Abstract
Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.
Original language | English |
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Pages (from-to) | 895-906 |
Number of pages | 12 |
Journal | Cell Metabolism |
Volume | 22 |
Issue number | 5 |
DOIs | |
Publication status | Published - 3 Nov 2015 |
Externally published | Yes |
Keywords
- Aging/genetics
- Animals
- Basic-Leucine Zipper Transcription Factors/genetics
- Caenorhabditis elegans/genetics
- Caloric Restriction
- DNA Damage/genetics
- Gene Deletion
- Gene Expression Regulation/genetics
- Genome
- Longevity/genetics
- Nuclear Pore Complex Proteins/genetics
- RNA, Transfer/genetics
- Saccharomyces cerevisiae/genetics
- Saccharomyces cerevisiae Proteins/genetics
- TOR Serine-Threonine Kinases/antagonists & inhibitors