Age and Gender Differences in Apoptosis and Stem Cells

描述（由申请人提供）：本申请的总体假设是，衰老的女性心脏参与了几种代偿机制来防止心肌病状态的发展。一个重要的机制涉及防止细胞凋亡。相反，衰老的男性心脏比衰老的女性心脏表现出更多的细胞凋亡，这需要肌细胞的增殖和干细胞的增加来帮助抵消细胞凋亡增加的后果。这一建议的两个主要特点是：1)使用灵长类动物的衰老模型，2)检查性别差异。事实上，大多数关于衰老的研究都是在啮齿动物模型或患有相关衰老疾病（如糖尿病或动脉粥样硬化）的人类身上进行的。灵长类动物模型是独特的，因为它在系统发育上更接近人类，但没有这些与衰老相关的疾病。这与该提案相关，该提案严重依赖于基因组学和蛋白质组学，其中非人灵长类动物与人类之间存在许多相似之处。此外，该领域的大多数先前工作都集中在雄性动物或人类受试者身上。因此，本提案的初始主题包括检查两个假设：1)在衰老的雄性猴子心脏中有更大的心肌细胞增生，包括增加的干细胞，可能作为对细胞凋亡增强的补偿机制；2)老龄猴心脏细胞凋亡的发生存在明显的性别差异。绝经后雌猴心脏随衰老而发生的细胞凋亡少于雄猴心脏，存在细胞存活的基因和蛋白程序。在心肌缺血时，这些机制对女性心脏的保护作用强于男性心脏。本研究的另一个组成部分是研究在衰老的猴子心脏中发现的两种新的保护细胞凋亡的分子机制：1)腺苷酸环化酶5型的下调和2)XIAP的上调。这些机制将在基因工程小鼠模型中进行检验，我们假设这些模型将显示出对细胞凋亡和衰老心肌病的保护，从而延长寿命。总之，这一建议将提供新的概念性信息，性别差异有关代偿适应机制的老化的心脏在一个新的灵长类动物模型。

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.