Role of Sirt3 in Aging and Caloric Restriction

描述（由申请人提供）：热量限制（CR）是哺乳动物中唯一完善的方案，可持续延长寿命并延迟与年龄相关的生理衰退。最近发现CR的健康益处适用于恒河猴，这增加了人们对开发可以模拟CR健康益处的干预措施的兴趣。然而，CR在衰老中的作用的分子基础知之甚少。我们和其他人已经假设，一个深刻的“代谢重编程”的基础CR的健康益处。最近的研究表明，线粒体sirtuin Sirt 3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Sirt 3。基于这些和其他观察结果，我们的中心假设是，Sirt 3介导的关键代谢靶点的脱乙酰化反应CR增加抗氧化应激，并因此防止年龄相关的线粒体功能障碍。在本申请中，我们建议广泛且机械地研究CR在生物体水平上影响的主要过程之一，即线粒体响应热量摄入减少的适应。拟议的研究将通过分析线粒体中的Sirt 3靶点，在生化水平上，通过分析年龄相关的线粒体功能障碍，在细胞水平上，以及在组织特异性水平上，通过老年动物的心脏和骨骼肌功能测定，来解决Sirt 3介导的线粒体适应性对CR的影响。我们还将确定CR增加寿命和预防年龄相关病理的能力是否需要Sirt 3。该研究的结果将提供对线粒体适应CR的详细分子理解以及sirtuins在这些途径中的作用;对分子机制和关键途径的了解有可能通过开发专门针对这些途径的新型疗法来显着改善健康结果。

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.