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）：卡路里限制（CR）是一种饮食方案，可扩展各种生物的最大寿命。 CR还可以防止衰老相关的疾病，包括II型糖尿病和癌症。有几种理论可以解释CR如何预防衰老的有害作用，但是分子机制尚未阐明。因此，目前衰老研究的主要目标之一是了解CR的工作原理，这将有助于确定未来的预防或治疗与年龄相关疾病的治疗靶标。值得注意的是，有一个CR的酵母模型包括将生长培养基中的葡萄糖从2％降低到0.5％（或更少），这导致了复制寿命（RLS）的延长，定义为次数母细胞可以分裂，按年代寿命（CLS）定义为细胞在非分裂状态下生存的天数。 SIR2是调节酵母RLS和卡路里限制的核心参与者，但不是按时间顺序寿命或CR介导的CLS扩展的关键调节器。因此，该项目的长期目标是使用酵母CLS系统来识别和分子遗传学对新型CR介导的寿命途径的识别。为了促进对多个突变体和生长条件的快速分析，对CLS分析进行了优化，因此可以同时处理-100个样品。该项目的具体目的首先关注调节酵母寿命的细胞外寿命因子的纯化和识别。此外，我们建议利用高吞吐量遗传筛选来识别在卡路里限制介导的CLS扩展中起作用的基因。最后的特定目的是剖析高度保守的从头嘌呤合成途径在调节响应Cr的时间顺序和复制寿命中的作用。鉴于酵母和人类细胞之间共有的大量基因和基本细胞过程，该研究有望生成非常适用于哺乳动物CR研究的数据。