How does dietary restriction retard diseases and aging?
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Biomedical subjects
R Weindruch
Publications and source records attributed to R Weindruch.
Influences of aging and dietary restriction on serum thymosin alpha 1 levels in mice.
Influences of age (3 wk, 2, 7, 19, or 26 mo), long-term dietary restriction (DR) started at 3 wk of age, and acute fasting state on serum thymosin alpha 1 (T alpha 1) levels were measured by radioimmunoassay in female mice from a long-lived strain. The average T alpha 1 level was highest (approximately 60 ng/ml) at 3 wk and fell sharply such that 2 mo old mice fed either normal (N, approximately 80% of ad libitum intake) or restricted (R, approximately 50% of ad libitum intake) diets averaged approximately 20 ng/ml. Any age-related declines after 2 mo of age were mild and statistically significant only for R mice bled 2-4 h (but not 24-48 h) post-feeding. T alpha 1 levels were lower in group R than in group N mice in one experiment at 19 mo of age but not in another at 26 mo. The decline with age in serum T alpha 1 levels is mainly a very early life event for mice of this hybrid strain and appears uninfluenced by DR. T alpha 1 levels are variably reduced by DR later in life.
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Dietary restriction benefits learning and motor performance of aged mice.
Female C3B10RF1 mice maintained on either a control (approximately 95 kcal/week) or restricted (approximately 55 kcal/week) diet since weaning were tested in a behavioral battery at 11 to 15 or 31 to 35 months of age (middle-aged vs. aged). Age-related declines observed among control groups in tests of motor coordination (rotorod) and learning (complex maze) were prevented by the restriction regime. In addition, diet restriction increased locomotor activity in a runwheel cage among mice of both ages but did not affect exploratory activity in a novel arena.
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Dietary restriction and aging: historical phases, mechanisms and current directions.
Energy intake restriction (ER) without essential nutrient deficiency retards aging and extends life span in all species tested so far, and across wide phylogenetic differences. Historical phases of this model system for studying aging have included modulation of the survival curve, effects on disease susceptibility and effects on physiological indices of aging; the current phase focuses upon possible mechanisms whereby ER influences such widely diverse phenomena. Mechanistic possibilities include effects on the immune system, on basal state and proliferation potential, metabolic rate, DNA repair, levels of free radical scavengers, chromatin structure and protein synthesis and turnover. The ER model may also be useful in analyzing unifactorial versus multifactorial theories of aging, and in clarifying the possible significance of physiological markers that correlate with differences in maximum life spans between species.
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Influences of dietary restriction and age on liver enzyme activities and lipid peroxidation in mice.
Dietary restriction extends maximum life span in rodents by unknown mechanisms. We compared livers from 12- and 24-mo-old mice fed control (C, approximately 95 kcal/wk) or restricted (R, approximately 55 kcal/wk) amounts of diet since 3 wk of age. We hypothesized that dietary restriction might alter the activity levels of enzymes with possible relevance to aging processes. The enzymes included several xenobiotic metabolizers, radical scavengers (catalase, superoxide dismutase, glutathione peroxidase), superoxide sources (xanthine oxidase, peroxisomal beta-oxidation of palmitoyl-CoA) and glucose-6-phosphatase. Lipid peroxidation (LP) was also measured. Comparing 12- and 24-mo-old mice, the strongest diet or age effect was an increased catalase activity for group R (42% higher at 12 mo, 64% at 24 mo). LP was clearly lower in group R at 12 mo (a 30% decrease) and somewhat lower (13%) at 24 mo than in group C. Similarly, in 12-mo-old C and R mice injected with either the P-450 inducer beta-naphthoflavone (beta-NF in corn oil) or with corn oil alone. R mice showed higher catalase activity (40-44%) and lower LP (43-46%) in both beta-NF-injected and vehicle-injected groups. These data suggest that if free radical damage is involved in aging, it may be a particular kind of damage, that is, that in part prevented by a selective increase in catalase activity.
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The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake.
We sought to clarify the impact of dietary restriction (undernutrition without malnutrition) on aging. Female mice from a long-lived strain were fed after weaning in one of six ways: group 1) a nonpurified diet ad libitum; 2) 85 kcal/wk of a purified diet (approximately 25% restriction); 3) 50 kcal/wk of a restricted purified diet enriched in protein, vitamin and mineral content to provide nearly equal intakes of these essentials as in group 2 (approximately 55% restriction); 4) as per group 3, but also restricted before weaning; 5) 50 kcal/wk of a vitamin- and mineral-enriched diet but with protein intake gradually reduced over the life span; 6) 40 kcal/wk of the diet fed to groups 3 and 4 (approximately 65% restriction). Mice from groups 3-6 exhibited mean and maximal life spans 35-65% greater than for group 1 and 20-40% greater than for group 2. Mice from group 6 lived longest of all. The longest lived 10% of mice from group 6 averaged 53.0 mo which, to our knowledge, exceeds reported values for any mice of any strain. Beneficial influences on tumor patterns and on declines with age in T-lymphocyte proliferation were most striking in group 6. Significant positive correlations between adult body weight and longevity occurred in groups 3-5 suggesting that increased metabolic efficiency may be related to longevity in restricted mice. Mice from groups 3-6 ate approximately 30% more calories per gram of mouse over the life span than did mice from group 2. These findings show the profound anti-aging effects of dietary restriction and provide new information for optimizing restriction regimes.
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Aging in rodents fed restricted diets.
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Dietary restriction retards age-related loss of gamma crystallins in the mouse lens.
The soluble crystallins in lenses from diet-restricted and control mice of diverse ages (2, 11, or 30 months) were studied by high-performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Results obtained with both methods suggest that dietary restriction decelerates age-related loss of soluble gamma crystallins.
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Food intake reduction and immunologic alterations in mice fed dehydroepiandrosterone.
A diet containing 0.4% DHEA was fed to male mice of a long-lived strain from 3 weeks until 18 weeks of age. These mice were compared with others fed a control diet ad libitum and with mice pair-fed the control diet in amounts approximating the intake of the DHEA-fed group. Mice fed the DHEA diet failed to eat all of the food presented to them whereas the pair-fed mice ate all of their food. All mice were studied at 18 weeks of age for two age-sensitive immune parameters (spleen lymphocyte proliferation induced by T-cell mitogens [PHA or ConA] and natural killer cell lysis of an allogeneic tumor). DHEA feeding led to: 1) a decrease in food intake (approximately 30% less than for mice fed the control diet ad libitum), 2) a lower body weight at 18 weeks of age (approximately 40% lower than for ad libitum controls) due to a decrease in the body weight gained from 3 weeks through 18 weeks of age (approximately 55% lower than controls), 3) a lower spleen weight (approximately 30% lower than controls) but without lower numbers of nucleated cells per spleen, 4) an increase in PHA-induced proliferation by spleen lymphocytes (approximately 100% higher than for controls) and, 5) no influence on splenic natural killer cell activity. The inhibition of body weight gain for mice fed DHEA appeared due to both a reduction in food intake and a metabolic effect since mice eating DHEA gained less body weight per gram of food eaten than did mice in either group eating the control diet.
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Influence of dietary restriction and aging on natural killer cell activity in mice.
Natural killer cells (NK) are believed to defend against tumor growth. Because rodents subjected to dietary restriction without malnutrition live longer and develop spontaneous tumors less often or later in life than unrestricted controls, we measured NK activity in restricted and in unrestricted mice. An age-related decline in NK responses to YAC-1 tumor target cells was detected in both groups. NK responses for control mice were highest in 2- to 3-mo-old mice, sharply reduced in middle-age mice (14 to 15 mo), and slightly reduced further in old mice (30 to 33 mo). At all ages the response of restricted mice was less than that of controls. However, after injection with Poly I:C (which increases NK activity), old restricted mice showed NK cytolysis not different from young mice on either diet, and substantially higher responses than old unrestricted mice. In addition, restricted mice showed increased in vitro generation of cytotoxic T lymphocytes (CTL) to YAC-1 and P815 compared with age-matched controls. Restricted mice may better resist cancer via an NK system very responsive to induction signals coupled with a CTL system more effective than that of unrestricted controls.
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Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence.
Lifelong dietary restriction beginning at 3 to 6 weeks of age in rodents is known to decelerate the rate of aging, increase mean and maximum life-spans, and inhibit the occurrence of many spontaneous cancers. Little is known about the effects of dietary restriction started in middle age. In the experiments now reported the food intake of 12- to 13-month-old mice of two long-lived strains was restricted by using nutrient-enriched diets in accordance with the concept of "undernutrition without malnutrition." The mice on the restricted diet averaged 10 to 20 percent increases in mean and maximum survival times compared to the control mice. Spontaneous lymphoma was inhibited by the food restriction.
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Modification of age-related immune decline in mice dietarily restricted from or after midadulthood.
Although weaning-initiated dietary restriction of rodents is known to increase maximum survivorship and inhibit spontaneous late-life disease and immunologic aging, restriction begun in adulthood has been much less thoroughly evaluated. In the present studies, male mice of a long-lived F1 hybrid strain were gradually restricted dietarily beginning at 12 mo or older until their body weights stabilized at 60-70% of controls. Underfeeding decreased the number of nucleated cells per spleen but increased the percentage of T cells. For mice restricted at 12, 17, or 22 mo and tested at various ages thereafter, the [3H]thymidine uptake of spleen cells after phytohemagglutinin stimulation significantly exceeded values for age-matched unrestricted controls. Restriction did not, however, alter either splenocyte responses to concanavalin A or to B-cell mitogens or phytohemagglutinin responses of peripheral lymph node cells. In the splenic plaque-forming cell response to injected sheep erythrocytes, restricted and control mice differed more clearly in response kinetics than in peak levels. The splenic cell-mediated lymphocytotoxic response to alloantigens was comparable in old mice (27-29 mo) restricted since 12 mo of age with that of young (5- to 6-mo) controls and was greater than that of age-matched old controls. Spontaneous tumors were observed less frequently in 19- to 25-mo-old mice restricted at 12 mo of age than in mice restricted at 17 mo or in controls. Our results indicate that appropriate food restriction initiated in adulthood influences immunosenescence and spontaneous tumor incidence in a fashion not unlike its weaning-initiated counterpart.
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Failure of dietary restriction to retard age-related neurochemical changes in mice.
Age-sensitive neurochemical measures and estrous cyclicity were studied in female mice from the long-lived C3B10F1 strain fed either a control diet or subjected to dietary restriction (DR) from 3 weeks of age. Striatal dopaminergic D2 receptor density decreased by 25% from 9-10 months to 28-30 months of age in the control group. This decline was uninfluenced by DR. Anterior pituitary dopamine + dihydroxyphenylacetic acid content increased by 2.5 fold with age in the control group but DR failed to oppose this age-related change. In contrast to DR's lack of influence on these two neurochemical measures were findings on estrous cyclicity. Although mice on DR did not display estrous cycles, cyclicity was rapidly initiated when these mice were switched to the control diet at 12 and even at 22 months of age. Thus, limited aspects of neuroendocrine aging were retarded by DR in this long-lived mouse model.
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Use of caloric restriction to investigate neuroendocrine involvement in aging.
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Effect of caloric restriction on age-associated cancers.
Caloric restriction (CR) without malnutrition in mice and rats reduces the incidence of spontaneous tumors and delays their appearance while increasing maximum life span. These results depend largely on CR per se, and not on low intakes of fat or other nutrients. Although most studies have tested CR imposed early in life, CR started in midadulthood also retards cancer and aging. The way(s) by which CR impedes cancers remain unclear, but possibilities include less cellular oxidative damage, retarded immunologic aging, hormonal changes, less energy available for cell proliferation, reduced exposure to dietary carcinogens and promoters, enhanced DNA repair, and less carcinogen activation. Far less is known about the relationship between caloric intake and cancer incidence in humans; however, recent findings suggest a positive association for certain cancers.
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Influences of aging and dietary restriction on red blood cell density profiles and antioxidant enzyme activities in rhesus monkeys.
Dietary restriction (DR) retards aging processes in rodents and other animals but its influence on aging in primates is unknown. In rats, the average density of red blood cells (RBCs) reportedly increases with RBC age and decreases with host age and RBC antioxidant enzyme activities fall with both types of aging. We determined RBC density profiles and antioxidant enzyme activities in four groups (n = 5) of male rhesus monkeys. The "Control" group (11-14 years) was fed a purified diet ad lib and the "DR" group (11-16 years) were fed 70% of the ad lib level for two years. "Young" (6-10 years) and "Old" (27-36 years) monkeys were fed a nonpurified diet ad lib. The average RBC size was least in the most dense fraction (F4) and internal structural complexity increased with RBC density based on flow cytometry analysis but these were not influenced by host age or DR. Catalase activity decreased with increasing density. In contrast to findings in rats, age and fraction differences in glutathione peroxidase activities were insignificant. DR did not influence enzyme activities. These data suggest that aging in rhesus monkeys influences RBC density profiles and antioxidant enzyme activities far less strikingly than has been reported in rats.
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Controlling caloric consumption: protocols for rodents and rhesus monkeys.
One approach for investigating biological aging is to compare control-fed animals with others restricted in calorie intake by 20% or more. Caloric restriction (CR) is the only intervention shown to extend the maximum lifespan of several invertebrates and vertebrates including spiders, fish, rats and mice. The capacity of CR to retard aging in nonhuman primates is now being explored. The rodent studies show that CR opposes the development of many age-associated pathophysiological changes, including changes to the brain and changes in learning and behavior. One goal of studying CR in rodent is to determine the mechanisms by which it retards aging to design interventions that duplicate those effects. The methods that we use for conducting CR studies on mice and rhesus monkeys are described. We employ procedures designed to achieve a high degree of caloric control for all animals in the study. As used in our studies, this control includes the following features: 1) animals are individually housed, and 2) all individuals in the control group eat the same number of calories (i.e., they are not fed ad lib). Although this method results in strict caloric control for all animals, there seems to be considerable procedural flexibility for the successful conduct of CR studies.
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The retardation of aging by caloric restriction: studies in rodents and primates.
Caloric restriction (CR), which has been investigated by gerontologists for more than 60 yr, provides the only intervention tested to date in mammals (typically mice and rats) that repeatedly and strongly increases maximum life span while retarding the appearance of age-associated pathologic and biologic changes. Although the large majority of rodent studies have initiated CR early in life (1-3 mo of age), CR started in midadulthood (at 12 mo) also extends maximum life span in mice. Two main questions now face gerontologists investigating CR. By what mechanisms does CR retard aging and disease processes in rodents? There is evidence to suggest that age-associated increases in oxidative damage may represent a primary aging process that is attenuated by CR. Will CR exert similar actions in primates? Studies in rhesus monkeys subjected to CR and limited human epidemiological data support the notion of human translatability. However, no matter what the answers are to these questions, the prolongation of the health span and life span of rodents by CR has major implications for many disciplines, including toxicologic pathology, and raises important questions about the desirability of ad libitum feeding.
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