Periodic Fasting, GHR/IGF-1, Multisystem Regeneration, and 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、心血管疾病和神经退行性疾病。 疾病。生物老年学研究处于有利地位，可以通过以下方式帮助预防或至少推迟这些疾病 确定延缓衰老的策略并改变其对大分子、细胞和细胞外的影响 损害的程度和类型未达到导致疾病发病率或 进步。我的实验室已经描述了长时间禁食和模拟禁食饮食的有益效果 在促进细胞复原力和再生以及生物体健康方面。来自以前的数据 资助的PO1导致最近完成的100名患者的随机临床试验，表明一个周期性的 禁食模拟饮食在减少衰老和年龄相关疾病的危险因素/生物标志物方面是有效的。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 在人体试验的基础上，定期使用新设计的禁食模拟饮食(FMD5)的效果 等量热量蛋白限制循环(PRC)对免疫和神经衰老的临床试验和研究 系统。项目1的一个重要目标将是确定这些周期性的饮食干预是否可以 在高龄时延长健康寿命而不会产生不良影响。将作出重大努力，致力于 周期性禁食模拟饮食影响的分子机制研究 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 在免疫和神经系统的功能恢复方面。我们期待着我们的 项目和项目2，将调查饮食限制的影响和作用机制-- 模仿线粒体多肽Human in和Project 3，该项目将测试气体硫化氢是一种 禁食依赖保护的中枢调停者。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，以确定安全有效的改善干预措施 人类的健康跨度。

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.