Does SIRT1 regulate mammalian health and longevity?

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）会延迟 大多数与年龄有关的疾病的发病，并延长哺乳动物的平均寿命和最长寿命。药物 或模仿这些效果的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是如何工作的。已经提出，Sir 2/SIRT 1脱乙酰酶是一种关键酶， 事实上，Sir 2是简单生物体中CR延长寿命所必需的 如酵母和苍蝇。激活Sir 2的小分子，如白藜芦醇， 不同的物种，被认为是潜在的CR模拟物。白藜芦醇已经被证明可以防止 各种各样的疾病过程，并可以降低哺乳动物的全因死亡率，使其成为可以说是 最有希望的CR模拟物候选者。然而，目前，SIRT 1的参与， 在CR中最接近的哺乳动物Sir 2同源物，以及白藜芦醇的作用机制仍然是热门话题。 辩论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功能衰退和疾病的本质的新见解， 以及治疗干预的机会。该提案的总体目标是 为了确定SIRT 1参与CR和白藜芦醇在哺乳动物中的有益作用， 组织特异性和可诱导SIRT 1敲除小鼠。在每一种情况下，癌症预防和代谢 将在不存在SIRT 1的情况下测试效果。具体目标是：（1）确定是否保护 CR和/或白藜芦醇的肿瘤发生在Ipc模型中由SIRT 1介导，2）为了测试是否 白藜芦醇对脂肪肝和胰岛素抵抗的保护作用是通过SIRT 1介导的，以及3）测试 禁食和CR的代谢适应是否需要体内SIRT 1。CR已被证明具有保护作用 针对西方世界大多数导致死亡和残疾的主要原因，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 这是一个重要的争议，有助于揭示CR如何在分子水平上发挥作用，并可能指出通往 在许多疾病领域开发有效的人类疗法。

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 development 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 a 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 diseases 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 and inducible 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 tumorigenesis by CR and/or resveratrol is mediated by SIRT1 in the /\pc"'"'* model, 2) to test whether protection from fatty liver and insulin resistance by resveratrol are mediated via SIRT1, and 3) to test whether metabolic adaptations 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 development of effective human therapeutics in a number of disease areas.