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

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.

SUBMITTER: McCormick MA

PROVIDER: S-EPMC4862740 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

McCormick Mark A MA Delaney Joe R JR Tsuchiya Mitsuhiro M Tsuchiyama Scott S Shemorry Anna A Sim Sylvia S Chou Annie Chia-Zong AC Ahmed Umema U Carr Daniel D Murakami Christopher J CJ Schleit Jennifer J Sutphin George L GL Wasko Brian M BM Bennett Christopher F CF Wang Adrienne M AM Olsen Brady B Beyer Richard P RP Bammler Theodor K TK Prunkard Donna D Johnson Simon C SC Pennypacker Juniper K JK An Elroy E Anies Arieanna A Castanza Anthony S AS Choi Eunice E Dang Nick N Enerio Shiena S Fletcher Marissa M Fox Lindsay L Goswami Sarani S Higgins Sean A SA Holmberg Molly A MA Hu Di D Hui Jessica J Jelic Monika M Jeong Ki-Soo KS Johnston Elijah E Kerr Emily O EO Kim Jin J Kim Diana D Kirkland Katie K Klum Shannon S Kotireddy Soumya S Liao Eric E Lim Michael M Lin Michael S MS Lo Winston C WC Lockshon Dan D Miller Hillary A HA Moller Richard M RM Muller Brian B Oakes Jonathan J Pak Diana N DN Peng Zhao Jun ZJ Pham Kim M KM Pollard Tom G TG Pradeep Prarthana P Pruett Dillon D Rai Dilreet D Robison Brett B Rodriguez Ariana A AA Ros Bopharoth B Sage Michael M Singh Manpreet K MK Smith Erica D ED Snead Katie K Solanky Amrita A Spector Benjamin L BL Steffen Kristan K KK Tchao Bie Nga BN Ting Marc K MK Vander Wende Helen H Wang Dennis D Welton K Linnea KL Westman Eric A EA Brem Rachel B RB Liu Xin-Guang XG Suh Yousin Y Zhou Zhongjun Z Kaeberlein Matt M Kennedy Brian K BK

Cell metabolism 20151008 5

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, deleti ...[more]

PMID: 26456335

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Project description:Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS-related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans.

Dataset Information

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

Publications

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

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