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

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 clu...

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Published in:Cell metabolism 2015-11, Vol.22 (5), p.895-906
Main Authors: McCormick, Mark A., Delaney, Joe R., Tsuchiya, Mitsuhiro, Tsuchiyama, Scott, Shemorry, Anna, Sim, Sylvia, Chou, Annie Chia-Zong, Ahmed, Umema, Carr, Daniel, Murakami, Christopher J., Schleit, Jennifer, Sutphin, George L., Wasko, Brian M., Bennett, Christopher F., Wang, Adrienne M., Olsen, Brady, Beyer, Richard P., Bammler, Theodor K., Prunkard, Donna, Johnson, Simon C., Pennypacker, Juniper K., An, Elroy, Anies, Arieanna, Castanza, Anthony S., Choi, Eunice, Dang, Nick, Enerio, Shiena, Fletcher, Marissa, Fox, Lindsay, Goswami, Sarani, Higgins, Sean A., Holmberg, Molly A., Hu, Di, Hui, Jessica, Jelic, Monika, Jeong, Ki-Soo, Johnston, Elijah, Kerr, Emily O., Kim, Jin, Kim, Diana, Kirkland, Katie, Klum, Shannon, Kotireddy, Soumya, Liao, Eric, Lim, Michael, Lin, Michael S., Lo, Winston C., Lockshon, Dan, Miller, Hillary A., Moller, Richard M., Muller, Brian, Oakes, Jonathan, Pak, Diana N., Peng, Zhao Jun, Pham, Kim M., Pollard, Tom G., Pradeep, Prarthana, Pruett, Dillon, Rai, Dilreet, Robison, Brett, Rodriguez, Ariana A., Ros, Bopharoth, Sage, Michael, Singh, Manpreet K., Smith, Erica D., Snead, Katie, Solanky, Amrita, Spector, Benjamin L., Steffen, Kristan K., Tchao, Bie Nga, Ting, Marc K., Vander Wende, Helen, Wang, Dennis, Welton, K. Linnea, Westman, Eric A., Brem, Rachel B., Liu, Xin-guang, Suh, Yousin, Zhou, Zhongjun, Kaeberlein, Matt, Kennedy, Brian K.
Format: Article
Language:English
Subjects:
Aging - genetics
Aging - metabolism
Aging - pathology
Animals
Basic-Leucine Zipper Transcription Factors - genetics
Basic-Leucine Zipper Transcription Factors - metabolism
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
Saccharomyces cerevisiae Proteins - metabolism
TOR Serine-Threonine Kinases - antagonists & inhibitors
TOR Serine-Threonine Kinases - genetics
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Summary: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. [Display omitted] •4,698 deletions tested yields the most comprehensive yeast data set on aging•Longevity clusters center on known, conserved biological processes•Enrichment of lifespan-extending C. elegans orthologs suggests conservation•Genome-wide information uncovered aging pathways such as tRNA transport Analysis of 4,698 viable yeast single-gene deletion strains yielded 238 with increased lifespan, in multiple functional groups, showing a significant conservation in longevity pathways between yeast and C. elegans. Deletion of tRNA exporter LOS1 extended lifespan; DNA damage response and mTOR converge on Los1-mediated tRNA export to regulate Gcn4 activity.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2015.09.008