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

基本信息

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
项目类别：
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

项目摘要

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）：Paul B. Beeson临床科学家发展申请（K08）介绍了加利福尼亚大学旧金山大学老年医生部的老年医生和年轻医师科学家约翰·纽曼博士的职业发展计划。纽曼博士的长期职业目标是阐明广泛调节哺乳动物健康状况和寿命的途径的机制，并将这些进步转化为针对以高风险，认知能力下降和功能依赖的长者的疗法。本应用程序中概述的特定职业发展目标包括在研究线粒体和细胞代谢，脱乙酰基酶和组蛋白修饰方面发展专业知识；评估小鼠模型系统中代谢健康和行为功能的评估；以及衰老生物学的翻译应用。实现这些职业发展目标的主要导师是UCSF医学教授埃里克·韦丁（Eric Verdin），兼Gladstone Institutes的高级研究员。 Verdin博士将由Co-Enctor迈克尔·斯坦曼（Michael Steinman）博士，研究培训副主任兼UCSF老年医学部研究联合主任，也是一位出色的医师科学家。纽曼博士的职业发展计划包括与他的指导团队的个性化指导，以及一项研究计划，该计划基于纽曼博士在老年医学，分子生物学方面的先前经验以及对代谢，蛋白质生物化学和小鼠行为分析的彻底培训的生物信息学经验。研究计划的总体目的是阐明？ - 羟基丁酯（BOHB），这是人类主要的酮体。 BOHB是在禁食或剧烈运动过程中由储存的脂肪产生的。 Verdin博士的实验室的工作最近发现BOHB在体外和体内抑制脱乙酰基酶，并导致小鼠肾脏中氧化应激反应基因的上调。该项目的核心假设是Bohb是卡路里限制的某些健康和寿命益处的内源性表观遗传介体。该项目的具体目的包括在各种小鼠器官中系统地绘制基因表达的变化和由BOHB引起的组蛋白修饰；测试BOHB改善中年小鼠的代谢，认知或神经肌肉健康的假设；并评估始终暴露于BOHB的小鼠中的寿命。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的详细机理跟踪研究，并鉴定出BOHB下游的靶标。该应用与NIH和NIA有关，因为纽曼博士的职业目标是利用对调节衰老和寿命的多因素途径的理解，以为多因素老年综合症提供转化疗法。