1. A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging
- Author
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Brady Olsen, Marc K. Ting, Simon C. Johnson, Annie Chou, Dennis Wang, Monika Jelic, Zhongjun Zhou, Dillon Pruett, Eric C. Liao, Sarani Goswami, Mitsuhiro Tsuchiya, Ariana A. Rodriguez, Arieanna C. Anies, Theodor K. Bammler, Elroy H. An, Sylvia Sim, Diana N. Pak, Kristan K. Steffen, Juniper K. Pennypacker, Kim M. Pham, Christopher F. Bennett, Helen Vander Wende, Richard M. Moller, Bopharoth Ros, Tom Pollard, Richard P. Beyer, Mark A. McCormick, Winston Lo, Joe R. Delaney, Jennifer Schleit, Shannon Klum, Diana Kim, Anthony S. Castanza, Rachel B. Brem, Ki Soo Jeong, Benjamin L. Spector, Daniel B. Carr, Brian M. Wasko, K. Linnea Welton, Eric A. Westman, Donna Prunkard, Scott Tsuchiyama, Katie Kirkland, Amrita Solanky, Dilreet Rai, Shiena Enerio, Christopher J. Murakami, Manpreet K. Singh, Marissa Fletcher, Anna Shemorry, George L. Sutphin, Elijah D. Johnston, Molly A. Holmberg, Zhao Jun Peng, Lindsay A. Fox, Sean Higgins, Yousin Suh, Michael Lim, Dan Lockshon, Jin Kim, Jessica Hui, Erica D. Smith, Eunice Choi, Brian Muller, Xinguang Liu, Soumya Kotireddy, Nick Dang, Hillary Miller, Prarthana Pradeep, Di Hu, Brett Robison, Brian K. Kennedy, Matt Kaeberlein, Katie Snead, Michael Sage, Emily O. Kerr, Michael S. Lin, Umema Ahmed, Bie N. Tchao, Jonathan A. Oakes, and Adrienne M. Wang
- Subjects
Aging ,Saccharomyces cerevisiae Proteins ,Physiology ,DNA damage ,Saccharomyces cerevisiae ,Longevity ,Article ,RNA, Transfer ,Animals ,Caenorhabditis elegans ,Molecular Biology ,Transcription factor ,Gene ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Caloric Restriction ,Regulation of gene expression ,Genetics ,Genome ,biology ,TOR Serine-Threonine Kinases ,Cell Biology ,biology.organism_classification ,Yeast ,Nuclear Pore Complex Proteins ,Basic-Leucine Zipper Transcription Factors ,Gene Expression Regulation ,biology.protein ,Gene Deletion ,DNA Damage - Abstract
SummaryMany 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.
- Published
- 2015