Role of Sirt3 in Aging and Caloric Restriction

描述（由申请人提供）：热量限制（CR）是哺乳动物中唯一成熟的方案，可以持续延长寿命并延缓与年龄相关的生理衰退。最近发现CR对恒河猴的健康益处，这增加了人们对开发可以模仿CR对健康益处的干预措施的兴趣。然而，CR对衰老作用的分子基础知之甚少。最近的研究表明，线粒体sirtuin Sirt3在线粒体代谢控制中起着重要作用，我们已经证明，CR预防年龄相关性听力损失的能力完全依赖于Sirt3。基于这些和其他观察结果，我们的中心假设是Sirt3介导的关键代谢靶点去乙酰化，以响应CR增加对氧化应激的抵抗力，从而防止与年龄相关的线粒体功能障碍。在这一应用中，我们建议在机体水平上广泛和机械地研究CR影响的主要过程之一，即线粒体对减少热量摄入的适应。拟议的研究将通过分析线粒体中的Sirt3靶点，在生化水平上通过分析与年龄相关的线粒体功能障碍，在细胞水平上通过分析衰老动物的心脏和骨骼肌功能分析，在组织特异性水平上解决Sirt3介导的线粒体适应对CR的影响。我们还将确定CR延长寿命和预防年龄相关病理的能力是否需要Sirt3。该研究的结果将提供线粒体对CR的适应和sirtuins在这些途径中的作用的详细分子理解；通过开发专门针对这些途径的新疗法，了解分子机制和关键调控途径具有显著改善健康结果的潜力。

DESCRIPTION (provided by applicant): Caloric Restriction (CR) is the only well-established protocol in mammals that consistently increases lifespan and delays age-related physiological declines. The recent finding that the health benefits of CR apply to rhesus monkeys has increased interest in developing interventions that can mimic the health benefits of CR. However, the molecular basis of the CR effects in aging is poorly understood. We and others have postulated that a profound "metabolic reprogramming" underlies the health benefits of CR. Recent studies suggest that the mitochondrial sirtuin Sirt3 plays a major role in mitochondrial metabolic control, and we have shown that the ability of CR to prevent age-related hearing loss is completely dependent on Sirt3. Based on these and other observations, our central hypothesis is that Sirt3 mediated deacetylation of key metabolic targets in response to CR increases resistance to oxidative stress and as a consequence prevents age-related mitochondrial dysfunction. Within this application we propose to extensively and mechanistically investigate one of the major processes underlying the effects of CR at the organismal level, the mitochondrial adaptations in response to reduced caloric intake. The proposed studies will address the effects of Sirt3-mediated mitochondrial adaptations in response to CR at the biochemical level through the analysis of Sirt3 targets in mitochondria, at the cellular level through the analysis of age-related mitochondrial dysfunction, and at the tissue-specific level through cardiac and skeletal muscle functional assays of aged animals. We will also determine if the ability of CR to increase lifespan and prevent age-related pathology requires Sirt3. Results from the study will provide a detailed molecular understanding of mitochondrial adaptation to CR and the role of sirtuins in these pathways; Knowledge of the molecular mechanisms and key pathways regulated has potential for significantly improving health outcomes through the development of novel therapeutics that specifically target these pathways.