Role of Sirt3 in Aging and Caloric Restriction

Sirt3 在衰老和热量限制中的作用

• 批准号: 8706746
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8706746
• 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）是哺乳动物中唯一完善的方案，可持续增加寿命并延迟与年龄相关的生理下降。最近的发现，CR的健康益处适用于恒河猴，对开发可以模仿CR的健康益处的干预措施的兴趣增加了。但是，衰老中CR效应的分子基础知之甚少。我们和其他人认为，深刻的“代谢重编程”是CR的健康益处的基础。最近的研究表明，线粒体SIRTUIN SIRT3在线粒体代谢控制中起主要作用，我们已经表明，CR预防与年龄相关的听力损失的能力完全取决于SIRT3。基于这些和其他观察结果，我们的中心假设是SIRT3介导的关键代谢靶标的脱乙酰基化响应CR会增加对氧化应激的耐药性，从而阻止与年龄相关的线粒体功能障碍。在此应用程序中，我们建议对CR在有机体水平上的影响的主要过程进行广泛，机械学研究，即响应减少热量摄入的线粒体适应性。拟议的研究将通过分析线粒体中的SIRT3靶标，通过分析与年龄相关的线粒体功能障碍，以及在细胞级，以及在组织特异性水平通过心脏和骨架功能性的动物效果，通过分析线粒体的SIRT3靶标，通过分析线粒体的SIRT3靶标，通过分析线粒体的SIRT3靶标，通过分析线粒体的SIRT3靶标，来解决SIRT3介导的线粒体适应的影响。我们还将确定CR增加寿命和预防与年龄相关的病理的能力是否需要SIRT3。该研究的结果将对线粒体适应Cr和Sirtuins在这些途径中的作用提供详细的分子理解。通过开发专门针对这些途径的新型治疗剂，对分子机制和关键途径的知识具有显着改善健康结果的潜力。