Cellular Aging and Rejuvenation: A Comprehensive Picture from a Dynamic and Network Perspective

细胞衰老与复兴：动态和网络视角的综合图景

• 批准号: 10406920
• 负责人: BRIAN K KENNEDY
• 金额: $ 52.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406920
• 关键词: Age; Aging; Animal Model; Attention; Behavior; Cell Aging; Cell Fraction; Cell division; Cell model; Cell physiology; Cells; Cessation of life; Complex; Development; Disease; Dissection; Eukaryota; Event; Exhibits; Failure; Gene Expression; Genes; Genetic; Genetic Epistasis; Genomics; Goals; Homeostasis; Human; Individual; Intervention; Life; Light; Link; Longevity; Maps; Measurement; Methods; Microfluidic Microchips; Modeling; Molecular; Molecular Analysis; Monitor; Mothers; Mutation; Organelles; Pathway interactions; Phenotype; Population; Process; Proteins; Proteome; Rejuvenation; Reporter; Repression; Research; Saccharomycetales; Series; Specific qualifier value; System; Systems Biology; Testing; Time; Tissues; Translating; Yeasts; aging gene; causal variant; cell age; experimental study; gene environment interaction; gene network; genetic analysis; healthspan; insight; microfluidic technology; molecular dynamics; molecular phenotype; mortality; mutant; new technology; novel; novel therapeutics; protein profiling; rate of change; response; senescence; single cell analysis; therapeutically effective

Project Summary Aging can be characterized as the progressive loss of homeostasis starting at maturity and ending with senescence and death. Discoveries of the molecular mechanisms of aging can enable the development of new therapies to block age-associated disease and extend healthspan, the healthy years of life. This goal has been elusive even in the simplest model eukaryote, single-celled budding yeast. Yeast longevity has been associated with each of hundreds of genes. Such complexity suggests that yeast aging is controlled by interactions between many molecules and organelles, with any link in this network potentially subject to compromise during a given cell division. But the chain of molecular events by which homeostasis is gradually lost has been obscure to date, in part due to the reliance of the field on bulk-culture measurements in the study of the genomics of aging. The premise of the current proposal is that dissecting the breakdown of the network in many single cells — observing its many facets over time, perturbing them, and analyzing their response, is critical for a molecular understanding of the phenomenon of aging. Toward this end, we propose to analyze yeast molecular aging trajectories via comprehensive single-cell profiling of protein reporters (Aim 1), to connect lifespan extending mutations to their downstream effectors through systematic epistasis analysis (Aim 2), and to test whether perturbing critical genes at a particular point in life (just-in-time interventions) can decrease mortality rates early in life and/or extend lifespan (Aim 3). Together, these experiments will shed light on the molecular events of the breakdown of homeostasis with age in yeast, identify dynamic interventions for rejuvenation, and reveal novel aging genes and mechanisms to serve as prime candidates for testing in metazoans.

项目摘要 衰老可以被描述为从成熟开始开始稳健的稳态丧失，结束时以 衰老和死亡。衰老分子机制的发现可以使新的发展 疗法可阻止与年龄相关的疾病并扩展健康状态，即健康的生活。这个目标是 即使在最简单的真核生物，单细胞发芽的酵母中也难以捉摸。酵母长寿 与数百个基因相关。这种复杂性表明酵母老化是由 许多分子与细胞器之间的相互作用，与该网络中的任何链接都可能受到 在给定的细胞分裂期间妥协。但是，体内稳态的分子事件链逐渐 迄今为止，丢失一直晦涩 衰老的基因组学。当前建议的前提是剖析网络的故障 在许多单个单元格中 - 随着时间的流逝，观察其许多方面，扰动它们并分析其响应，是 对分子对衰老现象的理解至关重要。为此，我们建议分析 酵母分子衰老轨迹通过蛋白质报道的全面单细胞分析（AIM 1）， 通过系统的上毒分析将寿命扩展到其下游效应的寿命（目标） 2），并测试在生活中特定点（即时干预措施）的关键基因是否可以 降低生命早期的死亡率和/或延长寿命（AIM 3）。这些实验将在一起散发出光线 关于随着年龄的年龄在酵母上的分子发生的分子事件，确定动态干预措施 恢复活力，并揭示了新颖的衰老基因和机制，以作为测试的主要候选者 后生动物。