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

Mark A. McCormick, Joe R. Delaney, Mitsuhiro Tsuchiya, Scott Tsuchiyama, Anna Shemorry, Sylvia Sim, Annie Chia Zong Chou, Umema Ahmed, Daniel Carr, Christopher J. Murakami, Jennifer Schleit, George L. Sutphin, Brian M. Wasko, Christopher F. Bennett, Adrienne M. Wang, Brady Olsen, Richard P. Beyer, Theodor K. Bammler, Donna Prunkard, Simon C. Johnson & 61 others Juniper K. Pennypacker, Elroy An, Arieanna Anies, Anthony S. Castanza, Eunice Choi, Nick Dang, Shiena Enerio, Marissa Fletcher, Lindsay Fox, Sarani Goswami, Sean A. Higgins, Molly A. Holmberg, Di Hu, Jessica Hui, Monika Jelic, Ki Soo Jeong, Elijah Johnston, Emily O. Kerr, Jin Kim, Diana Kim, Katie Kirkland, Shannon Klum, Soumya Kotireddy, Eric Liao, Michael Lim, Michael S. Lin, Winston C. Lo, Dan Lockshon, Hillary A. Miller, Richard M. Moller, Brian Muller, Jonathan Oakes, Diana N. Pak, Zhao Jun Peng, Kim M. Pham, Tom G. Pollard, Prarthana Pradeep, Dillon Pruett, Dilreet Rai, Brett Robison, Ariana A. Rodriguez, Bopharoth Ros, Michael Sage, Manpreet K. Singh, Erica D. Smith, Katie Snead, Amrita Solanky, Benjamin L. Spector, Kristan K. Steffen, Bie Nga Tchao, Marc K. Ting, Helen Vander Wende, Dennis Wang, K. Linnea Welton, Eric A. Westman, Rachel B. Brem, Xin Guang Liu, Yousin Suh, Zhongjun Zhou, Matt Kaeberlein, Brian K. Kennedy

Research output: Contribution to journalArticle

75 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)895-906
Number of pages12
JournalCell Metabolism
Volume22
Issue number5
DOIs
StatePublished - Nov 3 2015

Fingerprint

Gene Deletion
Sirolimus
Transfer RNA
Yeasts
Genome
Saccharomycetales
Cell Nucleus Active Transport
Multigene Family
Transcriptional Activation
DNA Damage
Saccharomyces cerevisiae
Transcription Factors
Genes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

McCormick, M. A., Delaney, J. R., Tsuchiya, M., Tsuchiyama, S., Shemorry, A., Sim, S., ... Kennedy, B. K. (2015). A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging. Cell Metabolism, 22(5), 895-906. https://doi.org/10.1016/j.cmet.2015.09.008

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

In: Cell Metabolism, Vol. 22, No. 5, 03.11.2015, p. 895-906.

Research output: Contribution to journalArticle

McCormick, MA, Delaney, JR, Tsuchiya, M, Tsuchiyama, S, Shemorry, A, Sim, S, Chou, ACZ, Ahmed, U, Carr, D, Murakami, CJ, Schleit, J, Sutphin, GL, Wasko, BM, Bennett, CF, Wang, AM, Olsen, B, Beyer, RP, Bammler, TK, Prunkard, D, Johnson, SC, Pennypacker, JK, An, E, Anies, A, Castanza, AS, Choi, E, Dang, N, Enerio, S, Fletcher, M, Fox, L, Goswami, S, Higgins, SA, Holmberg, MA, Hu, D, Hui, J, Jelic, M, Jeong, KS, Johnston, E, Kerr, EO, Kim, J, Kim, D, Kirkland, K, Klum, S, Kotireddy, S, Liao, E, Lim, M, Lin, MS, Lo, WC, Lockshon, D, Miller, HA, Moller, RM, Muller, B, Oakes, J, Pak, DN, Peng, ZJ, Pham, KM, Pollard, TG, Pradeep, P, Pruett, D, Rai, D, Robison, B, Rodriguez, AA, Ros, B, Sage, M, Singh, MK, Smith, ED, Snead, K, Solanky, A, Spector, BL, Steffen, KK, Tchao, BN, Ting, MK, Vander Wende, H, Wang, D, Welton, KL, Westman, EA, Brem, RB, Liu, XG, Suh, Y, Zhou, Z, Kaeberlein, M & Kennedy, BK 2015, 'A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging', Cell Metabolism, vol. 22, no. 5, pp. 895-906. https://doi.org/10.1016/j.cmet.2015.09.008
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. / A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging. In: Cell Metabolism. 2015 ; Vol. 22, No. 5. pp. 895-906.
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AB - 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.

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