Anti-aging and Stress Resistance by Sir2

描述(由申请人提供)：越来越多的证据表明，生物体的寿命受到明确的分子机制的调节，包括沉默信息调节器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，以及Forkhead box，O类(FOXO)家族转录因子。这些机制在进化上是保守的，因此有望调节基本的生物功能。这些因素不仅延长了最长寿命，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素赋予了生物对应激的抵抗力。然而，目前尚不清楚这些长寿调节剂是否也影响衰老和包括心脏在内的高等生物体中个别有丝分裂后器官的抗应激能力。酵母Sir2是一种依赖NAD+的HDAC，也是HDAC III类家族的创始成员之一，它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，Sir2pha是一种小鼠同系物，在介导体外培养的心肌细胞存活方面发挥着重要作用。然而，目前对Sir2pha在哺乳动物器官水平上的功能知之甚少。为了阐明Sir2α在体内的功能，我们最近建立了心脏特异表达Sir2α的持续性和条件性转基因小鼠。我们在这项研究中的中心假设是，Sir2pha在体内介导了心脏的抗衰老和细胞保护作用。我们将：1)检查已知的长寿因素，如Sir2pha，是否减缓心脏老化；2)检查已知的长寿因素，包括Sir2pha，是否赋予心脏应激抵抗；以及3)确定长寿因素赋予心肌细胞应激抵抗的分子机制。我们的研究将阐明心肌细胞衰老的调节机制，并寻找有效的方法使心脏抵抗应激。从这项研究中获得的知识不仅有助于开发治疗缺血性心脏病和充血性心力衰竭的新方法，而且还有助于预防老年人与年龄相关的并发症。

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.