Role of Sirt3 in Aging and Caloric Restriction

描述(申请人提供)：卡路里限制(CR)是哺乳动物中唯一公认的持续延长寿命和延缓与年龄相关的生理衰退的方案。最近的研究发现，CR的健康益处也适用于恒河猴，这增加了人们对开发能够模仿CR的健康益处的干预措施的兴趣。然而，CR在衰老过程中的分子基础尚不清楚。我们和其他人假设，CR的健康益处是一种深刻的“新陈代谢重新编程”。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预防老年性听力损失的能力完全依赖于SIRT3。基于这些和其他观察，我们的中心假设是SIRT3介导的对CR反应的关键代谢靶点的脱乙酰化增加了对氧化应激的抵抗力，从而防止了与年龄相关的线粒体功能障碍。在这项应用中，我们建议广泛和机械地研究CR在机体水平上的影响的主要过程之一，即线粒体对热量摄入减少的反应。建议的研究将通过分析线粒体中的SIRT3靶标，在细胞水平上通过分析与年龄相关的线粒体功能障碍来解决SIRT3介导的线粒体适应对CR反应的影响，并通过老年动物的心肌和骨骼肌功能分析在组织特异性水平上进行研究。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。这项研究的结果将提供对线粒体对CR的适应以及sirtuins在这些途径中的作用的详细的分子理解；对调节的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疗法来显著改善健康结果。 与公共健康相关：减少卡路里摄入量可延缓衰老参数并改善一般健康状况。拟议研究的主要目标是确定SIRT3蛋白是否以及如何介导卡路里限制的有益影响。这些研究将为与年龄相关的治疗方法创造新的机会。

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. PUBLIC HEALTH RELEVANCE: A reduction in caloric intake retards aging parameters and improves general health. The main goal of the proposed studies is to determine if and how the protein Sirt3 mediates the beneficial effects of caloric restriction. These studies will generate novel opportunities for age-related therapeutic approaches.