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; 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 细胞在停止分裂和鼻子之前将固定次数（称为复制寿命）划分。 表征正常复制衰老的生物大分子的变化加速 过程使我们容易缩短复制寿命和诸如后代等条件。尽管有 复制性衰老过程的基本重要性，我们对 引起衰老的生物学变化和这些变化的分子基础。鉴于该机制 衰老是在真核生物中高度保守的，我们使用芽的无与伦比的遗传能力来获得 深入了解所有真核生物中复制衰老的分子机制。使用母亲富集 程序（MEP）以隔离前所未有的旧细胞，我们进行了系统的表征 酵母中的复制衰老过程，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，真的 第一次在任何生物体中。我们对核小体位置的全基因组映射发现了全球的损失 衰老过程中的核小体，导致基因组中每个基因的转录上调。深处 在衰老过程中基因组的测序我们发现逆转录置换染色体的全球增加 易位，DNA扩增，rDNA不稳定性，线粒体DNA转移到核基因组和 衰老1中的DNA断裂。我们现在进行了代谢组学分析和核糖体分析（Ribo-Seq） 在衰老期间，导致我们实现了当前的假设，并发现了如何发现蛋白质的分子细节 综合随老化，有益的后果而变化，并利用此信息延长寿命 和HealthSpan。