Control of Yeast Life Span

酵母寿命的控制

• 批准号: 6401159
• 负责人: Kurt W Runge
• 金额: $ 25.9万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6401159
• 关键词: aging; bioenergetics; caloric dietary content; cell age; chromatin; dietary restriction; free radical oxygen; fungal genetics; gene induction /repression; gene mutation; longevity; microarray technology; microorganism culture; mitochondria; nutrition of aging; nutrition related tag; oxidative stress; ribosomal RNA; telomere; yeasts

Caloric restriction (CR), i.e. the reduction of the daily caloric intake, can prolong the life span of mice and yeast. CR has long been thought to extend life span by reducing the number of reactive oxygen species (ROS) produced by cellular energy metabolism. It is not known if CR only reduces the production of ROS or also induces a state that protects the cell from potential damage from ROS. Our studies on the control of yeast silencing provide novel insights into the molecular mechanisms of CR. Silencing, the reversible repression of gene expression, changes in old yeast and plays a role in the yeast response to CR. We isolated mutations that mimic the silencing phenotype of aged yeast. Remarkably, we found mutations known to increase yeast life span and identified pathways homologous to mouse pathways whose expression changes during CR and aging. 60 percent of our mutants have defective mitochondria, a hallmark of aging in mammalian cells. Thus, our identification of genetic pathways that control silencing has also identified pathways modulated by CR and aging in mice. We have also isolated a second set of mutations that block the silencing phenotype of aged yeast. These mutants identify a chromatin remodeling factor and chromatin components. Changes in chromatin are the likely endpoints of pathways that modulate transcription in response to CR. Thus, our two sets of mutants most likely identify signal generating and signal responding ends of pathways that control life span. The goal of this proposal is to understand how gene silencing and life span are controlled in response to defective mitochondria and CR. We hypothesize that CR and our mutants induce pathways that the cell normally uses to respond to changes in energy source, and to control the rate of aging through specific chromatin components. To test these hypotheses, we will pursue the following specific aims: Aim 1. What life span- and silencing-modulating pathways do our mutants identify? Aim 2. Do our control of silencing mutations delay the appearance of aging phenotypes in the same way as CR? Aim 3. Which life span extending genes are controlled by CR and the pathways identified and characterized in aims 1 and 2? The results of this work will elucidate the molecular mechanisms of CR-mediated life span extension and provide a model for mammalian systems.

热量限制（CR），即减少每日热量摄入，可以延长小鼠和酵母的寿命。 长期以来，人们一直认为CR可以通过减少细胞能代谢产生的活性氧（ROS）的数量来延长寿命。 尚不清楚CR是否仅减少ROS的产生或诱导保护细胞免受ROS潜在损害的状态。 我们对酵母沉默控制的研究为CR的分子机制提供了新的见解。 沉默，对基因表达的可逆抑制，旧酵母的变化，并在酵母对CR的反应中起作用。 我们分离了模仿老年酵母沉默表型的突变。 值得注意的是，我们发现已知会增加酵母寿命并确定与小鼠途径同源的途径的突变，这些途径在Cr和衰老过程中的表达变化。 我们60％的突变体的线粒体有缺陷，这是哺乳动物细胞衰老的标志。 因此，我们对控制沉默的遗传途径的鉴定也确定了小鼠CR和衰老调节的途径。 我们还分离了第二组突变，该突变阻断了老年酵母的沉默表型。 这些突变体鉴定了染色质重塑因子和染色质成分。 染色质的变化是响应Cr的转录的途径的可能终点。 因此，我们的两组突变体最有可能识别控制寿命的途径的信号产生和信号响应末端。该提案的目的是了解基因沉默和寿命如何响应有缺陷的线粒体和CR控制。 我们假设CR和我们的突变体会诱导细胞通常用来响应能源变化的途径，并通过特定的染色质成分来控制衰老速率。 为了检验这些假设，我们将追求以下特定目标：目标1。我们的突变体可以识别哪些寿命和沉默调节途径？ 目标2。我们对沉默突变的控制是否以与CR相同的方式延迟衰老表型的出现？ AIM 3。哪个延长基因的寿命由CR控制以及目标1和2中识别和表征的途径？ 这项工作的结果将阐明CR介导的寿命延长的分子机制，并为哺乳动物系统提供模型。