Does SIRT1 regulate mammalian health and longevity?

描述（由申请人提供）：自20世纪30年代以来，人们已经知道，严重减少能量摄入（热量限制，CR）可以延缓大多数与年龄有关的疾病的发生，并延长哺乳动物的平均寿命和最长寿命。模仿这些效果的药物或疗法将给社会带来巨大的好处，但它们的发展需要更好地理解CR的工作原理。已经提出sirr2 /SIRT1去乙酰化酶是CR作用的关键介质，事实上，在酵母和苍蝇等简单生物中，Sir2是CR延长寿命所必需的。激活Sir2的小分子，如白藜芦醇，可以延长多种物种的寿命，被认为是潜在的CR模拟物。白藜芦醇已经被证明可以预防多种疾病的发生，并可以降低哺乳动物的全因死亡率，这使它成为最有希望的CR模仿物。然而，目前，哺乳动物中与SIR2最接近的同系物SIRT1在CR中的作用以及白藜芦醇的作用机制仍然是争论的热点。解决这些问题是当今衰老领域最重要的努力之一，因为这些发现可能会对衰老过程中发生的功能衰退和疾病的本质产生新的见解，并为治疗干预提供机会。本提案的总体目标是通过组织特异性SIRT1敲除小鼠，确定SIRT1参与CR和白藜芦醇在哺乳动物中的有益作用。在每种情况下，癌症预防和代谢作用都将在SIRT1缺失的情况下进行测试。具体目的是：1)确定ApcMin/+模型中CR和/或白藜芦醇对肿瘤发生的保护作用是否由SIRT1介导；2)测试白藜芦醇对脂肪肝和胰岛素抵抗的保护作用是否通过SIRT1介导；3)测试体内对禁食和CR的代谢适应是否需要SIRT1。在西方世界，CR已被证明可以预防大多数主要的死亡和残疾原因，包括癌症、心血管疾病和代谢综合征。本提案中概述的实验将解决一个重要的争议，有助于揭示CR如何在分子水平上起作用，并可能为在许多疾病领域开发有效的人类治疗方法指明方向。

DESCRIPTION (provided by applicant): Since the 1930s it has been known that a severe reduction in energy intake (caloric restriction, CR) delays the onset of most age-related diseases and extends both mean and maximum lifespan in mammals. Drugs or therapies that mimic these effects would be of enormous benefit to society but their developmental requires a better understanding of how CR works. It has been proposed that the Sir2/SIRT1 deacetylase is a critical mediator of CR's effects and indeed, Sir2 is necessary for lifespan extension by CR in simple organisms such as yeast and flies. Small molecules that activate Sir2, such as resveratrol, extend the lifespan of diverse species and are considered potential CR mimetics. Resveratrol has already been shown to prevent a wide variety of disease processes and can reduce all-cause mortality in mammals, making it arguably the most promising candidate for CR mimetic. At present, however both the involvement of SIRT1, the closest mammalian SIR2 homolog in CR, and the mechanism of resveratrol's effects remain topics of heated debate. Resolving these issues is one of the most important endeavors in the aging field today because these findings may lead to new insights into the nature of functional decline and disease that occur as part of the aging process as well as opportunities for therapeutic interventions. The broad goal of this proposal is to determine the involvement of SIRT1 in the beneficial effects of both CR and resveratrol in mammals using tissue-specific SIRT1 knockout mice. In each case both cancer-preventive and metabolic effects will be tested in the absence of SIRT1. The specific aims are 1) to determine whether protection from tumorgenesis by CR and/or resveratrol is mediated by SIRT1 in the ApcMin/+ model, 2) to test whether protection from fatty liver and insulin resistance by resveratrol are mediated via SIRT1, and 3) to test whether metabolic adapations to fasting and CR require SIRT1 in vivo. CR has been shown to be protective against most of the major causes of death and disability in the Western world, including cancer, cardiovascular disease, and the metabolic syndrome. The experiments outlined in this proposal will resolve an important controversy, help to reveal how CR works at the molecular level, and may point the way to the developmental of effective human therapeutics in a number of disease areas.