title: 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.
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McCormick
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Joe R
authors.initials: JR
authors.lastname: Delaney
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tsuchiya
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Tsuchiyama
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Shemorry
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Sim
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Annie Chia-Zong
authors.initials: AC
authors.lastname: Chou
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Umema
authors.initials: U
authors.lastname: Ahmed
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carr
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Murakami
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schleit
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Sutphin
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Wasko
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Adrienne M
authors.initials: AM
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Brady
authors.initials: B
authors.lastname: Olsen
authors.affiliation: Department of Occupational and Environmental Health Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.affiliation: Department of Occupational and Environmental Health Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Theodor K
authors.initials: TK
authors.lastname: Bammler
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Prunkard
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
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authors.initials: SC
authors.lastname: Johnson
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
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authors.initials: JK
authors.lastname: Pennypacker
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Elroy
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authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Arieanna
authors.initials: A
authors.lastname: Anies
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Castanza
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Eunice
authors.initials: E
authors.lastname: Choi
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Nick
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authors.lastname: Dang
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Shiena
authors.initials: S
authors.lastname: Enerio
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Marissa
authors.initials: M
authors.lastname: Fletcher
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Fox
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sarani
authors.initials: S
authors.lastname: Goswami
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Higgins
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Holmberg
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jessica
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Monika
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authors.lastname: Jelic
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ki-Soo
authors.initials: KS
authors.lastname: Jeong
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Elijah
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authors.lastname: Johnston
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Emily O
authors.initials: EO
authors.lastname: Kerr
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.lastname: Kim
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Kirkland
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
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authors.initials: S
authors.lastname: Klum
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Soumya
authors.initials: S
authors.lastname: Kotireddy
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Eric
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.initials: M
authors.lastname: Lim
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
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authors.initials: MS
authors.lastname: Lin
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Winston C
authors.initials: WC
authors.lastname: Lo
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
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authors.initials: D
authors.lastname: Lockshon
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Hillary A
authors.initials: HA
authors.lastname: Miller
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Moller
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Muller
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.initials: J
authors.lastname: Oakes
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Diana N
authors.initials: DN
authors.lastname: Pak
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Zhao Jun
authors.initials: ZJ
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authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
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authors.initials: KM
authors.lastname: Pham
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.initials: TG
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.lastname: Pradeep
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.initials: D
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Dilreet
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authors.lastname: Rai
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
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authors.lastname: Robison
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Ariana A
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authors.lastname: Rodriguez
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.initials: MK
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authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
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authors.initials: ED
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
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authors.initials: BL
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authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
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authors.initials: KK
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authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
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authors.initials: BN
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authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
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authors.initials: MK
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authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
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authors.initials: H
authors.lastname: Vander Wende
authors.affiliation: Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Dennis
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authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: K Linnea
authors.initials: KL
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authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Westman
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945, USA.
authors.forename: Rachel B
authors.initials: RB
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authors.affiliation: Aging Research Institute, Guangdong Medical College, Dongguan 523808, Guangdong, P.R. China.
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authors.initials: XG
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.affiliation: Department of Biochemistry, University of Hong Kong, Hong Kong.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address: kaeber@uw.edu.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.affiliation: 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.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics; D031204:Caloric Restriction; D004249:DNA Damage / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D016678:Genome; D008136:Longevity / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D012343:RNA, Transfer / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C501391:GCN4 protein, S cerevisiae; C408090:Los1 protein, S cerevisiae; D028861:Nuclear Pore Complex Proteins; D029701:Saccharomyces cerevisiae Proteins; D012343:RNA, Transfer; D058570:TOR Serine-Threonine Kinases