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 摘要 后生动物有机体的寿命是由时间寿命（时间长度）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（细胞死亡的次数） 在不可逆转地逮捕之前分裂；在芽殖酵母 [Saccharomyces cerevisiae] 中研究最准确）。 许多化学、饮食和遗传干预措施可以延长寿命。这些通常首先被发现于 芽殖酵母，随后被证明适用于后生动物。但目前人们的了解还很少 它们延长寿命的潜在分子机制。各种干预措施，包括 药物、基因操作和热量限制 (CR) 已被证明可以延长 几个物种的寿命。然而，对于最终的身份存在着巨大的知识差距。 这些抗衰老干预措施产生的分子变化可延长寿命。我们最近表明 Gcn4 的过度表达，Gcn4 是后生动物 ATF4 蛋白的酵母对应物，可诱导多重应激 反应途径，延长酵母复制寿命（RLS）（细胞分裂前的次数） 不可逆地阻止）以依赖于自噬的方式。这一发现启发我们思考是否 其他抗衰老干预措施需要自噬来延长酵母 RLS。我们的初步调查结果 表明干预措施可以延长许多生物体的寿命，包括雷帕霉素、二甲双胍、核糖体 耗竭、CR 和增加的 Sirtuin 活性，以自噬依赖性方式延长酵母 RLS。 此外，我们发现自噬的诱导足以延长酵母 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结果 促进抗衰老的自噬分子靶标。