Discovering the molecular mechanisms that determine replicative lifespan

总结 细胞在停止分裂和衰老之前，会分裂固定的次数，称为复制寿命。 加速生物大分子的改变，这是正常复制性衰老的特征 这一过程使我们更容易缩短复制寿命，并出现早衰症等症状。尽管 复制性衰老过程的根本重要性，我们对衰老过程的理解仍然存在巨大的差距。 导致衰老的生物学变化以及这些变化的分子基础。考虑到 衰老在真核生物中是高度保守的，我们利用芽殖酵母无与伦比的遗传力量来获得 深入了解所有真核生物中复制性衰老的分子机制。使用母亲富集 程序（MEP）分离前所未有数量的老细胞，我们进行了系统的表征， 酵母中的复制老化过程，目的是将我们的发现转移到哺乳动物系统中。 使用MEP，我的实验室一直在对衰老过程进行系统生物学分析， 在任何生物体中都是第一次我们对核小体位置的全基因组定位揭示了一个全球性的缺失， 衰老过程中的核小体，导致基因组中每个基因的转录上调。通过深 在衰老过程中的基因组测序中，我们发现逆转录转座，染色体 易位，DNA扩增，rDNA不稳定性，线粒体DNA转移到核基因组中， DNA在衰老过程中断裂1.我们现在已经进行了代谢组学分析和核糖体分析（Ribo-seq） 在衰老过程中，导致我们目前的假设和目标，发现蛋白质如何在分子上的细节， 合成随着年龄的增长而变化，有益的后果，并利用这些信息来延长寿命 和健康。

SUMMARY Cells divide a fixed number of times, termed replicative lifespan, before they stop dividing and senesce. Acceleration of the alterations to biological macromolecules that characterize the normal replicative aging process predisposes us to shortened replicative lifespan and conditions such as progeria. Despite the fundamental importance of the replicative aging process, there are still huge gaps in our understanding of the biological changes that cause aging and the molecular basis of these changes. Given that the mechanisms of aging are highly conserved across eukaryotes, we use the unparalleled genetic power of budding yeast to gain insight into the molecular mechanisms of replicative aging in all eukaryotes. Using the Mother Enrichment Program (MEP) to isolate unprecedented quantities of old cells, we performed a systematic characterization of the replicative aging process in yeast, with the intention of transferring our discoveries to mammalian systems. Using the MEP, my laboratory has been performing a systems biology analysis of the aging process, really for the first time in any organism. Our genome-wide mapping of nucleosome positions uncovered a global loss of nucleosomes during aging, leading to transcriptional upregulation of every gene in the genome. By deep sequencing of the genome during aging we discovered a global increase in retrotransposition, chromosomal translocation, DNA amplification, rDNA instability, transfer of mitochondrial DNA into the nuclear genome and DNA breaks during aging 1. We have now performed metabolomics analysis and ribosome profiling (Ribo-seq) during aging, leading us to our current hypothesis and goal of discovering the molecular details of how protein synthesis changes with aging, the beneficial consequences, and to leverage this information to extend lifespan and healthspan.