Role of Sirt3 in Aging and Caloric Restriction

Sirt3 在衰老和热量限制中的作用

• 批准号: 8313913
• 负责人: JOHN M DENU
• 金额: $ 30.52万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313913
• 关键词: Acetates; Address; Age; Aging; Animals; Antioxidants; Apoptosis; Apoptotic; Biochemical; Biological Assay; Caloric Restriction; Cardiac; Cardiac Myocytes; Cells; Data; Deacetylase; Deacetylation; Defect; Development; Diet; Energy Intake; Enzymes; Fasting; Functional disorder; Generations; Goals; Health; Health Benefit; In Vitro; Intervention; Isocitrate Dehydrogenase; Knowledge; Life; Link; Liver; Longevity; Lysine; Macaca mulatta; Mammals; Measurement; Mediating; Membrane Potentials; Metabolic; Metabolic Control; Mitochondria; Mitochondrial DNA; Molecular; Motor; Mus; Muscle Fibers; Myocardium; Neurons; Outcome; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Physiological; Play; Presbycusis; Prevention; Process; Production; Proteins; Protocols documentation; Recycling; Resistance; Role; Sirtuins; Skeletal Muscle; Testing; Therapeutic; Tissues; Wild Type Mouse; Work; age related; aged; base; fatty acid oxidation; feeding; improved; in vivo; interest; mitochondrial dysfunction; mitochondrial membrane; muscle form; novel; novel therapeutics; oxidative damage; prevent; research study; response; sarcopenia; urea cycle

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.

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 对健康的益处适用于恒河猴，这增加了人们对开发可以模仿 CR 的健康益处的干预措施的兴趣。然而，人们对 CR 衰老效应的分子基础知之甚少。我们和其他人推测，CR 的健康益处背后是深​​刻的“代谢重编程”。最近的研究表明，线粒体sirtuin Sirt3在线粒体代谢控制中发挥着重要作用，并且我们已经证明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 CR 响应的关键代谢靶标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。在此应用中，我们建议广泛和机械地研究 CR 在有机体水平上影响的主要过程之一，即线粒体对热量摄入减少的适应。拟议的研究将通过分析线粒体中的 Sirt3 靶标，在生化水平上解决 Sirt3 介导的线粒体适应对 CR 的影响；在细胞水平上，通过分析与年龄相关的线粒体功能障碍；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。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。该研究的结果将为线粒体对 CR 的适应以及去乙酰化酶在这些途径中的作用提供详细的分子理解；了解所调节的分子机制和关键途径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。