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

项目摘要 衰老可以被表征为从成熟开始到衰老结束的内稳态的逐渐丧失。 衰老和死亡衰老的分子机制的发现可以使新的 治疗，以阻止与年龄相关的疾病，并延长healthspan，健康的生活年。这个目标已经 甚至在最简单的真核生物模型单细胞芽殖酵母中也难以找到。酵母的寿命一直是 与数百个基因中的每一个相关。这种复杂性表明酵母的老化是由 许多分子和细胞器之间的相互作用，在这个网络中的任何链接都可能受到 在特定的细胞分裂过程中妥协。但是体内平衡逐渐被破坏的分子链 到目前为止，lost一直是模糊的，部分原因是该领域对研究中大量培养测量的依赖 衰老的基因组学。目前提案的前提是，剖析网络故障 在许多单细胞中-随着时间的推移观察其多个方面，干扰它们，并分析它们的反应， 这对于从分子水平理解衰老现象至关重要。为此，我们建议分析 酵母分子老化轨迹通过全面的单细胞分析蛋白质报告（目的1）， 通过系统上位性分析将延长寿命的突变与其下游效应子连接起来（Aim 2），并测试在生命的特定时刻扰乱关键基因（及时干预）是否可以 降低生命早期的死亡率和/或延长寿命（目标3）。这些实验将揭示 在分子事件的破坏稳态与年龄的酵母，确定动态干预， 年轻化，并揭示新的衰老基因和机制，作为主要候选人测试， 后生动物。

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.