Anti-aging and Stress Resistance by Sir2

描述（由申请方提供）：越来越多的证据表明，生物体的寿命受确定的分子机制调节，包括沉默信息调节因子2（Sir2）家族组蛋白脱乙酰酶（HDAC）、抗氧化剂（如过氧化氢酶和超氧化物歧化酶）和Forkhead box，O类（FOXO）家族转录因子。这些机制在进化上是保守的，因此预计将调节基本的生物学功能。这些因素不仅延长了最大寿命，而且还延缓了各种动物的衰老过程。重要的是，低等生物中的长寿因子赋予生物体抗逆能力.然而，目前还不清楚这些长寿调节因子是否也影响衰老和个体有丝分裂后器官（包括心脏）的抗应激能力。酵母Sir2是一种NAD+依赖性HDAC和HDAC III类家族的创始成员，在广泛的细胞过程中发挥作用，包括基因沉默、长寿和DNA损伤修复。我们已经报道了Sir2 α，一个小鼠同源物，在体外介导心肌细胞的细胞存活中起着至关重要的作用。然而，目前对Sir2 α在哺乳动物器官水平上的功能知之甚少。为了阐明Sir2 α在体内的功能，我们最近已经产生了持续性和条件性转基因小鼠与心脏特异性表达的Sir2 α。我们在这项研究中的中心假设是，Sir2alpha介导抗衰老以及体内心脏细胞保护作用。我们将：1）检查已知的长寿因素，如Sir2 α，是否减缓心脏衰老，2）检查已知的长寿因素，包括Sir2 α，是否赋予心脏抗应激性，3）确定长寿因素赋予心肌细胞抗应激性的分子机制。本研究将进一步阐明心肌细胞衰老的调控机制，并寻找提高心脏抗应激能力的有效方法。从这项研究中获得的知识应该是有用的，不仅为缺血性心脏病和充血性心力衰竭的治疗，但也为预防老年人与年龄相关的并发症的新模式的发展。

DESCRIPTION (provided by applicant): Growing lines of evidence suggest that the life span of the organisms are regulated by defined molecular mechanisms, including silent information regulator2 (Sir2) family histone deacetylases (HDACs), anti- oxidants, such as catalase and superoxide dismutase, and Forkhead box, class O (FOXO) family transcription factors. These mechanisms are evolutionarily conserved and thus expected to regulate fundamental biological functions. These factors not only extend the maximum lifespan, but also retard aging process in a wide variety of animals. Importantly, the longevity factors in the lower organisms confer stress- resistance to the organism. However, it is unclear whether or not these regulators of longevity also affect aging and the stress resistance of individual post-mitotic organs, including the heart, in higher organisms. Yeast Sir2, an NAD+ dependent HDAC and a founding member of the HDAC class III family, functions in a wide array of cellular processes, including gene silencing, longevity, and DNA damage repair. We have reported that Sir2alpha, a mouse homologue, plays an essential role in mediating cell survival in cardiac myocytes in vitro. At present, however, very little is known about the function of Sir2alpha in mammals at the organ levels. In order to elucidate the in vivo function of Sir2alpha, we have recently generated both persistent and conditional transgenic mice with cardiac specific expression of Sir2alpha. Our central hypotheses in this study are that Sir2alpha mediates anti-aging as well as cell protective effects in the heart in vivo. We will: 1) Examine whether the known longevity factors, such as Sir2alpha, slow cardiac aging, 2) Examine whether the known longevity factors, including Sir2alpha, confer stress resistance to the heart, and 3) Identify the molecular mechanisms by which the longevity factors confer stress resistance to cardiac myocytes. Our study will elucidate the mechanisms regulating aging of cardiac myocytes and identify the effective method to make the heart stress-resistant. Knowledge obtained from this study should be useful not only for the development of novel modalities for treatment of ischemic heart diseases and congestive heart failure but also for the prevention of age-associated complications in the elderly.