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(卡路里限制，CR)会推迟大多数与年龄相关的疾病的发生，并延长哺乳动物的平均和最长寿命。模仿这些影响的药物或疗法将对社会产生巨大的好处，但它们的发展需要更好地了解CR的工作原理。有人提出，Sir2/SIRT1脱乙酰酶是CR效应的关键介质，实际上，Sir2对于CR在酵母和苍蝇等简单生物中延长寿命是必要的。激活Sir2的小分子，如白藜芦醇，可以延长不同物种的寿命，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过程，并可以降低哺乳动物的全因死亡率，这使得它可以说是最有希望的CR模拟候选药物。然而，目前，在CR中最接近的哺乳动物Sir2同源基因SIRT1的参与以及白藜芦醇的作用机制仍然是激烈争论的话题。解决这些问题是当今老龄化领域最重要的努力之一，因为这些发现可能会导致对衰老过程中发生的功能衰退和疾病的性质的新见解，以及治疗干预的机会。这项建议的主要目标是利用组织特异性SIRT1基因敲除小鼠，确定SIRT1参与CR和白藜芦醇对哺乳动物的有益影响。在每种情况下，都将在没有SIRT1的情况下测试预防癌症和代谢的效果。其具体目的是1)在ApcMin/+模型中确定CR和/或白藜芦醇对肿瘤的保护是否通过SIRT1介导，2)测试白藜芦醇对脂肪肝和胰岛素抵抗的保护是否通过SIRT1介导，以及3)测试体内对空腹和白藜芦醇的代谢适应是否需要SIRT1。CR已被证明对西方世界的大多数主要死亡和残疾原因具有保护作用，包括癌症、心血管疾病和代谢综合征。这项提案中概述的实验将解决一个重要的争议，有助于揭示CR在分子水平上的工作原理，并可能为在许多疾病领域开发有效的人类疗法指明方向。

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.