Discovering how autophagy is sufficient to extend yeast replicative lifespan

发现自噬如何足以延长酵母复制寿命

• 批准号: 10744971
• 负责人: Jessica K Tyler
• 金额: $ 53.5万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744971
• 关键词: Acidity; Age; Aging; Autophagocytosis; Caloric Restriction; Cell Nucleolus; Cells; Chemicals; Chronology; Coupled; DNA; DNA Repair; DNA Repair Gene; DNA biosynthesis; DNA replication origin; Data; Defect; Dietary Intervention; Exclusion; Fire - disasters; Genome; Genome Stability; Genomic Instability; Goals; Heart Diseases; Histones; Intervention; Iron; Knowledge; Length; Longevity; Loss of Heterozygosity; Maintenance; Malignant Neoplasms; Metformin; Microfluidics; Modeling; Molecular; Molecular Genetics; Molecular Target; Mus; Nerve Degeneration; Organism; Pathway interactions; Pharmaceutical Preparations; Play; Production; Proteins; Regulation; Ribosomal DNA; Ribosomes; Saccharomyces cerevisiae; Saccharomycetales; Sirolimus; Sirtuins; Stress; Sulfur; System; Testing; Time; Up-Regulation; Vacuole; Work; Yeast Model System; Yeasts; anti aging; biological adaptation to stress; cofactor; gene therapy; genetic manipulation; healthspan; human disease; improved; new therapeutic target; overexpression; prevent; repaired; response; single cell analysis

Summary Abstract Metazoan organismal lifespan is determined by a combination of chronological lifespan (the length of time a cell exists in a non-dividing state before dying) and replicative lifespan (the number of times a cell divides before irreversibly arresting; most accurately studied in budding yeast [Saccharomyces cerevisiae]). Many chemical, dietary and genetic interventions can extend lifespan. These are usually first discovered in budding yeast, and subsequently shown to apply in metazoans. However, there is still little understanding of their underlying molecular mechanisms for lifespan extension. A variety of interventions, including medications, genetic manipulations, and calorie restriction (CR), have been demonstrated to extend the lifespan of several species. However, there is a significant knowledge gap as to the identity of the ultimate molecular changes enacted by these antiaging interventions to extend lifespan. We recently showed that overexpression of Gcn4, the yeast counterpart of the metazoan ATF4 protein that induces multiple stress response pathways, extended the yeast replicative lifespan (RLS) (the number of times a cell divides before irreversibly arresting) in a manner dependent on autophagy. This finding inspired us to ask whether autophagy is required for other antiaging interventions to extend the yeast RLS. Our preliminary findings indicate that interventions that extend lifespan in many organisms, including rapamycin, metformin, ribosome depletion, CR, and increased sirtuin activity, extend the yeast RLS in an autophagy-dependent manner. Furthermore, we find that induction of autophagy is sufficient to extend the yeast RLS. Given that autophagy induction is also sufficient to extend lifespan in metazoans, we will use the yeast model to seek ultimate molecular targets of autophagy that promote antiaging.

摘要 后生动物有机体的寿命是由按时间顺序排列的寿命（长度）的组合决定的。 细胞在死亡前处于非分裂状态的时间）和复制寿命（细胞在死亡前处于非分裂状态的次数）。 在不可逆的停滞之前分裂;在芽殖酵母[酿酒酵母]中研究得最准确）。 许多化学、饮食和遗传干预可以延长寿命。这些通常首先发现于 芽殖酵母，并随后被证明适用于后生动物。然而，人们对 它们延长寿命的潜在分子机制。各种干预措施，包括 药物、基因操作和卡路里限制（CR）已被证明可以延长 几个物种的寿命。然而，对于最终目标的身份， 通过这些抗衰老干预来延长寿命的分子变化。我们最近发现， Gcn 4的过表达，Gcn 4是后生动物ATF 4蛋白的酵母对应物，其诱导多重应激 反应途径，延长酵母复制寿命（RLS）（细胞分裂之前的次数） 不可逆地阻止）。这一发现启发我们去问， 自噬是其他抗衰老干预所必需的，以延长酵母RLS。我们的初步研究结果 表明在许多生物体中延长寿命干预，包括雷帕霉素、二甲双胍、核糖体 消耗、CR和增加的沉默调节蛋白活性以自噬依赖性方式延长酵母RLS。 此外，我们发现诱导自噬足以延长酵母RLS。鉴于自噬 诱导也足以延长后生动物的寿命，我们将使用酵母模型来寻求最终的 促进抗衰老的自噬分子靶点。