The Role of Metabolic Signaling in Longevity Regularion

描述(申请人提供)：衰老是一个复杂的过程，影响着我们生活的许多方面，但人们对调节这一过程的分子途径知之甚少。卡路里限制(CR)延长了多种生物体的寿命。了解CR延长寿命的机制将有助于阐明长寿调节的分子途径。 这项建议的主要目标是利用遗传易驯化的酿酒酵母作为一个模式系统来识别和揭开长寿调控途径。本研究的主要假设是，长寿因子在热量限制(CR)下受到代谢调节，细胞内NAD/NADH动态平衡因子在调节这一调节中起重要作用。 目的1)：了解代谢酶在长寿调节中的作用。利用亲和纯化、分子和遗传学研究，我们将阐明代谢酶是如何调节长寿的，并确定其他调节长寿的代谢因素。目的：研究NAD/NADH动态平衡在长寿代谢调节中的作用。体内NAD和NADH水平将使用Nano-HPLC/AMS分析进行测定。NADINADH动态平衡因子调节寿命的机制将被研究。目的3)：寻找长寿信号通路中的新成分。在这个特定的目标中，我们提出了三种不同的方法，结合遗传、基因组和生化方法来详细描述CR的途径，并确定新的长寿途径。 许多细胞通路在酵母和哺乳动物中是保守的。因此，深入了解酵母中的这些分子过程也将为人类衰老和年龄相关疾病的分子基础提供线索。

DESCRIPTION (provided by applicant): Aging is a complex process that influences many aspects of our lives yet little is known about the molecular pathways that regulate this process. Calorie Restriction (CR) extends life span in a wide sprectrum of organisms. Understanding the mechanism by which CR extends life span will help to elucidate the molecular pathways of longevity regulations. The main goal of this proposal is to utilize the genetically tractable yeast Saccharomyces cerevisiae as a model system to identify and unravel the longevity regulating pathways. The major hypothesis of this research is that longevity factors are subject to metabolic regulation under Calorie Restriction (CR) and the intracellular NAD/NADH homeostasis factors play an important role in mediating this regulation. Aim 1): To understand the role of metabolic enzymes in longevity regulation. Using Affinity-purification, molecular and genetic studies, we will elucidate how metabolic enzymes regulate longevity and to identify other longevity regulating metabolic factors. Aim 2): To study the role of NAD/NADH homeostasis in the metabolic regulation of longevity. In vivo levels of NAD and NADH will be determined using Nano-HPLC/AMS analysis. The mechanisms by which the NADINADH homeostasis factors regulate life span will be studied. Aim 3): To identify new components in the longevity signaling pathway. In this Specific Aim, we propose three different approaches that combine genetic, genomic and biochemical methods to detail the pathways of CR and to identify new longevity pathways. Many cellular pathways are conserved in yeast and mammals. Therefore, insight into these molecular processes in yeast will also provide clues to the molecular basis of human aging and age-associated diseases.