Discovering the molecular mechanisms that determine replicative lifespan

发现决定复制寿命的分子机制

• 批准号: 9317795
• 负责人: Jessica K Tyler
• 金额: $ 56.57万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317795
• 关键词: Acceleration; Adult; Age; Aging; Aging-Related Process; Alpha Cell; Amino Acids; Bioinformatics; Biological; Caloric Restriction; Calories; Cardiovascular Diseases; Cells; Chromatin Structure; Chromosomal translocation; DNA; DNA amplification; Data; Diabetes Mellitus; Disease; Employee Strikes; Eukaryota; Event; Genes; Genetic; Genetic Transcription; Genome; Global Change; Goals; Health; Histones; Human; Intention; Knowledge; Laboratories; Longevity; Macaca mulatta; Malignant Neoplasms; Malnutrition; Maps; Mediating; Messenger RNA; Mitochondrial DNA; Molecular; Mothers; Nature; Nuclear; Nucleosomes; Nutrient; Organism; Pharmacologic Substance; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Progeria; Protein Biosynthesis; Proteins; Recombinant DNA; Retrotransposition; Risk Factors; Saccharomycetales; System; Systems Biology; Therapeutic; Therapeutic Intervention; Time; Transcript; Translations; Up-Regulation; Yeasts; deep sequencing; design; genome sequencing; genome-wide; high risk; improved; insight; macromolecule; metabolomics; mutant; novel; programs; proteostasis; reduced food intake; ribosome profiling; targeted treatment; translation factor; yeast genome

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.

概括 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，这是正常复制衰老的特征 这个过程使我们容易出现复制寿命缩短和早衰等状况。尽管 复制性衰老过程的根本重要性，但我们对复制衰老过程的理解仍然存在巨大差距 导致衰老的生物变化以及这些变化的分子基础。鉴于该机制 衰老在真核生物中高度保守，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复制衰老的分子机制。使用母亲浓缩 计划（MEP）分离出前所未有数量的旧细胞，我们对 酵母的复制衰老过程，旨在将我们的发现转移到哺乳动物系统中。 我的实验室利用 MEP 对衰老过程进行了系统生物学分析，实际上是为了 在任何有机体中都是第一次。我们对核小体位置的全基因组图谱发现了全局丢失 衰老过程中的核小体，导致基因组中每个基因的转录上调。由深 对衰老过程中的基因组进行测序，我们发现逆转录转座、染色体 易位、DNA 扩增、rDNA 不稳定、线粒体 DNA 转移到核基因组中以及 衰老过程中的 DNA 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，使我们得出当前的假设和目标，即发现蛋白质如何发挥作用的分子细节 合成随着年龄的增长而变化，产生有益的后果，并利用这些信息来延长寿命 和健康寿命。