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Cell Metab. 2015 Nov 3;22(5):895-906. doi: 10.1016/j.cmet.2015.09.008. Epub 2015 Oct 8.

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging.

Author information

1
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
2
Department of Pathology, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
3
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
4
Department of Occupational and Environmental Health Sciences, University of Washington, Seattle, WA 98195, USA.
5
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
6
Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
7
Aging Research Institute, Guangdong Medical College, Dongguan 523808, Guangdong, P.R. China.
8
Aging Research Institute, Guangdong Medical College, Dongguan 523808, Guangdong, P.R. China; Department of Genetics, Albert Einstein College of Medicine, New York, NY 10461, USA.
9
Department of Biochemistry, University of Hong Kong, Hong Kong.
10
Department of Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address: kaeber@uw.edu.
11
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Electronic address: bkennedy@buckinstitute.org.

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.

PMID:
26456335
PMCID:
PMC4862740
DOI:
10.1016/j.cmet.2015.09.008
[Indexed for MEDLINE]
Free PMC Article

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