Physiology of Lifespan Extension and Metabolic Hormesis with Riboflavin Depletion

核黄素消耗延长寿命和代谢兴奋作用的生理学

• 批准号: 10663638
• 负责人: Armen I Yerevanian
• 金额: $ 16.92万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663638
• 关键词: Address; Adipocytes; Advisory Committees; Aging; Animal Model; Animals; Area; Automobile Driving; Biological Assay; Biological Availability; Biology; Biology of Aging; Body Composition; Caenorhabditis elegans; Caloric Restriction; Cell Line; Cells; Cellular biology; Characteristics; Data; Disease; Doctor of Philosophy; Dose; Down-Regulation; Environment; Enzymes; FOXO1A gene; Five-Year Plans; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Flavins; Functional disorder; Funding; General Hospitals; Goals; Health Benefit; Hepatic; Hepatocyte; Human; Insulin Resistance; Lipids; Longevity; Mammals; Massachusetts; Mediating; Medicine; Mentors; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Micronutrients; Mitochondria; Modeling; Molecular; Mus; Nematoda; Neurodegenerative Disorders; Obesity; Organism; Orthologous Gene; Oxidases; Oxidation-Reduction; Pathway interactions; Pharmacology; Phenotype; Physicians; Physiological; Physiology; Process; Production; Reactive Oxygen Species; Regulation; Research; Research Personnel; Respiration; Riboflavin; Role; Scientist; Signal Transduction; Succinate Dehydrogenase; Therapeutic; Time; Tissues; Training; Vocational Guidance; Work; Yeasts; biological adaptation to stress; career development; cofactor; functional genomics; healthspan; healthy aging; insight; knock-down; lipid metabolism; medical schools; member; mid-career faculty; mimetics; mouse model; new therapeutic target; novel; oxidation; professor; programs; protective effect; response; skills; therapeutic target; tool; translational model; translational potential; uptake

This proposal describes a five-year plan for Armen Yerevanian MD to transition to an independently-funded investigator with expertise in the metabolism of aging and the molecular physiology of riboflavin. He will be mentored by Alexander Soukas MD PhD, Associate Professor of Medicine at Harvard Medical School and an expert in both functional genomics and the biology of C. elegans. He will be co-mentored by Marcia Haigis PhD, Professor of Cell Biology at Harvard Medical School and a member of the Paul F. Glenn Center for the Biology of Aging. An advisory committee of physician-scientists with expertise in human aging, C. elegans aging, and metabolism have been assembled, including Gary Ruvkun PhD, Keith Blackwell MD PhD, Jose Florez MD PhD, and Richard Lee MD to provide scientific direction and career guidance during the transition to independence. Dr. Yerevanian will carry out the planned career development activities in the research and training environment at the Massachusetts General Hospital and Harvard Medical School. This research program utilizes the organism C. elegans, murine cell lines and mouse models to examine the physiology of riboflavin depletion and identify the core molecular mechanisms that underpin the lifespan extending effects of riboflavin depletion in C. elegans. The biology of riboflavin utilization and transport is strongly conserved through metazoans, making it an attractive area to study as a translational target. The ability to modulate cellular energetics and metabolic hormesis through riboflavin depletion may provide key therapeutic targets for the complications of aging, particularly metabolic complications including insulin resistance, changes in body composition and neurodegenerative diseases. Preliminary studies have already shown that riboflavin depletion extends lifespan in C. elegans, and utilizes canonical pathways associated with longevity including AMPK and FOXO. We hope to further elucidate the metabolic regulators of this process, including flavin co- factor synthesis, mitochondrial energetics, and lipid metabolism. The investigator will utilize functional genomics of C. elegans, metabolic assays of enzyme regulation, and novel mechanisms for altering cellular energetics to explore these aims. The ultimate goal of this work is to characterize the fundamental biology of riboflavin depletion, promote metabolic hormesis and healthy aging via riboflavin depletion in translational models, and to transition to independent investigator status.

该提案描述了阿尔门埃里温MD向独立资助的MD过渡的五年计划 在衰老代谢和核黄素分子生理学方面具有专业知识的研究员。他会成为 由哈佛医学院医学副教授Alexander Soukas医学博士和 功能基因组学和线虫生物学方面的专家。他将由Marcia Haigis博士共同指导， 哈佛医学院细胞生物学教授，保罗·F·格伦生物学中心成员 衰老的问题。一个由内科科学家组成的咨询委员会，他们对人类老龄化、线虫衰老和 包括加里·鲁夫昆博士、基思·布莱克韦尔博士、何塞·弗洛雷斯博士、 和理查德·李博士，在向独立过渡的过程中提供科学指导和职业指导。 埃里瓦尼安博士将在研究和培训环境中执行计划的职业发展活动。 在马萨诸塞州总医院和哈佛医学院。 这项研究计划利用生物体线虫、小鼠细胞系和小鼠模型来检查 核黄素消耗的生理学和确定支撑寿命的核心分子机制 线虫核黄素耗竭的延伸效应。核黄素的利用和运输的生物学是强有力的 通过后生动物保存，使其成为一个有吸引力的研究领域作为翻译的目标。有能力 通过核黄素耗竭调节细胞能量和代谢兴奋作用可能是关键的治疗方法 衰老并发症，特别是包括胰岛素抵抗在内的代谢并发症的目标变化 身体成分和神经退行性疾病。初步研究已经表明，核黄素 耗竭延长线虫的寿命，并利用与长寿相关的规范途径，包括 AMPK和FOXO。我们希望进一步阐明这一过程中的代谢调节因子，包括黄素-co- 因子合成、线粒体能量学和脂类代谢。研究人员将利用功能基因组学 线虫，酶调节的代谢试验，以及改变细胞能量学的新机制 探索这些目标。这项工作的最终目标是描述核黄素的基本生物学特征。 在翻译模型中，通过核黄素耗竭，促进代谢兴奋和健康衰老，并 过渡到独立调查员身份。