Interdisciplinary topics in gerontology最新文献

The scope of data now available for primates from long-term field and captive studies has opened up exciting possibilities for investigating age-related patterns of reproduction. Valuable information on the aging process can be gleaned through broad cross-taxonomic comparative studies that include lemurs, monkeys, apes and humans. Thus, across all taxa discussed in this volume, female reproduction was found to be complex and dynamic, affected by the interplay of multiple exogenous and endogenous factors. Throughout their lives, females differ in their individual reproductive output. As they age, a period of reproductive instability is common among female primates and perimenopausal- like hormonal changes have been noted in many species. Available data from lemurs and callitrichids indicate that at least in some species, age-related declines in reproduction are manifested as diminished success of females to rear their young to weaning age. Few data are available for New World primates, but the same observation holds true for Old World monkey females, who also are characterized by declines in sexual activity and decreased birth rates. In apes, captive data suggest the presence of an appreciable postreproductive lifespan but this has not been confirmed in the wild. Menopause may be manifested as an evolutionary continuum across primate taxa with the potential for an extended postreproductive lifespan evident in cercopithecines and apes.

Menopause and reproductive senescence can be more fully understood by examining these phenomena where they occur in nonhuman mammals, as well as humans, and especially by comparisons among primates. In addition to concerns about human health and welfare, successful programs for wildlife management and agriculture, and the propagation and conservation of endangered species depend on detailed understanding of reproduction and fertility throughout the life span. Appropriate care of elderly primates in zoological gardens also requires knowledge of their health, behavior, and reproductive status. Information on female primate fertility, reproductive senescence, and associated health-risks is scattered throughout the scientific literature, and includes emphases ranging from comparative medicine and primate models of human health to zoology and human evolution. This chapter introduces a range of issues and reviews studies of female primate reproductive senescence and menopause. These topics are examined in greater depth in the subsequent chapters of this volume.

As our closest living relatives, great apes likely experience physiological patterns associated with reproductive aging that are similar to humans. We present results from a nationwide zoo-based study on female western lowland gorillas during which we evaluated concentrations of progestogens via daily fecal sampling in 30 gorillas, 22 of whom were geriatric (>or=30). Whereas control females cycled regularly, ca. 23% of geriatric females were acyclic (menopausal), and approximately 1/3 showed variable hormonal patterns suggestive of perimenopause. Patterns included increased cycle variability, low luteal phase rises of progestogens - possibly indicative of anovulatory cycling - and peak height variability of progestogens in the luteal phase of the cycle. We discovered a progressive trend toward increased variability in estrous cycle length and toward decreased concentrations of fecal progestogens when we compared control to geriatric cycling and to geriatric noncycling females. Noncycling females had significantly lower overall progestogen concentrations than the cycling females, though differences were not significant when cycle phase was incorporated. Preliminary analyses of follow-up data on 10 perimenopausal females indicated that subjects experienced age-related changes in reproductive function that mirrored those observed in aging human females including a female who transitioned from perimenopause to menopause. To date, maximum longevity in captive female gorillas is 52 years, with poor reproductive prognosis beginning from the age of 37 suggesting a postreproductive lifespan of >25%. Continued study of aging apes is warranted, with emphasis on longitudinal monitoring of aged subjects.

Long-term dietary restriction (DR) robustly inhibits various types of carcinogenesis in rodents. Because malignancies are a major cause of death in humans, reducing the incidence or, at least, delaying the time of onset of neoplasia may significantly increase longevity of a large proportion of the human population. Long-term DR may not however be practical in humans and, judging from religious practices, several days of fasting to several weeks of DR is what a large segment of the human population can adhere to. In contrast to long-term DR, a single episode of fasting or several fasting-refeeding cycles did not have any long-lasting beneficial and usually had even a deleterious effect on carcinogenesis in rodent models. On the other hand, DR of a relatively short (1-3 months) duration often significantly increased latency and reduced the incidence of cancer over the entire life span. These results suggest that the immediate anticarcinogenic action of DR is to slow down the expansion of initiated clones, but that several months of DR may be sufficient for the elimination of a significant portion of initiated precancerous clones through apoptosis. The development of optimized DR regimens for humans will be contingent on further advances in our understanding of the mechanisms of cancer suppression by DR.

Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in beta-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

The level of food restriction that results in life extension and retarded aging in rodents also enhances their ability to cope with intense stressors. Moreover, this level of dietary restriction (DR) leads to a modest increase in the daily peak concentration of plasma free corticosterone, which strongly points to DR as a low-intensity stressor. These findings suggest that hormesis plays a role in the life-extending and anti-aging actions of DR. The evidence for and against this possibility is considered, and it is concluded that hormesis does have an important role.

The nematode Caenorhabditis elegans has proved to be an excellent model organism for the study of development and aging. Many aging mutants have been discovered in the past two decades, and much has been discovered about the physiology of long-lived mutants. It therefore seems surprising that dietary restriction (DR) has not been extensively studied using C. elegans. The main reason for this is the lack of an ideal method to subject C. elegans to DR. However, several authors have tried to study the effect of DR on the metabolism and physiology of C. elegans, and epistasis-type interaction studies have been carried out in order to detect genes that might be involved in DR effects. These studies show that DR life extension is not caused by a reduced metabolic rate, consistent with results in other species. Moreover, the well-known insulin/IGF-1 pathway seems not to mediate life-extending effects. One possibility is that target of rapamycin signaling mediates the effects of DR on life span in C. elegans.

Alzheimer's disease (AD) is a rapidly growing public health concern with potentially devastating effects. Presently, there are no known cures or effective preventive strategies. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset sporadic AD cases, the most common form of AD. Due to the fact that the disease typically strikes very late in life, delaying symptoms could be as good as a cure for many people. For example, it is now widely accepted that if the onset of the disease could be delayed by even 5 years, the incidence could be cut in half. Both clinical and epidemiological evidence suggests that modification of lifestyle factors such as nutrition may prove crucial to AD management given the mounting experimental evidence suggesting that brain cells are remarkably responsive to "what somebody is doing". Among other nongenetic factors influencing AD, recent studies strongly support the evidence that caloric intake may play a role in the relative risk for AD clinical dementia. Indeed, the effect of diet in AD has been an area of research that has produced promising results, at least experimentally. Most importantly, as mechanistic pathways are defined and their biochemical functions scrutinized, the evidence supporting a direct link between nutrition and AD neuropathology continues to grow. Our work, as well as that of others, has recently resulted in the development of experimental dietary regimens that might promote, attenuate or even reverse features of AD. Most remarkably, while we found that high caloric intake based on saturated fat promotes AD type Beta-amyloidosis, conversely we found that dietary restriction based on reduced carbohydrate intake is able to prevent it. This evidence is very exciting and is, in part, consistent with current epidemiological studies suggesting that obesity and diabetes are associated with a >4-fold increased risk of developing AD. The clarification of the mechanisms through which dietary restriction may beneficially influence AD neuropathology and the eventual discovery of future "mimetics" capable of anti-Beta-amyloidogenic activity will help in the development of "lifestyle therapeutic strategies" in AD and possibly other neurodegenerative disorders.

Diet restriction (DR) was first shown to extend adult survival in Drosophila only a bit longer than a dozen years ago. Limiting the amount of dietary yeast was sufficient to increase life span. In the short time since this initial observation, work with Drosophila has revealed several insights into the mechanisms of DR. It has also uncovered many unanticipated technical issues. This paper describes how resolving the way we study DR in Drosophila is a prerequisite to discover the way nutrition modulates aging. Key empirical problems include the necessity of measuring the impact of DR upon life span with multiple levels of diet, analysis of the demographic response to diet with mortality data and, in the context of reaction norms, methods of diet modification, and uncertainty as to how diet dilution translates to changes in actual nutrient uptake. We review the accumulated literature of DR in Drosophila from this methodological lens to distill four important results: yeast restriction alone is sufficient to increase survival; diet affects survival through two distinct physiological responses, starvation and longevity assurance; mortality has no memory of its past with respect to nutrition; the molecular operation of DR may involve processes of deacetylation via Sir-2 and Rpd-3. Finally, it remains unknown whether or not DR functions through insulin-related signaling.