Caloric intake and aging: mechanisms in rodents and a study in nonhuman primates.
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Caloric restriction (CR) increases maximum life span in rodents while attenuating the development of age-associated pathological and biological changes. Although nearly all of the rodent studies have initiated CR early in life (1-3 months of age), CR, when started at 12 months of age, also extends maximum life span in mice. Two main questions face investigators of CR. One concerns the mechanisms by which CR retards aging and diseases in rodents. There is evidence that CR may act, at least in part, by reducing oxidative stress. A CR-induced decrease in oxidative stress appears to be most profound in post-mitotic tissues and may derive from lower mitochondrial production of free radicals. The second issue is whether CR will exert similar effects in primates. Studies on CR in rhesus monkeys (maximum life span approximately 40 years) support the notion of human translatability. We describe the University of Wisconsin Study of rhesus monkeys subjected to a 30% reduction of caloric intake starting at either 1989 or 1994 when they were approximately 10 years old. The data from our study and from other trials suggest that CR can be safely carried out in monkeys and that certain physiological effects of CR that occur in rodents (e.g., decreased blood glucose and insulin levels, improved insulin sensitivity, and lowering of body temperature) also occur in monkeys. Whether oxidative stress in monkeys is reduced by CR will be known by the year 2000, while effects on longevity and diseases should be clearly seen by, appropriately, 2020. (+info)
Calorie restriction in nonhuman primates: effects on diabetes and cardiovascular disease risk.
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The effects of calorie restriction (CR) on life span, disease, and aging in physiological systems have been documented extensively in rodent models. However, whether CR has similar effects in longer-lived species more closely related to humans remains unknown. Studies of CR and aging using nonhuman primates (rhesus monkeys) have been ongoing for several years at the National Institute on Aging and the University of Wisconsin-Madison. The majority of data published from these studies are consistent with the extensive findings reported in rodents. For example, monkeys on CR weigh less and have less body fat. Monkeys on CR also exhibit lower body temperature, fasting blood glucose and insulin, and serum lipids. In addition, insulin sensitivity is increased in monkeys on CR. Recent efforts in the NIA study have focused on the effect of this intervention on risk factors for various age-related diseases, in particular for diabetes and cardiovascular disease. We have shown that monkeys on CR have lower blood pressure, reduced body fat, and a reduced trunk:leg fat ratio. Also, monkeys on CR have reduced triglycerides and cholesterol and have increased levels of HDL2B. Low levels of this HDL subfraction have been associated with increased cardiovascular disease in humans. In short-term studies, older (> 18 years) monkeys on CR exhibit reductions in insulin and triglycerides before changes in body composition and fat distribution became evident. These and other findings have suggested that CR might have beneficial effects on certain disease risk factors independent of reductions in body weight or prevention of obesity. (+info)
Calorie restriction in nonhuman primates: mechanisms of reduced morbidity and mortality.
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Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbidity and increases median age of death. The present review is focused upon an ongoing study of sustained adult-onset calorie restriction, which has been underway for 15 years. Monkeys, initially calorie restricted at about 10 years of age, are now approximately 25 years old. The median life span of these restricted monkeys is increasing, now exceeding that of ad libitum (AL)-fed monkeys. In our laboratory, maximum life span for AL-fed monkeys appears to be about 40 years. Thus, whether CR can also increase maximal life span, as it does in rodents, cannot be determined for at least another 15 years. The earliest detectable positive benefit on morbidity in these monkeys was previously reported as the prevention of obesity. Current evidence, as reviewed here, suggests that much obesity-associated morbidity is also mitigated by sustained calorie restraint in nonhuman primates. Furthermore, probably because of the prevention of obesity, diabetes has also been prevented. Recent findings include the identification of extraordinary changes in the glycogen synthesis pathway, and on the phosphorylation of glycogen synthase in response to insulin. This calorie restriction-induced prevention of morbidity does not require excessive leanness, but is clearly present when body fat is within the normal range of 10 to 22%, and this is likely to be true in humans as well. (+info)
Influence of diet on survival of mice.
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The longevity of mice of the (NZB X NZW)F1 (B/W) strain and the DBA/2f strain of mice is dramatically prolonged by dietary restriction. B/W mice are susceptible to, and die at an early age from, immunocomplex nephritis. Mice of the DBA/2f strain are also relatively short-lived. Restriction of caloric intake prolonged life of B/W mice more than did protein restriction. DBA/2f mice showed prolongation of life when the diet was restricted only with respect to protein. Caloric restriction alone prolonged life less in DBA/2f mice than in B/W mice. These observations show that dietary manipulations have profound effects on immunity functions, including inhibition of the development of life-shortening autoimmune disease. (+info)
Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene.
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Branch points and flexures in the high pressure arterial system have long been recognized as sites of unusually high turbulence and consequent stress in humans are foci for atherosclerotic lesions. We show that mice that are homozygous for a null mutation in the gene encoding an endogenous antiinflammatory cytokine, interleukin 1 receptor antagonist (IL-1ra), develop lethal arterial inflammation involving branch points and flexures of the aorta and its primary and secondary branches. We observe massive transmural infiltration of neutrophils, macrophages, and CD4(+) T cells. Animals appear to die from vessel wall collapse, stenosis, and organ infarction or from hemorrhage from ruptured aneurysms. Heterozygotes do not die from arteritis within a year of birth but do develop small lesions, which suggests that a reduced level of IL-1ra is insufficient to fully control inflammation in arteries. Our results demonstrate a surprisingly specific role for IL-1ra in the control of spontaneous inflammation in constitutively stressed artery walls, suggesting that expression of IL-1 is likely to have a significant role in signaling artery wall damage. (+info)
Heritability of fitness in a wild mammal population.
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Classical population genetics theory predicts that selection should deplete heritable genetic variance for fitness. We show here that, consistent with this prediction, there was a negative correlation between the heritability of a trait and its association with fitness in a wild population of red deer (Cervus elaphus) and there was no evidence of significant heritability of total fitness. However, the decline in heritability was caused, at least in part, by increased levels of residual variance in longevity and, hence, in total fitness: in this population, longevity is known to be heavily influenced by environmental factors. Other life history traits that were not associated with longevity, such as average annual breeding success, had higher heritabilities. Coefficients of additive genetic variance differed markedly between traits, but highly skewed measures, such as male breeding success, generally had greater coefficients of variance than morphometric traits. Finally, there were significant maternal effects in a range of traits, particularly for females. (+info)
Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM.
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Individuals with systemic lupus erythematosus and rheumatoid arthritis are characterized by the presence of high levels of circulating IgM and IgG autoantibodies. Although IgG autoantibodies often are pathogenic, the role of IgM autoantibodies in autoimmune disease is not clear. Using mice that are unable to secrete IgM but are able to express surface IgM and IgD and to secrete other classes of immunoglobulins, we examined the effect of the absence of secreted IgM in the development of IgG autoantibodies and autoimmune disease in lupus-prone lymphoproliferative (lpr) mice. Compared with regular lpr mice, lpr mice that lack secreted IgM developed elevated levels of IgG autoantibodies to double-stranded DNA and histones and had more abundant deposits of immune complexes in the glomeruli; they also suffered more severe glomerulonephritis and succumbed to the disease at an earlier age. Similarly, the absence of secreted IgM also resulted in an accelerated development of IgG autoantibodies in normal mice. These findings suggest that secreted IgM, including IgM autoantibodies produced naturally or as part of an autoimmune response, may lessen the severity of autoimmune pathology associated with IgG autoantibodies. (+info)
Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals.
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DNA damage is considered of paramount importance in aging. Among causes of this damage, free radical attack, particularly from mitochondrial origin, is receiving special attention. If oxidative damage to DNA is involved in aging, long-lived animals (which age slowly) should show lower levels of markers of this kind of damage than short-lived ones. However, this possibility has not heretofore been investigated. In this study, steady-state levels of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) referred to deoxyguanosine (dG) were measured by high performance liquid chromatography (HPLC) in the mitochondrial (mtDNA) and nuclear (nDNA) DNA from the heart of eight and the brain of six mammalian species ranging in maximum life span (MLSP) from 3.5 to 46 years. Exactly the same digestion of DNA to deoxynucleosides and HPLC protocols was used for mtDNA and nDNA. Significantly higher (three- to ninefold) 8-oxodG/dG values were found in mtDNA than in nDNA in all the species studied in both tissues. 8-oxodG/dG in nDNA did not correlate with MLSP across species either in the heart (r=-0.68; P<0.06) or brain (r = 0.53; P<0.27). However, 8-oxodG/dG in mtDNA was inversely correlated with MLSP both in heart (r=-0.92; P<0.001) and brain (r=-0.88; P<0.016) tissues following the power function y = a(.)x(b), where y is 8-oxodG/dG and x is the MLSP. This agrees with the consistent observation that mitochondrial free radical generation is also lower in long-lived than in short-lived species. The results obtained agree with the notion that oxygen radicals of mitochondrial origin oxidatively damage mtDNA in a way related to the aging rate of each species.-Barja, G., Herrero, A. Oxidative damage to mitochondrial DNA is inversely related to maximum life span in the heart and brain of mammals. (+info)