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.

该提案描述了一个为期五年的计划，为亚美尼亚医学博士过渡到一个独立资助的 他是一位研究衰老代谢和核黄素分子生理学的专家。他将 由哈佛医学院医学副教授、医学博士亚历山大索卡斯指导， 他是功能基因组学和C.优美的他将由Marcia Haigis博士共同指导， 他是哈佛医学院细胞生物学教授，也是保罗F。格伦生物学中心 的老化。一个由在人类衰老方面有专长的医生和科学家组成的咨询委员会，elegans老化， 代谢已汇集，包括加里·鲁夫昆博士、基思·布莱克韦尔医学博士、何塞·弗洛雷斯医学博士、 和理查德·李医学博士在向独立过渡期间提供科学指导和职业指导。 博士埃里温将在研究和培训环境中开展计划的职业发展活动 在马萨诸塞州总医院和哈佛医学院。 该研究计划利用生物体C。elegans，鼠细胞系和小鼠模型，以检查 核黄素消耗的生理学，并确定支持寿命的核心分子机制 核黄素耗竭对C.优美的核黄素利用和转运的生物学是强烈的 通过后生动物保守，使其成为一个有吸引力的领域，研究作为一个翻译的目标。的能力 通过核黄素消耗调节细胞能量学和代谢兴奋效应可以提供关键的治疗作用， 针对衰老并发症，特别是包括胰岛素抵抗在内的代谢并发症， 在身体组成和神经退行性疾病方面。初步研究表明，核黄素 耗尽延长了C的寿命。elegans，并利用与长寿相关的经典途径，包括 AMPK和FOXO。我们希望进一步阐明这一过程的代谢调节剂，包括黄素共- 因子合成、线粒体能量学和脂质代谢。研究者将利用功能基因组学 梭酶调节的代谢测定，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性 在翻译模型中，通过核黄素消耗促进代谢兴奋效应和健康衰老， 过渡到独立调查员身份。