell size in 10 fat depots were measured. Female baboons overfed as infants had markedly greater fat depot mass, primarily because of fat cell hypertrophy, than normally fed or underfed females. Overfed male baboons had a greater fat mass in 4 of 10 depots compared with males underfed or fed normally as infants. Underfeeding did not affect body weight, nor adipose mass of either sex. The results show that infant food intake does not have a major influence on the fat cell number of young adult baboons.

Biology of aging. Current state of knowledge.

The nature of the primary aging processes has yet to be defined. Mortality and aspects of longevity (eg, life expectancy) do not provide significant information about aging. The maximum life span potential of a species does provide information about the comparative rate of aging between species, however, and also is a good marker for evaluating interventions aimed at modulating the rate of aging in a particular species. Physiological deterioration occurs with age, but it is not known how much is due to aging per se and how much is secondary to age-related disease and life-style. There are similar reservations about the changes in body composition that have been noted with increasing age. Many diseases are age related in terms of prevalence, but how these diseases relate to the primary aging processes remains to be defined. Finally, many claims have been made concerning interventions that will retard the aging processes; of these, only food restriction in rodents has been unequivocally shown to retard the aging processes of a mammalian species.

Maintenance of glucagon-promoted lipolysis in adipocytes by food restriction.

Life-prolonging food restriction is known to delay physiological changes that occur during senescence. The aim of the present study was to learn if this nutritional manipulation also can influence changes that occur during the developmental phase of life. Male, specific pathogen-free Fischer 344 rats were fed ad libitum (group A) or 60% of the ad libitum intake (group R) beginning at 6 weeks of age. The group R rats had a markedly increased median length of life. Starting at 6 months of age, rats were periodically killed, and free adipocytes were prepared from epididymal and perirenal depots. The free adipocytes were used for the in vitro study of the promotion of lipolysis by glucagon. At 6 months of age and all older ages, adipocytes from group A rats were not responsive to the lipolytic action of glucagon; this agrees with earlier studies showing a marked loss in responsiveness to glucagon between 4-15 weeks of age. However, adipocytes from group R rats were quite responsive to glucagon at 6 and 12 months of age. Although after 12 months of age there was a loss in responsiveness to glucagon, this response remained significant through 36 months of age in the group R rats. Thus, life-prolonging food restriction delays not only functional changes that take place late in life (senescent changes) but also those occurring during the developmental period of life. The value of these findings as a model for experimental gerontology is discussed.

Modulation of age-related hyperparathyroidism and senile bone loss in Fischer rats by soy protein and food restriction.

Studies were carried out to explore the influence of soy protein and food restriction on age-related changes in serum PTH and bone. Three groups of male Fischer 344 rats were studied from 6 weeks of age. Group A rats were fed ad libitum diet A, which has casein as the protein source. Group B rats were fed diet B (with casein as protein source) at 60% of the mean ad libitum food intake. Group C rats were fed ad libitum diet C, which has soy protein as the protein source. The animals were killed at periodic intervals beginning at 6 months of age after an overnight fast. Serum PTH, measured with an intact N-terminal-specific RIA, and immunoreactive calcitonin increased progressively with aging. The increase was markedly suppressed by food restriction, and in the case of PTH by the soy protein diet as well. Serum creatinine started to increase after 18 months of age, and both dietary regimens of groups 2 and 3 retarded the increase. Aging was associated with a fall in serum 25-hydroxyvitamin D, and loss of bone occurred during the terminal part of life in the ad libitum-fed animals. These were prevented by food restriction, while the soy protein diet delayed the onset of bone loss. We conclude from these findings and other data from this study that in the male F344 rats 1) an age-related increase in serum PTH precedes an age-related increase in serum creatinine concentration; 2) an age-related decline in renal function probably contributes to age-related hyperparathyroidism, which, in turn, contributes to senile bone loss; 3) food restriction inhibits age-related hyperparathyroidism and senile bone loss; 4) on the basis of the data from rats fed a soy protein-containing diet, a decline in renal function and progressive hyperparathyroidism are not inevitable consequences of aging in the ad libitum fed rats.

Use of rodents as models for the study of "normal aging": conceptual and practical issues.

Certain guidelines may exist for selecting and using rodent models for aging research. These are based, however, on only operational criteria because we presently lack good biomarkers for (or even a suitable definition of) normal aging. Longevity and disease characteristics of the experimental population are the most important of the operational criteria for choosing a particular rodent model. These factors, in turn, are influenced by genetics and by environmental factors, including diet, housing, and physical activity.

Retardation of aging processes by food restriction: an experimental tool.

The importance of food restriction in rats, mice, and hamsters as a tool for the study of aging is discussed. The evidence that food restriction retards the aging processes is summarized and includes its ability to extend the maximum life span, to decrease the rate of increase in age-specific mortality, to retard age changes in physiological processes, and to delay or prevent most age-associated diseases. Food restriction has its anti-aging action by reducing the intake of energy rather than a specific nutrient. Research findings on the possible mechanisms by which food restriction retards the aging processes are discussed. The use of food restriction to test theories of aging is described and the controversial issue of its possible use as an intervention of human aging is addressed.

Fat metabolism in normal and abnormal states.

Various aspects of the use of fatty acids as fuel in normal and abnormal states in mammals are described. The discussion includes use of dietary lipid as fuel, the functioning of adipose tissue as a fuel reservoir, the use of free fatty acids mobilized from adipose tissue as fuel, the liver as a source of lipid fuel, and the use of intracellular lipids as fuel sources. In addition, the responses of lipid metabolism to fasting and exercise are reviewed. Finally, selected data on the effects of infections on the use of lipids as fuels are considered in relation to our current knowledge metabolism.

Dietary modulation of the progression of nephropathy in aging rats: an evaluation of the importance of protein.

Chronic nephropathy involving glomerular sclerosis markedly progresses in severity with age in male Fischer 344 rats fed ad libitum. Restricting food intake by 40% almost totally prevents progression of these lesions. Restricting food intake by 40% without restricting protein intake is also highly effective although somewhat less so than food restriction that includes protein restriction. These findings indicate that reducing the intake of protein is not the major reason for the retardation by food restriction of the age-associated progression of nephropathy in rats.

Modulation of age-related loss of glucagon-promoted lipolysis by food restriction.

Male Fischer 344 rats were fed ad libitum (Group A) or 60% of the ad libitum intake (Group R) starting at 6 weeks of age. The latter is a dietary manipulation that prolongs life. At 6, 10 and 15 weeks of age, rats were killed, free adipocytes prepared, and lipolytic, adenylate cyclase, and phosphodiesterase activities of adipocytes measured. The ability of glucagon to promote lipolysis markedly declined between 6 and 15 weeks of age in adipocytes from Group A rats but not in those from Group R rats. Glucagon-promoted adenylate cyclase activity paralleled lipolytic activity. Phosphosdiesterase activities increased with age, to a greater extent in adipocytes from Group A rats than in those from Group R rats. It is concluded that the loss in glucagon-promoted lipolysis with age in adipocytes from Group A rats is primarily the result of either a loss of or a change in the characteristics of the glucagon receptors or an alteration in the system coupling the receptors with adenylate cyclase and that food restriction prevents these changes. The relevance of these findings in analysis of the mode by which food restriction delays the aging process is discussed.

The effect of rat age on the composition and functional activities of skeletal muscle sarcoplasmic reticulum membrane preparations.

The complex of membranes of which cells are comprised have been considered as likely sites of deterioration underlying the decline on physiologic competence with age. Although this concept is an attractive one on theoreical grounds, few direct experimental data are available on the effect of age on biological membranes. Since the sarcoplasmic reticulum of skeletal muscle has been well characterized and is an easily studied membrane system in regard both to its composition and function, the effect of age on this membrane system was explored. Rats of 1, 2, 3, 6, 12, 24 and 28 months of age were the source of sarcoplasmic reticulum membranes which were characterized by the following measurements: phospholipid/protein weight ratio; phospholipid composition; the activity of the (Ca++ + Mg++) -ATPase and the steady state concentration of its phosphorylated intermediate; the ATP-dependent, oxalatepromoted Ca++ transport activity. Although there were some differences between age groups in these basic parameters of sarcoplasmic reticulum composition and function, the data obtained provide no clear evidence of deterioration of these membranes with age.

Age changes in hepatic metabolic characteristics and their modulation by dietary manipulation.

Starting at 6 weeks of age, male Fischer 344 rats were provided five different dietary regimens: group 1, fed ad libitum; group 2, restricted to 60% of the food intake of group 1; group 3, restricted to 60% of the food intake of group 1 until 6 months of age and then fed ad libitum; group 4, fed ad libitum until 6 months of age and then restricted to 60% of the food intake of group 1; group 5, given the same caloric intake as group 1 but 60% of the protein intake. The weight of the liver was maintained at about 2.5% of body weight over the wide range of body weight, age (6 through 30 months of age) and diets of this study. Liver cholesterol concentration increased with age in the rats of group 1 but not in the other groups; the hepatic cholesterol concentration was lower in the rats of groups 2 and 4 than in the others. The liver microsomal 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase activity was higher in 4-month-old rats than in rats 12 months of age and older; also, the microsomal activity from group 2 and group 4 rats was higher than that from rats of the other groups. Liver triglyceride levels increased with age in groups 1, 2, 3 and 5 but not in group 4. At all ages, postabsorptive (15 h without food) hepatic glycogen concentrations were much higher in groups 2 and 4 than in the other groups. Liver phospholipid concentration was not affected by age or diet. Basal adenylate cyclase activity in liver homogenates increased with age in all but group 4, but hormone-stimulated adenylate cyclase activity was little affected by age or diet. The age-related hepatic changes in lipids and in hormone responsiveness noted in the present study were much less marked than those previously found in blood and adipose tissue.

Physiological system markers of aging.

Superficially physiological measurements and processes would appear to be excellent candidates to serve as biomarkers of aging. A considered analysis reveals that the validation of them as biomarkers of aging is difficult. The available evidence indicates that the concept of physiological age does not appear to be of much value. Although physiological measurements can serve as predictors of the future occurrence of age-associated diseases and as predictors of impending mortality, such predictors may be of little value as markers of the aging processes. It seems likely that physiological markers of aging can be validated only through the appropriate use of maximum life span and the knowledge base that must be obtained to do so is discussed.

Dietary restriction.

Dietary restriction (DR) slows the rate of actuarial aging of rats and mice and in addition retards and/or delays many phenotypic characteristics of aging such as the age-associated deterioration of physiological systems and the occurrence and progression of age-associated disease. These antiaging actions result from a reduction of energy intake by the animal but are not due to a decrease in metabolic rate per unit of lean body mass. However, there is evidence that altered characteristics of fuel use (but not the intensity of fuel use) may underlie the antiaging action of DR. There is also evidence that DR has a general protective action in regard to damage caused by acute stressors; possibly a similar protective action in regard to damage caused by prolonged, low intensity aging processes plays a major role in the antiaging action of DR.

Caloric restriction and aging: an update.

Restricting food intake to 50 to 70% of that eaten by ad lib-fed rats and mice markedly increases longevity, retards age-associated physiological deterioration, and delays and, in some cases, prevents age-associated diseases. These actions are due to the reduced intake of calories, and thus the phenomenon has been called the antiaging action of caloric restriction (CR). This article focuses on the possible biological mechanisms underlying the antiaging action. The following three proposed mechanisms are considered in depth: 1) attenuation of oxidative damage; 2) modulation of glycemia and insulinemia; 3) hormesis. The evolution of the antiaging action of CR is also considered. Based on this consideration, a scenario unifying the above mechanisms is presented.

Hormesis and the antiaging action of dietary restriction.

Hormesis refers to the often encountered phenomenon of a beneficial biological action from a factor or agent that is generally viewed as detrimental. Beneficial actions that have been observed include life span extension. It is proposed that life span extension in rodents by dietary restriction is an example of hormesis and that sustained moderate hyperadrenocorticism underlies this life prolongation. Evidence supporting this concept is presented. The possibility is also suggested that whenever hormesis leads to an extension of mammalian life span, it is likely that moderate hyperadrenocorticism plays a major role.

An electron microscopic examination of age-related changes in the rat kidney: the influence of diet.

The changes with age in the ultrastructure of the kidneys were explored in ad libitum fed rats with restricted food intake started soon after weaning or started in young adult life or limited to early life and in rats restricted in protein but not caloric intake. Many ultrastructural changes occurred with age both in the glomeruli and the tubules. Food restriction started soon after weaning or in adult life modulated most of these age changes. By providing detailed information on basement membrane and tubular cell structure, these findings complement previous light microscopic and functional studies in regard to the effects of food restriction on progressive kidney disease in the rat. Food restriction limited to early life and protein restriction without caloric restriction were less effective in modulating these age changes in kidney ultrastructure than food restriction initiated at 6 weeks or 6 months of age and continued for the rest of the life span.

Dietary restriction and aging.

The diet-restricted rodent model has been and is a major tool in experimental biogerontology. A spectrum of findings indicates that dietary restriction retards the aging processes of mice and rats, the most salient of which is the increase in mortality rate doubling time. It also maintains many physiological processes in a youthful state and, most strikingly, retards or prevents almost all age-associated disease processes. Current emphasis is on the mechanisms underlying the anti-aging actions of dietary restriction. The major effort for determining mechanism has focused on putative primary aging processes. A clue has emerged from the findings that it is the restriction of energy intake that is the dietary factor responsible for the anti-aging actions. However, reducing the metabolic rate is not involved. The challenge is to learn how the reduction of energy intake per animal (not per unit of body mass) is coupled to the retardation of aging processes. One of our working hypotheses is that dietary restriction alters nervous and/or endocrine functions that influence the characteristics (not the rate) of fuel use; this modulation in fuel-use characteristics is proposed to retard the aging processes. Our findings on carbohydrate metabolism are in accord with this view. Diet-restricted rats can use carbohydrate fuel as effectively as ad libitum fed rats while maintaining lower plasma glucose and insulin level. Maintenance of these low levels may protect against long-term damaging actions of these substances. Dietary restriction also protects against oxidative damage and, of course, oxidative damage is probably an inevitable component of fuel use.(ABSTRACT TRUNCATED AT 250 WORDS)

The evolution of the antiaging action of dietary restriction: a hypothesis.

Reducing the intake of dietary energy by laboratory rodents to well below that of animals allowed to eat ad libitum slows the rate of aging. This phenomenon, which is robust and reproducible, is known as the antiaging action of dietary restriction (DR). We hypothesize that this DR response arose because of its evolutionary advantage with respect to survival during periods of unpredictable, short-term food shortage. In our evolutionary scenario, food shortage led to an adaptive redirection of resources away from reproduction toward somatic maintenance via an enhanced heat shock protein response in invertebrates. In vertebrates, an additional involvement of the hypothalamic-adenohypophyseal-adrenal glucocorticoid system was necessitated to protect against excessive systemic defense responses. We suggest several general implications of our hypothesis.

Anti-tumor action of dietary restriction is lesion-dependent in male Fischer 344 rats.

The effects of dietary restriction (DR) on spontaneous oncogenesis in male Fischer 344 rats were analyzed. Previously reported analyses of studies carried out in our laboratory demonstrated that DR reduces the incidence and delays the onset, but not the progression, of leukemia in male F344 rats. In this report, the influence of DR on pituitary tumors, adrenal pheochromocytoma, pancreatic islet cell tumors, and interstitial cell tumors of the testis was analyzed. DR reduced the relative incidence (relative onset rates) and delayed the onset of the four tumors. DR also retarded the progression (duration from onset to death) of pituitary tumors and pheochromocytoma. DR has delayed the onset of all tumors of the male F344 rat so far analyzed, but its effect on tumor progression appears to be lesion-dependent.