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.

项目概要/摘要 年龄是许多疾病的主要危险因素，包括癌症、心血管疾病和神经退行性疾病 疾病。生物老年学研究可以通过以下方式帮助预防或至少推迟这些疾病： 确定延缓衰老并改变其对大分子、细胞和细胞外的影响的策略 损害的程度和类型未达到导致疾病发生或发生的阈值 进展。我的实验室描述了长期禁食和模仿禁食饮食的有益效果 促进细胞弹性和再生以及有机体健康寿命。之前的数据 PO1 资助的一项最近完成的 100 名患者随机临床试验表明，定期 模仿禁食饮食可有效减少衰老和与年龄相关疾病的危险因素/生物标志物。这里， 我们建议改进这些方案，测试它们对小鼠健康寿命的影响，并检验以下假设： 它们促进多个系统中的细胞保护和基于干细胞的再生。我们将研究 根据人体测试结果定期使用新设计的模拟禁食饮食 (FMD5) 的效果 正常热量蛋白质限制循环（PRC）对免疫和神经衰老的临床试验 系统。项目 1 的一个重要目标是确定这些定期饮食干预是否可以 延长健康寿命，而不会对高龄产生不利影响。将投入大量精力 确定周期性禁食模拟饮食影响的分子机制 对造血干细胞和神经干细胞再生的干预以及这种再生是否会导致 免疫和神经系统的功能恢复活力。我们预计我们之间将产生强大的协同效应 项目和项目2，将研究饮食限制的影响和作用机制- 模仿线粒体肽护脑素，以及项目 3，该项目将检验气体 H2S 是一种气体的假设 禁食依赖性保护的中心调节者。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，以确定安全有效的干预措施 人类的健康寿命。