Dietary Restriction, GH/IGF-1 & Mechanisms of Cellular Protection and Regeneration

项目总结/摘要 标题： 饮食限制、GH/IGF-1与细胞保护和再生机制 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很好地帮助预防或至少延缓这些疾病， 确定延缓衰老的安全策略，使细胞损伤的程度和类型不会达到 导致疾病发生或进展的阈值。在这里，我们建议把两个生物学 南加州大学老年学学院的实验室和哈佛大学的实验室 大学研究禁食，禁食模仿饮食和蛋白质限制的分子机制， 减少的营养信号，抗应激信号网络，线粒体肽humanin， 转，细胞保护，再生，和健康。这些研究将有助于确定 药物和饮食干预，通过作用于衰老过程来治疗和预防多种疾病， 多系统再生和恢复活力。饮食干预的一个重要优势是 测试的是，他们是周期性的，因此有潜力匹配，并可能超过有益的 长期热量限制的影响，同时尽量减少慢性和极端饮食的负担， 最大限度地减少不利影响。 这个P01应用程序包括3个主要项目，一个动物和生物统计学核心， 行政核心。我们的共同目标是：1）确定和研究新的周期性饮食干预， 促进老年人的健康而不造成不良影响; 2）研究禁食模仿的机制 饮食和蛋白质限制依赖的细胞保护，再生和复兴，重点是 造血和神经系统; 3）了解饮食干预，生长途径之间的联系 和humanin来测试这种线粒体肽作为健康维持介质的假设， 确定它是否可以作为禁食/蛋白质限制模拟物; 4）测试内源性 H2S是饮食干预（包括禁食、禁食模仿饮食）保护作用的关键介质 和蛋白质限制对器官和细胞抗缺血性和遗传毒性损伤的作用，并研究 半胱氨酸γ裂解酶介导的内源性H2S产生的饮食限制、生长因子 和humanin。 每个PI的独特背景和他们之间的密切合作已经产生并将 继续产生新的假设，新的细胞和小鼠模型，以及技术和概念， 发展理念这些进展无疑将加速研究进展，并支持 开展临床试验，以每个实验室无法实现的方式改善人类健康 独立进行研究。

PROJECT SUMMARY/ABSTRACT TITLE: Dietary Restriction, GH/IGF-1 and Mechanisms of Cellular Protection and Regeneration ABSTACT: Age is the major risk factor for many morbidities including cancer, cardiovascular and neurodegenerative diseases. Biogerontology research is well positioned to help prevent or at least delay these diseases by identifying safe strategies to retard aging so that the degree and type of cellular damage does not reach the threshold leading to disease incidence or progression. Here we propose to bring together two biogerontology laboratories from the University of Southern California School of Gerontology and a laboratory from Harvard University to study the molecular mechanisms linking fasting, fasting mimicking diets and protein restriction to reduced nutrient signaling, the stress resistance signaling network, the mitochondrial peptide humanin, and in turn, cellular protection, regeneration, and healthspan. These studies will contribute to the identification of drugs and dietary interventions to treat as well as prevent multiple diseases by acting on the aging process and on multi-system regeneration and rejuvenation. An important advantage of the dietary interventions being tested is that they are periodic and therefore have the potential to match and possibly surpass the beneficial effects of chronic calorie restriction while minimizing the burden of chronic and extreme diets, but also minimizing adverse effects. This P01 application consists of 3 major projects, an Animal and Biostatistics Core, and an Administrative Core. Our common goals are to: 1) identify and study novel periodic dietary interventions that promote healthspan without causing adverse effects at old ages; 2) study the mechanisms of fasting mimicking diet- and protein restriction-dependent cellular protection, regeneration and rejuvenation with focus on the hematopoietic and nervous systems; 3) understand the link between dietary interventions, growth pathways and humanin to test the hypothesis that this mitochondrial peptide functions as a healthspan mediator and determine whether it can serve as a fasting/protein restriction mimetic; 4) test the hypothesis that endogenous H2S is a key mediator of the protective effects of dietary interventions including fasting, fasting mimicking diets and protein restriction on resistance to ischemic and genotoxic injury to organs and cells, and study the regulation of cysteine gamma lyase-mediated endogenous H2S production by dietary restriction, growth factors and humanin. The unique background of each PI and the close collaboration between them has generated and will continue to generate new hypotheses, novel cellular and mouse models, as well as technical and conceptual developments. These advances will undoubtedly accelerate the research progress and support the development of clinical trials to improve human health in ways that could not be achieved by each laboratory performing research independently.