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

项目摘要 衰老可以被描述为从成熟期开始逐渐丧失动态平衡，直到 衰老和死亡。衰老分子机制的发现可以使新的 阻止与年龄相关的疾病和延长健康寿命的治疗方法。这个目标一直是 即使在最简单的真核生物单细胞发芽酵母模型中也是难以捉摸的。酵母菌的寿命一直是 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，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的妥协。但通过分子事件链，动态平衡逐渐 到目前为止，Lost还不为人所知，部分原因是研究中该领域对大宗养殖测量的依赖 关于衰老的基因组学。目前提议的前提是解剖网络的故障 在许多单个细胞中-随着时间的推移观察它的许多方面，扰乱它们，并分析它们的反应，是 这对于从分子水平上理解衰老现象至关重要。为此，我们建议分析 通过蛋白质报告的综合单细胞图谱分析酵母分子老化轨迹(目标1)，至 通过系统的上位性分析(AIM)将延长寿命的突变与其下游效应器联系起来 2)，并测试在生命的特定时间点干扰关键基因(及时干预)是否可以 降低生命早期死亡率和/或延长寿命(目标3)。总而言之，这些实验将揭示 关于酵母中随年龄的动态平衡破坏的分子事件，确定动态干预 返老还童，并揭示了新的衰老基因和机制，作为测试的主要候选对象 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.