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Discovering the molecular mechanisms that determine replicative lifespan

发现决定复制寿命的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

总结