Epigenetic regulation of healthspan and longevity by ketone bodies

描述(由申请者提供)：保罗·B·比森老年临床科学家发展奖(K08)的申请书描述了John Newman博士的五年职业发展计划，他是加州大学旧金山分校老年病学系的一名年轻内科医生兼科学家。纽曼博士的长期职业目标是阐明广泛调节哺乳动物健康寿命和寿命的途径的机制，并将这些进展转化为针对虚弱、认知衰退和功能依赖的高危老年人的治疗。在本申请中概述的具体职业发展目标包括发展线粒体和细胞代谢、脱乙酰酶和组蛋白修饰研究方面的专业知识；评估小鼠模型系统中的代谢健康和行为功能；以及衰老生物学的翻译应用。实现这些职业发展目标的主要导师是加州大学旧金山分校的医学教授兼格莱斯顿研究所高级研究员Eric Verdin博士，他是世界著名的细胞代谢、蛋白质酰化和衰老生物学专家。Verdin博士将由共同导师Michael Steinman博士、副教授、研究培训主任、加州大学旧金山分校老年病学部研究联席主任以及一位有成就的内科科学家协助。纽曼博士的职业发展计划包括与他的指导团队进行个性化的指导，正式的课程工作，以及一个研究计划，该计划以纽曼博士在老年病学、分子生物学和生物信息学方面的先前经验为基础，通过在新陈代谢、蛋白质生物化学和小鼠行为分析方面的全面培训来实现。该研究计划的总体目标是阐明人类主要酮体--羟丁酸酯(BOHB)抑制组蛋白去乙酰化的生物学效应。BOHB是在禁食或剧烈运动期间储存的脂肪中产生的。Verdin博士实验室的工作最近发现，BOHB在体外和体内都能抑制脱乙酰酶，并导致小鼠肾脏氧化应激反应基因的上调。该项目的中心假设是，BOHB是卡路里限制的一些健康和长寿益处的内源性表观遗传中介。该项目的具体目标包括系统地定位BOHB在小鼠不同器官中引起的基因表达和组蛋白修饰的变化；测试BOHB改善中年小鼠代谢、认知或神经肌肉健康的假设；以及评估持续暴露于BOHB的小鼠的寿命。这些目标将允许对BOHB调节的基因和特定组织中的表型之间的联系进行详细的机械性后续研究，并识别BOHB下游的药物发现靶点。 这项申请与NIH和NIA相关，因为纽曼博士的职业目标是利用对调节衰老和长寿的多因素途径的了解，为多因素老年综合征提供转化性治疗。

DESCRIPTION (provided by applicant): This application for the Paul B. Beeson Clinical Scientist Development Award in Aging (K08) describes the five-year career development plan of Dr. John Newman, a geriatrician and young physician-scientist in the Division of Geriatrics at the University of California, San Francisco. Dr. Newman's long-term career goal is to elucidate the mechanisms of pathways that broadly regulate healthspan and longevity in mammals, and translate these advances into therapies targeted at elders at high risk for frailty, cognitive decline, and functional dependence. The specific career development goals outlined in this application include developing expertise in the study of mitochondrial and cellular metabolism, deacetylases and histone modifications; the assessment of metabolic health and behavioral function in mouse model systems; and the translational application of aging biology. The primary mentor for accomplishing these career development goals is Dr. Eric Verdin, Professor of Medicine at UCSF and Senior Investigator at the Gladstone Institutes, a world-renowned expert on cellular metabolism, protein acylation, and the biology of aging. Dr. Verdin will be assisted by co-mentor Dr. Michael Steinman, Associate Professor, Director of Research Training, and Co-Director of Research in the UCSF Division of Geriatrics, and an accomplished physician-scientist. The career development plan of Dr. Newman includes individualized mentorship with his mentorship team, formal coursework, and a research program that builds upon Dr. Newman's prior experience in geriatrics, molecular biology, and bioinformatics with thorough training in metabolism, protein biochemistry, and mouse behavioral analysis. The overall objective of the research plan is to elucidate the biological effects of histone deacetylas inhibition by ?-hydroxybutyrate (BOHB), the major ketone body in humans. BOHB is produced from stored fat during fasting or strenuous exercise. Work in Dr. Verdin's laboratory recently found that BOHB inhibits deacetylases in vitro and in vivo and causes up-regulation of oxidative stress-response genes in the mouse kidney. The central hypothesis of this project is that BOHB is an endogenous epigenetic mediator of some of the health and longevity benefits of calorie restriction. The specific aims of the project include systematically mapping changes in gene expression and histone modifications caused by BOHB in various mouse organs; testing the hypothesis that BOHB improves metabolic, cognitive, or neuromuscular health in middle-aged mice; and assessing longevity in mice consistently exposed to BOHB. These aims will permit detailed mechanistic follow-on studies of links between BOHB -regulated genes and phenotypes in specific tissues, with identification of targets that are downstream of BOHB for drug discovery. The application is relevant to NIH and NIA because Dr. Newman's career goal is to leverage an understanding of the multifactorial pathways that regulate aging and longevity to provide translational therapies for the multifactorial geriatric syndromes.