Calorie Restriction-Mediated Life Span Extension in Yeast

热量限制介导的酵母寿命延长

• 批准号: 7895677
• 负责人: Jeffrey Scott Smith
• 金额: $ 29.83万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895677
• 关键词: Adverse effects; Age; Aging; Animal Model; Apoptotic; Biological Assay; Caloric Restriction; Candidate Disease Gene; Carbohydrates; Carbon; Cell physiology; Cells; Collection; Culture Media; Data; Diet; Disease; Dissection; Fission Yeast; Future; Gene Expression Microarray Analysis; Genes; Genetic; Genetic Screening; Glucose; Goals; Growth; Health; Human; Individual; Interphase Cell; Longevity; Longevity Pathway; Malignant Neoplasms; Mammals; Mediating; Molecular; Molecular Genetics; Mono-S; Mothers; Non-Insulin-Dependent Diabetes Mellitus; Organism; Pathway interactions; Population; Prevention; Process; Property; Purines; Regimen; Regulation; Reporting; Research; Research Priority; Resistance; Role; Saccharomyces cerevisiae; Saccharomycetales; Sampling; Source; System; Testing; Time; Work; Yeast Model System; Yeasts; age effect; age related; base; dietary supplements; extracellular; gene function; interest; mimetics; mutant; novel; purine; response; small molecule; theories; therapeutic target; tool

DESCRIPTION (provided by applicant): Calorie restriction (CR) is a dietary regimen that extends the maximum life span of a wide variety of organisms. CR also protects against aging-associated diseases, including type II diabetes and cancer. There are several theories to explain how CR protects against the detrimental effects of aging, but the molecular mechanism has yet to be elucidated. Therefore, one of the major goals of aging research at this time is to understand how CR works, which will help identify future therapeutic targets for the prevention or treatment of age-related disease. Remarkably, there is a yeast model of CR that consists of simply reducing the glucose in the growth medium from 2% to 0.5% (or less), which leads to an extension of replicative life span (RLS), defined as the number of times that a mother cell can divide, and chronological life span (CLS), defined as the number of days that cells survive in a non-dividing state. SIR2 is a central player in the regulation of yeast RLS and calorie restriction, but is not a key regulator of chronological longevity or CR-mediated extension of CLS. Therefore, the long-term goal of this project is to use the yeast CLS system for the identification and molecular-genetic dissection of novel CR-mediated longevity pathways. To facilitate rapid analysis of multiple mutants and growth conditions, the CLS assay has been optimized such that -100 samples can be processed at the same time. The specific aims of the project first focus on the purification and identification of an extracellular longevity factor that modulates yeast life span. In addition, we propose utilizing a high throughput genetic screen to identify genes that function in calorie restriction-mediated extension of CLS. The last specific aim is focused on dissecting the role of the highly conserved de novo purine synthesis pathway in modulating chronological and replicative life span in response to CR. Given the large number of genes and basic cellular processes shared between yeast and human cells, this study is expected to generate data that is highly applicable to CR research in mammals.

描述（由申请人提供）：热量限制（CR）是一种饮食方案，可延长各种生物的最大寿命。CR还可以预防衰老相关疾病，包括II型糖尿病和癌症。有几种理论可以解释CR如何防止衰老的不利影响，但分子机制尚未阐明。因此，目前衰老研究的主要目标之一是了解CR是如何工作的，这将有助于确定预防或治疗年龄相关疾病的未来治疗靶点。值得注意的是，存在CR的酵母模型，其由简单地将生长培养基中的葡萄糖从2%降低至0.5%（或更少）组成，这导致复制寿命（RLS）（定义为母细胞可以分裂的次数）和时序寿命（CLS）（定义为细胞在非分裂状态下存活的天数）的延长。SIR2是调节酵母RLS和热量限制的核心参与者，但不是时间寿命或CR介导的CLS延长的关键调节剂。因此，本项目的长期目标是使用酵母CLS系统鉴定和分子遗传学解剖新的CR介导的长寿途径。为了便于快速分析多个突变体和生长条件，CLS测定法已被优化，使得可以同时处理约100个样品。该项目的具体目标首先集中在调节酵母寿命的细胞外长寿因子的纯化和鉴定上。此外，我们建议利用高通量的遗传筛选，以确定在热量限制介导的延长CLS功能的基因。最后一个具体的目标是集中在解剖高度保守的从头嘌呤合成途径在调节时序和复制寿命响应CR的作用。鉴于酵母和人类细胞之间共享大量基因和基本细胞过程，这项研究有望产生高度适用于哺乳动物CR研究的数据。