Longevity and Stress Resistance

描述（由申请人提供）：该项目的总体主题是测试寿命延长，寿命和抗应激性由共同机制介导的假设。越来越多的证据表明，从酵母到蠕虫，从苍蝇到哺乳动物，各种各样的生物体的寿命都受到确定的分子机制的调节，包括Sir 2，NAD依赖性组蛋白脱乙酰酶和腺苷酸环化酶-蛋白激酶A途径。理解导致衰老的不利影响的关键调节机制或相反地延长寿命的机制的主要限制是缺乏表现出延长的寿命并且不发展心肌病或骨质疏松症或其他终点的动物模型，这些终点通常随着衰老而观察到。从酵母菌到灵长类动物，最被接受的延长寿命的模型是热量限制。相对较少的其他型号的寿命。在这方面，我们最近鉴定了一种新的基因工程动物模型，其比野生型动物寿命更长，并且不表现出许多老年的心脏和心脏病特征，即，腺苷酸环化酶（AC）5型“敲除”（ACS KO）的小鼠。我们认为，研究ACS KO模型特有的机制将为衰老过程提供重要的见解，并可能提供可用于逆转这一过程的机制。项目1和2在这个小鼠模型中研究这些机制。此外，项目3已经开发并将研究其他与Sir 2alpha相关的衰老和抗应激小鼠模型。该项目的核心假设是Sir 2alpha在体内心脏中介导抗衰老和细胞保护作用。这3个项目由5个核心支持：管理/生理学;动物护理;基因组学/蛋白质组学;生物信息学/生物统计学;病理学。该计划项目对公共卫生具有重大意义。与老龄化相关的残疾对公共卫生和美国经济产生重大影响。发现分子开关，如本项目中描述的那些，可以改善衰老引起的残疾，这将是向前迈出的重要一步。

DESCRIPTION (provided by applicant): The overall theme of this project is to test the hypothesis that life span extension, longevity and stress resistance are mediated by common mechanisms. Growing lines of evidence suggest that the longevity of a wide variety of organisms, from yeast to worms and flies to mammals, is regulated by defined molecular mechanisms, including Sir2, an NAD-dependent histone deacetylase, and the adenylyl cyclase-protein kinase A pathway. A major limitation to understanding the key regulatory mechanisms responsible for causing the adverse effects of aging, or conversely, those that extend longevity, is the lack of animal models which exhibit prolonged lifespan and which do not develop cardiomyopathy or osteoporosis or other end- points, which are normally observed with aging. The model, which is accepted best for increasing longevity from yeast to primates, is caloric restriction. Relatively few other models for longevity are available. In this connection, we have recently identified a novel, genetically engineered animal model, which lives longer than wild type animals and does not exhibit many of the cardiac and osteoporotic features of old age, i.e., mice with the adenylyl cyclase (AC) type 5 "knocked out" (ACS KO). It is our contention that examining mechanisms that are unique to the ACS KO model will provide important insight into the aging process and, potentially, mechanisms which might be utilized to reverse this process. Projects 1 and 2 examine these mechanisms in this mouse model. In addition, Project 3 has developed and will study other mouse models of aging and stress resistance, related to Sir2alpha. The central hypothesis in that project is that Sir2alpha mediates anti-aging as well as cell protective effects in the heart in vivo. These 3 projects are supported by 5 cores: Administration/Physiology; Animal Care; Genomics/Proteomics; Bioinformatics/Biostatistics; Pathology. This Program Project has major implications for public health. The disability associated with aging has a major impact on the public health and the U.S. economy. Finding molecular switches, such as the ones described in this project, could ameliorate disability with aging and would be a major step forward.