Longevity and Stress Resistance

描述(由申请人提供)：本项目的总体主题是测试寿命延长、寿命和抗应激能力是由常见机制调节的假设。越来越多的证据表明，从酵母到蠕虫和苍蝇再到哺乳动物，各种生物的长寿都受到明确的分子机制的调节，包括Sir2，一种依赖于NAD的组蛋白去乙酰化酶，以及腺酰环化酶-蛋白激酶A途径。理解导致衰老的不利影响的关键调控机制，或者反过来，那些延长寿命的关键调控机制，一个主要的限制是缺乏能够延长寿命的动物模型，这些动物模型不会发生心肌病或骨质疏松症或其他终点，而这些都是通常随着年龄增长而观察到的。从酵母到灵长类动物，这种模式被认为是最适合延长寿命的，它是热量限制。相对较少的其他长寿模型可用。在这方面，我们最近发现了一种新的基因工程动物模型，该模型比野生动物寿命更长，并且没有许多老年时的心脏和骨质疏松特征，即腺酰环化酶(AC)5型“敲除”(ACKO)小鼠。我们认为，研究ACS KO模型特有的机制将提供对衰老过程的重要洞察，并潜在地提供可能用于逆转这一过程的机制。项目1和2在这个老鼠模型中检查了这些机制。此外，项目3已经开发并将研究与Sir2pha相关的衰老和应激抵抗的其他小鼠模型。该项目的中心假设是，Sir2pha在体内介导了心脏的抗衰老和细胞保护作用。这3个项目得到了5个核心的支持：行政/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有重大影响。与老龄化相关的残疾对公共健康和美国经济有重大影响。寻找分子开关，比如这个项目中描述的那些，可以改善随着年龄增长的残疾，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.