Periodic Fasting, GHR/IGF-1, Multisystem Regeneration, and Healthspan

定期禁食、GHR/IGF-1、多系统再生和健康寿命

• 批准号: 10374749
• 负责人: VALTER D. LONGO
• 金额: $ 47.04万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374749
• 关键词: Adopted; Adverse effects; Age; Age-Years; Aging; Amino Acids; Animals; Autoimmune; Beta Cell; Biological Markers; Bone Marrow Transplantation; C57BL/6 Mouse; Cardiovascular Diseases; Cells; Cellular Metabolic Process; Clinical Trials; Cognition; Collaborations; Cyclic AMP-Dependent Protein Kinases; Cysteine; Data; Developmental Gene; Diet; Dietary Intervention; Disease; FOXO1A gene; Fasting; Female; Foundations; Funding; Gases; Generations; Genes; Gerontology; Glucose; Goals; Grant; Growth; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Hospitals; Human; Immune system; Immunity; In Vitro; Incidence; Individual; Insulin; Insulin-Like Growth Factor I; Intervention; Ketone Bodies; Laboratories; Lead; Link; Longevity; Lyase; Malignant Neoplasms; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Mitochondria; Molecular; Multiple Sclerosis; Mus; Natural regeneration; Nervous system structure; Neurodegenerative Disorders; Nutrient; Oligodendroglia; Oxidative Stress; Pancreas; Pathway interactions; Patients; Peptides; Periodicity; Pharmaceutical Preparations; Positioning Attribute; Process; Production; Proteins; Randomized Clinical Trials; Regimen; Rejuvenation; Reporting; Research; Resistance; Respiration; Risk Factors; Rodent; Role; Signal Transduction; Spinal Cord; Stress; Superoxides; Symptoms; System; Testing; Toxin; Transgenic Mice; Translating; Translational Research; age related; base; cognitive enhancement; cognitive function; cognitive performance; cognitive system; complement C2a; design; dietary restriction; disorder risk; extracellular; functional decline; healthspan; human disease; human very old age (85+); humanin; immune system function; improved; in vitro testing; in vivo; in vivo evaluation; insight; male; middle age; neoplastic cell; nerve stem cell; neurogenesis; overexpression; prevent; programs; protective effect; resilience; stem cell self renewal; stem cells; synergism; translational medicine

PROJECT SUMMARY/ABSTRACT Age is the major risk factor for many diseases including cancer, cardiovascular and neurodegenerative disease. Biogerontology research is well positioned to help prevent or at least postpone these diseases by identifying strategies to delay aging and altering its effects on macromolecular, cellular and extracellular damage so that the degree and type of damage does not reach the threshold leading to disease incidence or progression. My laboratory has described the beneficial effect of prolonged fasting and fasting-mimicking diets in promoting cellular resilience and regeneration and organismal healthspan. The data from the previously funded PO1 resulted in a recently completed 100 patient randomized clinical trial indicating that a periodic fasting mimicking diet is effective in reducing risk factors/biomarkers for aging and age-related diseases. Here, we propose to improve these regimens, test their effect on mouse healthspan, and test the hypothesis that they promote both cellular protection and stem cell-based regeneration in multiple systems. We will study the effects of periodic use of a newly designed fasting mimicking diet (FMD5) based on that tested in human clinical trials and of normocaloric protein restriction cycles (PRC) on the aging of the immune and nervous systems. An important goal of Project 1 will be to determine whether these periodic dietary interventions can extend healthspan without exerting adverse effects at very old ages. A major effort will be devoted to the identification of the molecular mechanisms responsible for the effects of periodic fasting mimicking dietary interventions on the regeneration of hematopoietic and neural stem cells and whether this regeneration results in a functional rejuvenation of the immune and nervous systems. We anticipate strong synergism between our project and Project 2, which will investigate the effects and mechanisms of action of the dietary restriction- mimicking mitochondrial peptide humanin, and Project 3, which will test the hypothesis that the gas H2S is a central mediator of fasting-depended protection. We predict that the new insights gained from this project will continue to be translated into clinical trials to identify interventions that are safe and effective in improving human healthspan.

项目总结/文摘