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. ? ? ?
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