Age and Gender Differences in Apoptosis and Stem Cells

描述(申请人提供)：这项申请的总体假设是，老化的女性心脏参与了几种代偿机制，以防止心肌病状态的发展。一种重要的机制涉及到对细胞凋亡的保护。相比之下，衰老的男性心脏比衰老的女性心脏表现出更多的凋亡，它会激活心肌细胞的增殖和干细胞的增加，以帮助抵消细胞凋亡增强的后果。这一建议的两个主要特点是：1)使用灵长类衰老模型，2)考察性别差异。事实上，大多数关于衰老的研究都是在啮齿动物模型上进行的，或者是在患有与衰老相关的疾病的人类身上进行的，例如糖尿病或动脉粥样硬化。灵长类动物模型是独一无二的，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。这与这一提议有关，该提议严重依赖基因组学和蛋白质组学，在这些领域，非人类灵长类动物和人类之间有许多相似之处。此外，这一领域以前的大多数工作都集中在雄性动物或人类受试者身上。因此，这项建议的初始主题包括两个假设的检验：1)在衰老的雄性猴心脏中存在更大的心肌细胞增殖，包括增加的干细胞，潜在地作为对增强的细胞凋亡的一种代偿机制；2)在衰老的猴子心脏中，细胞凋亡的发展存在重大的性别差异。在绝经后的雌性猴子中，随着年龄的增长，细胞凋亡的数量比男性心脏少，因此存在着细胞存活的基因和蛋白质程序。在应对心肌缺血时，这些机制也比老化的男性心脏更能保护老化的女性心脏。这项建议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，即：1)腺酰环化酶5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，我们假设这种模型将显示出对细胞凋亡和老化心肌病的保护，从而延长寿命。综上所述，这项建议将在一个新的灵长类动物模型中提供关于老化心脏代偿适应机制的性别差异的新的概念性信息。

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.