Epigenetic regulation of healthspan and longevity by ketone bodies

酮体对健康寿命和寿命的表观遗传调控

• 批准号: 8768977
• 负责人: John C Newman
• 金额: $ 16.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768977
• 关键词: 1 year old; Acetylation; Acylation; Affect; Age-associated memory impairment; Aging; Animal Model; Antioxidants; Award; Behavioral; Biochemical; Bioinformatics; Biological; Biological Models; Biology of Aging; Brain; California; Caloric Restriction; Caring; Cataloging; Catalogs; Cell physiology; Clinical; Cognitive; Cognitive deficits; Custodial Care; Data; Dementia; Dependence; Development; Development Plans; Diet; Disease; Doctor of Philosophy; Dose; Elderly; Energy Intake; Energy-Generating Resources; Epigenetic Process; Exercise; Exposure to; Family; Fasting; Fatty acid glycerol esters; Future; Gait; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Geriatrics; Goals; Health; Histone Acetylation; Histone H3; Histone H4; Histones; Human; Hydroxybutyrates; Impaired cognition; In Vitro; Individual; Institutes; Intervention; Intervention Studies; Ketone Bodies; Kidney; Laboratories; Life; Link; Lipids; Liver; Longevity; Longevity Pathway; Mammals; Maps; Mediating; Mediator of activation protein; Medical; Medicine; Mentors; Mentorship; Metabolic; Metabolism; Mitochondria; Molecular; Molecular Biology; Mus; Obesity; Organ; Oxidative Stress; Pathway interactions; Phenotype; Physicians; Post-Translational Protein Processing; Production; Protein Acetylation; Protein Biochemistry; Proteins; Public Health; Regimen; Regulation; Renal function; Research; Research Personnel; Research Training; Resistance; San Francisco; Scientist; Self Care; Site; Speed; Strenuous Exercise; Syndrome; Testing; Time; Tissues; Training; Translating; United States National Institutes of Health; Universities; Up-Regulation; Water; Western Blotting; Work; Yeasts; age related; base; behavioral health; biological adaptation to stress; career; career development; cohort; cost; drug discovery; experience; feeding; fly; frailty; functional decline; grasp; high risk; histone modification; improved; in vivo; inhibitor/antagonist; instrument; ketogenic diet; middle age; mouse model; neuromuscular; professor; programs; promoter; protein metabolism; stem; stressor; tool; transcription factor; translational study; verdin photosensitizer

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.

描述（由申请人提供）：这份 Paul B. Beeson 老年临床科学家发展奖 (K08) 申请描述了 John Newman 博士的五年职业发展计划，John Newman 博士是一位老年病学家和老年病科的年轻医师科学家在加州大学旧金山分校。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机制，并将这些进展转化为针对虚弱、认知衰退和功能依赖高风险老年人的疗法。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；小鼠模型系统中代谢健康和行为功能的评估；以及衰老生物学的转化应用。实现这些职业发展目标的主要导师是 Eric Verdin 博士，他是加州大学旧金山分校医学教授、格莱斯顿研究所高级研究员、细胞代谢、蛋白质酰化和衰老生物学领域的世界知名专家。 Verdin 博士将得到共同导师 Michael Steinman 博士的协助，他是 UCSF 老年病学部副教授、研究培训主任和研究联合主任，也是一位颇有成就的医师兼科学家。纽曼博士的职业发展计划包括其导师团队的个性化指导、正式课程以及基于纽曼博士先前在老年病学、分子生物学和生物信息学方面的经验以及在新陈代谢、蛋白质生物化学和小鼠方面的全面培训的研究计划行为分析。该研究计划的总体目标是阐明α-羟基丁酸（BOHB）（人类主要酮体）抑制组蛋白脱乙酰的生物学效应。 BOHB 是由禁食或剧烈运动期间储存的脂肪产生的。 Verdin 博士实验室的工作最近发现，BOHB 可在体外和体内抑制脱乙酰酶，并导致小鼠肾脏中氧化应激反应基因的上调。该项目的中心假设是 BOHB 是热量限制带来的一些健康和长寿益处的内源性表观遗传调节剂。该项目的具体目标包括系统地绘制不同小鼠器官中 BOHB 引起的基因表达和组蛋白修饰的变化；检验 BOHB 改善中年小鼠代谢、认知或神经肌肉健康的假设；并评估持续暴露于 BOHB 的小鼠的寿命。这些目标将允许对特定组织中 BOHB 调节的基因和表型之间的联系进行详细的机制后续研究，并鉴定 BOHB 下游的靶点以进行药物发现。 该申请与 NIH 和 NIA 相关，因为 Newman 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理解，为多因素老年综合症提供转化疗法。