The Role of Metabolic Signaling in Longevity Regularion

代谢信号在长寿规律中的作用

• 批准号: 7090606
• 负责人: Su-Ju Lin
• 金额: $ 24.93万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7090606
• 关键词: Saccharomyces cerevisiae; affinity chromatography; aging; biological signal transduction; caloric dietary content; fluorescence microscopy; green fluorescent proteins; homeostasis; longevity; metabolism; molecular genetics; nicotinamide adenine dinucleotide

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.

描述（由申请人提供）：衰老是一个复杂的过程，影响我们生活的许多方面，但对调节这一过程的分子途径知之甚少。热量限制（CR）延长了许多生物体的寿命。了解CR延长寿命的机制将有助于阐明寿命调节的分子途径。 该建议的主要目标是利用遗传上易处理的酵母酿酒酵母作为模型系统来识别和解开寿命调节途径。本研究的主要假设是，长寿因子受热量限制（CR）的代谢调控，细胞内NAD/NADH稳态因子在介导这一调控中起重要作用。 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，我们将阐明代谢酶如何调节寿命，并确定其他寿命调节代谢因子。目的2）：研究NAD/NADH稳态在长寿代谢调控中的作用。将使用Nano-HPLC/AMS分析测定NAD和NADH的体内水平。将研究NADINADH稳态因子调节寿命的机制。目的3）：鉴定长寿信号通路中的新组分。在这个具体的目标，我们提出了三种不同的方法，结合联合收割机遗传，基因组和生化方法，详细的CR的途径，并确定新的长寿途径。 许多细胞途径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。