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

项目摘要/摘要 标题： 饮食限制、GH/IGF-1与细胞保护和再生机制 ABSTACT： 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延缓这些疾病 确定安全的策略来延缓衰老，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，我们建议将两个生物老年学 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、禁食模拟饮食和蛋白质限制之间的分子机制 减少的营养信号，胁迫抗性信号网络，线粒体肽人素，以及 反过来，细胞保护、再生和健康跨度。这些研究将有助于确定 治疗和预防多种疾病的药物和饮食干预，通过对衰老过程和 论多系统的再生与振兴。饮食干预的一个重要优势是 测试表明，它们是周期性的，因此有潜力赶上并可能超过有益的 慢性卡路里限制的效果，同时将慢性和极端饮食的负担降至最低，而且 将不良影响降至最低。 这个P01应用程序由三个主要项目组成，一个是动物和生物统计核心，一个是 管理核心。我们的共同目标是：1)确定和研究新的周期性饮食干预措施， 促进老年健康而不产生不良影响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、再生和年轻化，重点是 造血和神经系统；3)了解饮食干预、生长途径 和人素来测试这种线粒体肽作为健康跨度介体和 确定它是否可以作为禁食/蛋白质限制的模拟物；4)检验内源性 硫化氢是饮食干预包括禁食、禁食和模拟饮食的保护效果的关键介质 和蛋白质限制对器官和细胞的缺血和遗传毒性损伤的抵抗，并研究 饮食限制、生长因子对半胱氨酸伽马裂解酶介导的内源性H_2S产生的调节 和人素。 每个PI的独特背景以及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 事态的发展。这些进展无疑将加快研究进展，并支持 开发临床试验，以改善人类健康的方式，这是每个实验室都无法实现的 独立开展研究工作。

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.