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: 10816720
• 负责人: VALTER D. LONGO
• 金额: $ 21.45万
• 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/10816720
• 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 System; Hematopoietic stem cells; Hospitals; Human; Immune system; Immunity; In Vitro; Incidence; Individual; Insulin; Insulin-Like Growth Factor I; Intervention; Ketone Bodies; Laboratories; Link; Longevity; Lyase; Malignant Neoplasms; Mediating; Mediator; Metabolic; Metabolic syndrome; Mitochondria; Molecular; Multiple Sclerosis; Mus; Natural regeneration; Nervous System; Neurodegenerative Disorders; Nutrient; Oligodendroglia; Oxidative Stress; Pancreas; Pathway interactions; Patients; Peptides; Periodicals; Pharmaceutical Preparations; Positioning Attribute; Process; Production; Proteins; Regimen; Rejuvenation; Reporting; Research; Resistance; Respiration; Risk Factors; Risk Reduction; Rodent; Role; Signal Transduction; Spinal Cord; Stress; Superoxides; Symptoms; System; Testing; Toxin; Transgenic Mice; Translating; Translational Research; age related; cell injury; cell regeneration; cellular resilience; cognitive enhancement; cognitive function; cognitive performance; cognitive system; complement C2a; design; dietary restriction; disorder risk; extracellular; functional decline; healthspan; hematopoietic stem cell self-renewal; 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; randomized, clinical trials; 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.

项目摘要/摘要 年龄是许多疾病的主要危险因素，包括癌症，心血管和神经退行性。 疾病。 Biogerontology研究处于良好状态，可以帮助预防或至少推迟这些疾病 确定延迟衰老并改变其对大分子，细胞细胞外的影响的策略 损害以使损害的程度和类型不会达到阈值，导致疾病发生率或 进展。我的实验室描述了延长禁食和禁食饮食的有益效果 在促进细胞弹性和再生和有机体健康状态方面。来自之前的数据 资助的PO1导致了最近完成的100名患者随机临床试验，表明周期性 禁食模仿饮食可有效减少衰老和与年龄有关的疾病的危险因素/生物标志物。这里， 我们建议改善这些方案，测试它们对小鼠健康范围的影响，并检验以下假设。 它们促进了多个系统中的细胞保护和基于干细胞的再生。我们将研究 基于人类测试的新设计的模仿饮食（FMD5）的新设计的禁食（FMD5）的影响 关于免疫和神经衰老的临床试验和正常蛋白质限制周期（PRC） 系统。项目1的重要目标是确定这些定期饮食干预措施是否可以 扩展健康范围，而不会在非常老年时发挥不良影响。一项重大努力将致力于 鉴定负责定期禁食的影响的分子机制模仿饮食 造血和神经干细胞再生的干预措施以及这种再生是否导致 在免疫和神经系统的功能恢复中。我们期望我们之间有着强烈的协同作用 项目和项目2，该项目将研究饮食限制的作用的影响和机制 - 模仿线粒体肽人类和项目3，这将检验以下假设：气体H2S是一个 禁食保护的中央调解人。我们预测，从这个项目中获得的新见解将 继续转化为临床试验，以确定可以安全有效改进的干预措施 人类HealthSpan。