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/摘要 年龄是许多疾病的主要风险因素，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很好地帮助预防或至少推迟这些疾病， 确定延缓衰老的策略，并改变其对大分子、细胞和细胞外的影响 损害程度和损害类型未达到导致疾病发生的阈值，或 进展我的实验室已经描述了长期禁食和禁食模仿饮食的有益效果 在促进细胞恢复和再生以及有机体健康方面。以前的数据 一项最近完成的100例患者随机临床试验表明， 禁食模仿饮食可有效减少衰老和年龄相关疾病的风险因素/生物标志物。在这里， 我们建议改进这些方案，测试它们对小鼠健康寿命的影响，并测试以下假设： 它们在多个系统中促进细胞保护和基于干细胞的再生。我们会研究 根据人体试验结果，定期使用新设计的禁食模拟饮食（FMD 5）的效果 临床试验和热量正常的蛋白质限制周期（PRC）对免疫和神经老化的影响 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，而不会对老年人产生不利影响。将作出重大努力， 确定负责周期性禁食模仿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 免疫系统和神经系统的功能恢复。我们期待着我们之间的强大协同作用， 项目2将调查饮食限制的影响和作用机制， 模拟线粒体肽humanin，和项目3，这将测试的假设，气体H2S是一个 禁食依赖性保护的中心介质。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， 人类健康。