Extension of chronological life span in yeast by decreased TOR pathway signaling.

Chronological life span (CLS) in Saccharomyces cerevisiae, defined as the time cells in a stationary phase culture remain viable, has been proposed as a model for the aging of post-mitotic tissues in mammals. We developed a high-throughput assay to determine CLS for approximately 4800 single-gene deletion strains of yeast, and identified long-lived strains carrying mutations in the conserved TOR pathway. TOR signaling regulates multiple cellular processes in response to nutrients, especially amino acids, raising the possibility that decreased TOR signaling mediates life span extension by calorie restriction. In support of this possibility, removal of either asparagine or glutamate from the media significantly increased stationary phase survival. Pharmacological inhibition of TOR signaling by methionine sulfoximine or rapamycin also increased CLS. Decreased TOR activity also promoted increased accumulation of storage carbohydrates and enhanced stress resistance and nuclear relocalization of the stress-related transcription factor Msn2. We propose that up-regulation of a highly conserved response to starvation-induced stress is important for life span extension by decreased TOR signaling in yeast and higher eukaryotes.

[1]  Matt Kaeberlein,et al.  Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients , 2005, Science.

[2]  Chao Cheng,et al.  Sir2 Blocks Extreme Life-Span Extension , 2005, Cell.

[3]  B. Kennedy,et al.  The Enigmatic Role of Sir2 in Aging , 2005, Cell.

[4]  Edward J. Masoro,et al.  Overview of caloric restriction and ageing , 2005, Mechanisms of Ageing and Development.

[5]  G. Ruvkun,et al.  A systematic RNAi screen for longevity genes in C. elegans. , 2005, Genes & development.

[6]  E. Cameroni,et al.  The TOR and EGO protein complexes orchestrate microautophagy in yeast. , 2005, Molecular cell.

[7]  A. Hsu,et al.  New Genes Tied to Endocrine, Metabolic, and Dietary Regulation of Lifespan from a Caenorhabditis elegans Genomic RNAi Screen , 2005, PLoS genetics.

[8]  L. Partridge,et al.  Counting the calories: the role of specific nutrients in extension of life span by food restriction. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[9]  M. Smith-Wheelock,et al.  Methionine‐deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF‐I and insulin levels, and increases hepatocyte MIF levels and stress resistance , 2005, Aging cell.

[10]  M. Hall,et al.  The expanding TOR signaling network. , 2005, Current opinion in cell biology.

[11]  E. Bon,et al.  Gln3p and Nil1p regulation of invertase activity and SUC2 expression in Saccharomyces cerevisiae. , 2005, FEMS yeast research.

[12]  S. W. Oh,et al.  JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[13]  C. Kenyon.  The Plasticity of Aging: Insights from Long-Lived Mutants , 2005, Cell.

[14]  B. Kennedy,et al.  Large-scale identification in yeast of conserved ageing genes , 2005, Mechanisms of Ageing and Development.

[15]  Kathleen Marchal,et al.  PKA and Sch9 control a molecular switch important for the proper adaptation to nutrient availability , 2004, Molecular microbiology.

[16]  E. B. Tahara,et al.  Higher Respiratory Activity Decreases Mitochondrial Reactive Oxygen Release and Increases Life Span in Saccharomyces cerevisiae* , 2004, Journal of Biological Chemistry.

[17]  A. Trančíková,et al.  Production of reactive oxygen species and loss of viability in yeast mitochondrial mutants: protective effect of Bcl-xL. , 2004, FEMS yeast research.

[18]  M. Kaeberlein.  Aging-related research in the "-omics" age. , 2004, Science of aging knowledge environment : SAGE KE.

[19]  M. Tyers,et al.  A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. , 2004, Genes & development.

[20]  David E Hill,et al.  Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. , 2004, Genome research.

[21]  V. Longo.  Ras: the other pro-aging pathway. , 2004, Science of aging knowledge environment : SAGE KE.

[22]  B. Meissner,et al.  Deletion of the Intestinal Peptide Transporter Affects Insulin and TOR Signaling in Caenorhabditis elegans* , 2004, Journal of Biological Chemistry.

[23]  E. Hafen,et al.  Long-Lived Drosophila with Overexpressed dFOXO in Adult Fat Body , 2004, Science.

[24]  M. Tatar,et al.  Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body , 2004, Nature.

[25]  Dagmar Ringe,et al.  “Sleeping Beauty”: Quiescence in Saccharomyces cerevisiae , 2004, Microbiology and Molecular Biology Reviews.

[26]  S. Benzer,et al.  Regulation of Lifespan in Drosophila by Modulation of Genes in the TOR Signaling Pathway , 2004, Current Biology.

[27]  R. Baumeister,et al.  C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. , 2004, Developmental cell.

[28]  I. Komuro,et al.  Akt-Induced Cellular Senescence: Implication for Human Disease , 2004, Cell cycle.

[29]  J. Vaupel,et al.  Chronological aging‐independent replicative life span regulation by Msn2/Msn4 and Sod2 in Saccharomyces cerevisiae , 2004, FEBS letters.

[30]  I. Komuro,et al.  Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21‐dependent pathway , 2004, The EMBO journal.

[31]  T. Schmelzle,et al.  Activation of the RAS/Cyclic AMP Pathway Suppresses a TOR Deficiency in Yeast , 2004, Molecular and Cellular Biology.

[32]  Tibor Vellai,et al.  Genetics: Influence of TOR kinase on lifespan in C. elegans , 2003, Nature.

[33]  E. O’Shea,et al.  Global analysis of protein localization in budding yeast , 2003, Nature.

[34]  Cori Bargmann,et al.  Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans , 2003, Nature.

[35]  V. Longo.  The Ras and Sch9 pathways regulate stress resistance and longevity , 2003, Experimental Gerontology.

[36]  P. Piper,et al.  Mnsod overexpression extends the yeast chronological (G(0)) life span but acts independently of Sir2p histone deacetylase to shorten the replicative life span of dividing cells. , 2003, Free radical biology & medicine.

[37]  Blanka Rogina,et al.  Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. Weindruch,et al.  Caloric restriction increases gluconeogenic and transaminase enzyme activities in mouse liver , 2003, Experimental Gerontology.

[39]  C. Finch,et al.  Evolutionary Medicine: From Dwarf Model Systems to Healthy Centenarians? , 2003, Science.

[40]  Matthias Blüher,et al.  Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue , 2003, Science.

[41]  Y. Dong,et al.  Systematic functional analysis of the Caenorhabditis elegans genome using RNAi , 2003, Nature.

[42]  Martin Holzenberger,et al.  IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice , 2003, Nature.

[43]  A. Diaspro,et al.  SOD2 functions downstream of Sch9 to extend longevity in yeast. , 2003, Genetics.

[44]  D. Goldfarb,et al.  Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. , 2003, Molecular biology of the cell.

[45]  Gary Ruvkun,et al.  A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity , 2003, Nature Genetics.

[46]  B. Rogina,et al.  Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[47]  V. Ganapathy,et al.  Functional identity of Drosophila melanogaster Indy as a cation-independent, electroneutral transporter for tricarboxylic acid-cycle intermediates. , 2002, The Biochemical journal.

[48]  T. Cooper.  Transmitting the signal of excess nitrogen in Saccharomyces cerevisiae from the Tor proteins to the GATA factors: connecting the dots. , 2002, FEMS microbiology reviews.

[49]  V. Longo,et al.  Visions & Reflections¶Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans? , 2002, Cellular and Molecular Life Sciences CMLS.

[50]  J. Crespo,et al.  The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[51]  X. Zheng,et al.  Convergence of TOR-Nitrogen and Snf1-Glucose Signaling Pathways onto Gln3 , 2002, Molecular and Cellular Biology.

[52]  J. Papaconstantinou,et al.  The Snell dwarf mutation Pit1 dw can increase life span in mice , 2002, Mechanisms of Ageing and Development.

[53]  Andrzej Bartke,et al.  Longevity: Extending the lifespan of long-lived mice , 2001, Nature.

[54]  M. McVey,et al.  Using yeast to discover the fountain of youth. , 2001, Science of aging knowledge environment : SAGE KE.

[55]  Richard A. Miller,et al.  Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[56]  V. Longo,et al.  Regulation of Longevity and Stress Resistance by Sch9 in Yeast , 2001, Science.

[57]  P. Piper,et al.  Chronological lifespan of stationary phase yeast cells; a model for investigating the factors that might influence the ageing of postmitotic tissues in higher organisms , 2001, Yeast.

[58]  P. Piper,et al.  Increasing Saccharomyces cerevisiae stress resistance, through the overactivation of the heat shock response resulting from defects in the Hsp90 chaperone, does not extend replicative life span but can be associated with slower chronological ageing of nondividing cells , 2001, Molecular Genetics and Genomics.

[59]  B. Rogina,et al.  Extended life-span conferred by cotransporter gene mutations in Drosophila. , 2000, Science.

[60]  Stuart L. Schreiber,et al.  Partitioning the transcriptional program induced by rapamycin among the effectors of the Tor proteins , 2000, Current Biology.

[61]  S. Jazwinski,et al.  An intervention resembling caloric restriction prolongs life span and retards aging in yeast , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[62]  J. François,et al.  Mitochondrial respiratory mutants of Saccharomyces cerevisiae accumulate glycogen and readily mobilize it in a glucose-depleted medium. , 2000, Microbiology.

[63]  P. Defossez,et al.  Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. , 2000, Science.

[64]  M. Jacquet,et al.  Hyperphosphorylation of Msn2p and Msn4p in response to heat shock and the diauxic shift is inhibited by cAMP in Saccharomyces cerevisiae. , 2000, Microbiology.

[65]  D. Clemmons,et al.  Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. , 2000, Endocrinology.

[66]  J. Heitman,et al.  The TOR signaling cascade regulates gene expression in response to nutrients. , 1999, Genes & development.

[67]  Michael N. Hall,et al.  The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors , 1999, Nature.

[68]  M. McVey,et al.  The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. , 1999, Genes & development.

[69]  Ronald W. Davis,et al.  Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. , 1999, Science.

[70]  L. Guarente,et al.  Passage through stationary phase advances replicative aging in Saccharomyces cerevisiae. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[71]  J. Valentine,et al.  Mitochondrial superoxide decreases yeast survival in stationary phase. , 1999, Archives of biochemistry and biophysics.

[72]  Jinnie M. Garrett,et al.  The Saccharomyces cerevisiae YCC5(YCL025c) Gene Encodes an Amino Acid Permease, Agp1, Which Transports Asparagine and Glutamine , 1998, Journal of bacteriology.

[73]  C. Kenyon,et al.  daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. , 1997, Science.

[74]  G. Ruvkun,et al.  The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans , 1997, Nature.

[75]  Koutarou D. Kimura,et al.  daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. , 1997, Science.

[76]  Andrzej Bartke,et al.  Dwarf mice and the ageing process , 1996, Nature.

[77]  T. Cooper,et al.  G1n3p is capable of binding to UAS(NTR) elements and activating transcription in Saccharomyces cerevisiae , 1996, Journal of bacteriology.

[78]  J S Valentine,et al.  Superoxide Dismutase Activity Is Essential for Stationary Phase Survival in Saccharomyces cerevisiae , 1996, The Journal of Biological Chemistry.

[79]  C. Kenyon.  Ponce d'elegans: Genetic Quest for the Fountain of Youth , 1996, Cell.

[80]  I. Stansfield,et al.  An MBoC Favorite: TOR controls translation initiation and early G1 progression in yeast , 2012, Molecular biology of the cell.

[81]  B. Magasanik,et al.  Role of the GATA factors Gln3p and Nil1p of Saccharomyces cerevisiae in the expression of nitrogen-regulated genes. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[82]  C. Kenyon,et al.  A C. elegans mutant that lives twice as long as wild type , 1993, Nature.

[83]  J. A. Zimmerman,et al.  Low methionine ingestion by rats extends life span. , 1993, The Journal of nutrition.

[84]  Richard Weindruch,et al.  The Retardation of Aging and Disease by Dietary Restriction , 1988 .

[85]  Piotr Mikolajczyk,et al.  A+A+C , 1964 .

[86]  R. Mortimer,et al.  Life Span of Individual Yeast Cells , 1959, Nature.