Age and Gender Differences in Apoptosis and Stem Cells

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The overall hypothesis of this application is that the aging female heart engages several compensatory mechanisms to prevent the development of a cardiomyopathic state. One important mechanism involves protection against apoptosis. In contrast, the aging male heart, which exhibits more apoptosis than the aging female heart, invokes a proliferation of myocytes and increased stem cells to help offset the consequences of the enhanced apoptosis. The two major unique features of this proposal are: 1 ) the use of the primate model of aging, and 2) examination of gender differences. Indeed, the majority of research in aging has been conducted in rodent models or in humans with associated diseases of aging, e.g., diabetes or atherosclerosis. The primate model is unique because it is phylogenetically closer to humans, yet does not have these associated diseases of aging. This is relevant to this proposal, which relies heavily on genomics and proteomics, where there are many similarities between non-human primates and humans. In addition, most prior work in this field has concentrated on male animals or human subjects. Accordingly, the initial themes in this proposal include examination of two hypotheses: 1) There is greater myocyte hyperplasia including increased stem cells in the aging male monkey heart, potentially as a compensatory mechanism in response to the enhanced apoptosis; 2) There are major gender differences in the development of apoptosis in the aging monkey heart. In the post-menopausal female monkey, where there is less apoptosis with aging than in the male heart, there is agene and protein program of cell survival. These mechanisms also protect the aging female heart more than the aging male heart in response to myocardial ischemia. An additional component of this proposal is to examine two novel molecular mechanisms protecting apoptosis identified in the aging monkey heart, which are: 1) downregulation of adenylyl cyclase type 5 and 2) upregulation of XIAP. These mechanisms will be examined in genetically engineered mouse models, which we hypothesize will exhibit protection from apoptosis and the cardiomyopathy of aging resulting in enhanced longevity. In summary, this proposal will provide new conceptual information on gender differences with regard to compensatory adaptive mechanisms in the aging heart in a novel primate model.