Genome-Wide Analysis of Yeast Aging

Part of the Subcellular Biochemistry book series (SCBI, volume 57)


In the past several decades the budding yeast Saccharomyces cerevisiae has emerged as a prominent model for aging research. The creation of a single-gene deletion collection covering the majority of open reading frames in the yeast genome and advances in genomic technologies have opened yeast research to genome-scale screens for a variety of phenotypes. A number of screens have been performed looking for genes that modify secondary age-associated phenotypes such as stress resistance or growth rate. More recently, moderate-throughput methods for measuring replicative life span and high-throughput methods for measuring chronological life span have allowed for the first unbiased screens aimed at directly identifying genes involved in determining yeast longevity. In this chapter we discuss large-scale life span studies performed in yeast and their implications for research related to the basic biology of aging.


Acetic acid Apoptosis Asymmetric segregation Chronological life span Counter flow centrifugation elutriation (CCE) Dietary restriction (DR) Genome-wide Genomics High-throughput Loss of heterozygosity (LOH) Metabolomics Microarrays Mitochondria Mitochondrial back-signaling Mother Enrichment Program (MEP) Oxidative damage Proteomics Replicative life span Retrograde response Ribosomal DNA (rDNA) Sirtuins Target of rapamycin (TOR) signaling Translation Worms Yeast Outgrowth Data Analysis (YODA) 

Abbreviations and Accronyms


counter flow centrifugation elutriation


dietary restriction


extrachromosomal rDNA circles


false negative rate


false positive rate




long-lived mutant


mother enrichment program


not long-lived


no significant extension


optical density


open reading frame


protein kinase A


reactive oxygen species




silent information regulator


target of rapamycin


upstream open reading frame


  1. Aguilaniu H, Gustafsson L, Rigoulet M, Nystrom T (2003) Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science 299(5613):1751–1753PubMedCrossRefGoogle Scholar
  2. Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423(6936):181–185PubMedCrossRefGoogle Scholar
  3. Arsham AM, Neufeld TP (2006) Thinking globally and acting locally with TOR. Curr Opin Cell Biol 18(6):589–597PubMedCrossRefGoogle Scholar
  4. Bacon JS, Davidson ED, Jones D, Taylor IF (1966) The location of chitin in the yeast cell wall. Biochem J 101(2):36C–38CPubMedGoogle Scholar
  5. Barros MH, Bandy B, Tahara EB, Kowaltowski AJ (2004) Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J Biol Chem 279(48):49883–49888PubMedCrossRefGoogle Scholar
  6. Barton AA (1950) Some aspects of cell division in saccharomyces cerevisiae. J Gen Microbiol 4(1):84–86PubMedGoogle Scholar
  7. Bonawitz ND, Chatenay-Lapointe M, Pan Y, Shadel GS (2007) Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression. Cell Metab 5(4):265–277PubMedCrossRefGoogle Scholar
  8. Borghouts C, Benguria A, Wawryn J, Jazwinski SM (2004) Rtg2 protein links metabolism and genome stability in yeast longevity. Genetics 166(2):765–777PubMedCrossRefGoogle Scholar
  9. Bryk M, Banerjee M, Murphy M, Knudsen KE, Garfinkel DJ, Curcio MJ (1997) Transcriptional silencing of Ty1 elements in the RDN1 locus of yeast. Genes Dev 11(2):255–269PubMedCrossRefGoogle Scholar
  10. Burgering BM, Coffer PJ (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376(6541):599–602PubMedCrossRefGoogle Scholar
  11. Burtner CR, Murakami CJ, Kennedy BK, Kaeberlein M (2009) A molecular mechanism of chronological aging in yeast. Cell Cycle 8(8):1256–1270PubMedCrossRefGoogle Scholar
  12. Burtner CR, Murakami CJ, Olsen B, Kennedy BK, Kaeberlein M (2011) A genomic analysis of chronological longevity factors in budding yeast. Cell Cycle 10(9):1385–1396PubMedCrossRefGoogle Scholar
  13. Buttner S, Eisenberg T, Herker E, Carmona-Gutierrez D, Kroemer G, Madeo F (2006) Why yeast cells can undergo apoptosis: death in times of peace, love, and war. J Cell Biol 175(4):521–525PubMedCrossRefGoogle Scholar
  14. Carr LL, Gottschling DE (2008) Does age influence loss of heterozygosity? Exp Gerontol 43(3):123–129PubMedCrossRefGoogle Scholar
  15. Chen C, Contreras R (2007) Identifying genes that extend life span using a high-throughput screening system. Methods Mol Biol 371:237–248PubMedCrossRefGoogle Scholar
  16. Chen D, Guarente L (2007) SIR2: a potential target for calorie restriction mimetics. Trends Mol Med 13(2):64–71PubMedCrossRefGoogle Scholar
  17. Cheng C, Fabrizio P, Ge H, Longo VD, Li LM (2007a) Inference of transcription modification in long-live yeast strains from their expression profiles. BMC Genomics 8:219PubMedCrossRefGoogle Scholar
  18. Cheng C, Fabrizio P, Ge H, Wei M, Longo VD, Li LM (2007b) Significant and systematic expression differentiation in long-lived yeast strains. PLoS One 2(10):e1095PubMedCrossRefGoogle Scholar
  19. Conrad-Webb H, Butow RA (1995) A polymerase switch in the synthesis of rRNA in Saccharomyces cerevisiae. Mol Cell Biol 15(5):2420–2428PubMedGoogle Scholar
  20. Cuervo AM, Dice JF (2000) Age-related decline in chaperone-mediated autophagy. J Biol Chem 275(40):31505–31513PubMedCrossRefGoogle Scholar
  21. Curran SP, Ruvkun G (2007) Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet 3(4):e56PubMedCrossRefGoogle Scholar
  22. D’Mello NP, Childress AM, Franklin DS, Kale SP, Pinswasdi C, Jazwinski SM (1994) Cloning and characterization of LAG1, a longevity-assurance gene in yeast. J Biol Chem 269(22):15451–15459PubMedGoogle Scholar
  23. Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A et al (2009) Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459(7248):802–807PubMedCrossRefGoogle Scholar
  24. Defossez PA, Prusty R, Kaeberlein M, Lin SJ, Ferrigno P, Silver PA et al (1999) Elimination of replication block protein Fob1 extends the life span of yeast mother cells. Mol Cell 3(4):447–455PubMedCrossRefGoogle Scholar
  25. DePinho RA (2000) The age of cancer. Nature 408(6809):248–254PubMedCrossRefGoogle Scholar
  26. Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG et al (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298(5602):2398–2401PubMedCrossRefGoogle Scholar
  27. Egilmez NK, Chen JB, Jazwinski SM (1990) Preparation and partial characterization of old yeast cells. J Gerontol 45(1):B9–B17PubMedGoogle Scholar
  28. Egilmez NK, Jazwinski SM (1989) Evidence for the involvement of a cytoplasmic factor in the aging of the yeast Saccharomyces cerevisiae. J Bacteriol 171(1):37–42PubMedGoogle Scholar
  29. Eisenberg T, Buttner S, Kroemer G, Madeo F (2007) The mitochondrial pathway in yeast apoptosis. Apoptosis 12(5):1011–1023PubMedCrossRefGoogle Scholar
  30. Eisenberg T, Knauer H, Schauer A, Buttner S, Ruckenstuhl C, Carmona-Gutierrez D et al (2009) Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 11(11):1305–1314PubMedCrossRefGoogle Scholar
  31. Epstein CB, Waddle JA, Hale W t., Dave V, Thornton J, Macatee TL et al (2001) Genome-wide responses to mitochondrial dysfunction. Mol Biol Cell 12(2):297–308PubMedGoogle Scholar
  32. Erjavec N, Larsson L, Grantham J, Nystrom T (2007) Accelerated aging and failure to segregate damaged proteins in Sir2 mutants can be suppressed by overproducing the protein aggregation-remodeling factor Hsp104p. Genes Dev 21(19):2410–2421PubMedCrossRefGoogle Scholar
  33. Erjavec N, Nystrom T (2007) Sir2p-dependent protein segregation gives rise to a superior reactive oxygen species management in the progeny of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 104(26):10877–10881PubMedCrossRefGoogle Scholar
  34. Fabrizio P, Battistella L, Vardavas R, Gattazzo C, Liou LL, Diaspro A et al (2004a) Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae. J Cell Biol 166(7):1055–1067PubMedCrossRefGoogle Scholar
  35. Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, McGrew K et al (2005) Sir2 blocks extreme life-span extension. Cell 123(4):655–667PubMedCrossRefGoogle Scholar
  36. Fabrizio P, Hoon S, Shamalnasab M, Galbani A, Wei M, Giaever G et al (2010) Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation. PLoS Genet 6(7):e1001024PubMedCrossRefGoogle Scholar
  37. Fabrizio P, Liou LL, Moy VN, Diaspro A, Valentine JS, Gralla EB et al (2003) SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163(1):35–46PubMedGoogle Scholar
  38. Fabrizio P, Longo VD (2003) The chronological life span of Saccharomyces cerevisiae. Aging Cell 2(2):73–81PubMedCrossRefGoogle Scholar
  39. Fabrizio P, Longo VD (2007) The chronological life span of Saccharomyces cerevisiae. Methods Mol Biol 371:89–95PubMedCrossRefGoogle Scholar
  40. Fabrizio P, Pletcher SD, Minois N, Vaupel JW, Longo VD (2004b) Chronological aging-independent replicative life span regulation by Msn2/Msn4 and Sod2 in Saccharomyces cerevisiae. FEBS Lett 557(1–3):136–142PubMedCrossRefGoogle Scholar
  41. Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD (2001) Regulation of longevity and stress resistance by Sch9 in yeast. Science 292(5515):288–290PubMedCrossRefGoogle Scholar
  42. Finkel T, Deng CX, Mostoslavsky R (2009) Recent progress in the biology and physiology of sirtuins. Nature 460(7255):587–591PubMedCrossRefGoogle Scholar
  43. Fritze CE, Verschueren K, Strich R, Easton Esposito R (1997) Direct evidence for SIR2 modulation of chromatin structure in yeast rDNA. EMBO J 16(21):6495–6509PubMedCrossRefGoogle Scholar
  44. Frohlich KU, Fussi H, Ruckenstuhl C (2007) Yeast apoptosis – from genes to pathways. Semin Cancer Biol 17(2):112–121PubMedCrossRefGoogle Scholar
  45. Goldberg AA, Bourque SD, Kyryakov P, Gregg C, Boukh-Viner T, Beach A et al (2009) Effect of calorie restriction on the metabolic history of chronologically aging yeast. Exp Gerontol 44(9):555–571PubMedCrossRefGoogle Scholar
  46. Gottlieb S, Esposito RE (1989) A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell 56(5):771–776PubMedCrossRefGoogle Scholar
  47. Gourlay CW, Carpp LN, Timpson P, Winder SJ, Ayscough KR (2004) A role for the actin cytoskeleton in cell death and aging in yeast. J Cell Biol 164(6):803–809PubMedCrossRefGoogle Scholar
  48. Gresham D, Boer VM, Caudy A, Ziv N, Brandt NJ, Storey JD et al (2011) System-level analysis of genes and functions affecting survival during nutrient starvation in Saccharomyces cerevisiae. Genetics 187(1):299–317PubMedCrossRefGoogle Scholar
  49. Hamilton B, Dong Y, Shindo M, Liu W, Odell I, Ruvkun G et al (2005) A systematic RNAi screen for longevity genes in C. elegans. Genes Dev 19(13):1544–1555PubMedCrossRefGoogle Scholar
  50. Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C (2008) A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4(2):e24PubMedCrossRefGoogle Scholar
  51. Hansen M, Hsu AL, Dillin A, Kenyon C (2005) New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet 1(1):119–128PubMedCrossRefGoogle Scholar
  52. Heeren G, Rinnerthaler M, Laun P, Seyerl Pv., Kössler S, Klinger H et al (2009) The mitochondrial ribosomal protein of the large subunit, Afo1p, determines cellular longevity through mitochondrial back‐signaling via TOR1. Aging 1(7):622–636PubMedGoogle Scholar
  53. Hekimi S, Guarente L (2003) Genetics and the specificity of the aging process. Science 299(5611):1351–1354PubMedCrossRefGoogle Scholar
  54. Herker E, Jungwirth H, Lehmann KA, Maldener C, Frohlich KU, Wissing S et al (2004) Chronological aging leads to apoptosis in yeast. J Cell Biol 164(4):501–507PubMedCrossRefGoogle Scholar
  55. Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59:407–450PubMedCrossRefGoogle Scholar
  56. Hosiner D, Lempiainen H, Reiter W, Urban J, Loewith R, Ammerer G et al (2009) Arsenic toxicity to Saccharomyces cerevisiae is a consequence of inhibition of the TORC1 kinase combined with a chronic stress response. Mol Biol Cell 20(3):1048–1057PubMedCrossRefGoogle Scholar
  57. Huang J, Moazed D (2003) Association of the RENT complex with nontranscribed and coding regions of rDNA and a regional requirement for the replication fork block protein Fob1 in rDNA silencing. Genes Dev 17(17):2162–2176PubMedCrossRefGoogle Scholar
  58. Irizarry RA, Warren D, Spencer F, Kim IF, Biswal S, Frank BC et al (2005) Multiple-laboratory comparison of microarray platforms. Nat Methods 2(5):345–350PubMedCrossRefGoogle Scholar
  59. Jazwinski SM (2004) Yeast replicative life span – the mitochondrial connection. FEMS Yeast Res 5(2):119–125PubMedCrossRefGoogle Scholar
  60. Jazwinski SM (2005) Yeast longevity and aging – the mitochondrial connection. Mech Ageing Dev 126(2):243–248PubMedCrossRefGoogle Scholar
  61. Jazwinski SM, Egilmez NK, Chen JB (1989) Replication control and cellular life span. Exp Gerontol 24(5–6):423–436PubMedCrossRefGoogle Scholar
  62. Jia K, Chen D, Riddle DL (2004) The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131(16):3897–3906PubMedCrossRefGoogle Scholar
  63. Jia K, Levine B (2007) Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 3(6):597–599PubMedGoogle Scholar
  64. Jia MH, Larossa RA, Lee JM, Rafalski A, Derose E, Gonye G et al (2000) Global expression profiling of yeast treated with an inhibitor of amino acid biosynthesis, sulfometuron methyl. Physiol Genomics 3(2):83–92PubMedGoogle Scholar
  65. Jiang JC, Jaruga E, Repnevskaya MV, Jazwinski SM (2000) An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J 14(14):2135–2137PubMedGoogle Scholar
  66. Johnston JR (1966) Reproductive capacity and mode of death of yeast cells. Antonie Van Leeuwenhoek 32(1):94–98PubMedCrossRefGoogle Scholar
  67. Jorgensen P, Rupes I, Sharom JR, Schneper L, Broach JR, Tyers M (2004) A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev 18(20):2491–2505PubMedCrossRefGoogle Scholar
  68. Juhasz G, Erdi B, Sass M, Neufeld TP (2007) Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev 21(23):3061–3066PubMedCrossRefGoogle Scholar
  69. Kaeberlein M (2006) Longevity and aging in the budding yeast. In: Conn PM (ed) Handbook of models for human aging. Elsevier, Boston, pp 109–120CrossRefGoogle Scholar
  70. Kaeberlein M, Burtner CR, Kennedy BK (2007) Recent developments in yeast aging. PLoS Genet 3(5):e84PubMedCrossRefGoogle Scholar
  71. Kaeberlein M, Hu D, Kerr EO, Tsuchiya M, Westman EA, Dang N et al (2005a) Increased life span due to calorie restriction in respiratory-deficient yeast. PLoS Genet 1(5):e69PubMedCrossRefGoogle Scholar
  72. Kaeberlein M, Kirkland KT, Fields S, Kennedy BK (2004) Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol 2(9):E296PubMedCrossRefGoogle Scholar
  73. Kaeberlein M, Kirkland KT, Fields S, Kennedy BK (2005b) Genes determining yeast replicative life span in a long-lived genetic background. Mech Ageing Dev 126(4):491–504PubMedCrossRefGoogle Scholar
  74. Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13(19):2570–2580PubMedCrossRefGoogle Scholar
  75. Kaeberlein M, Powers RW 3rd (2007) Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res Rev 6(2):128–140PubMedCrossRefGoogle Scholar
  76. Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N et al (2005c) Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310(5751):1193–1196PubMedCrossRefGoogle Scholar
  77. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S (2004) Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 14(10):885–890PubMedCrossRefGoogle Scholar
  78. Kennedy BK, Austriaco NR Jr, Guarente L (1994) Daughter cells of Saccharomyces cerevisiae from old mothers display a reduced life span. J Cell Biol 127(6 Pt 2):1985–1993PubMedCrossRefGoogle Scholar
  79. Kennedy BK, Austriaco NR Jr, Zhang J, Guarente L (1995) Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 80(3):485–496PubMedCrossRefGoogle Scholar
  80. Kennedy BK, Gotta M, Sinclair DA, Mills K, McNabb DS, Murthy M et al (1997) Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 89(3):381–391PubMedCrossRefGoogle Scholar
  81. Kennedy BK, Smith ED, Kaeberlein M (2005) The enigmatic role of Sir2 in aging. Cell 123(4):548–550PubMedCrossRefGoogle Scholar
  82. Kirchman PA, Kim S, Lai CY, Jazwinski SM (1999) Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics 152(1):179–190PubMedGoogle Scholar
  83. Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8(11):931–937PubMedCrossRefGoogle Scholar
  84. Knudson AG (2001) Two genetic hits (more or less) to cancer. Nat Rev Cancer 1(2):157–162PubMedCrossRefGoogle Scholar
  85. Komeili A, Wedaman KP, O’Shea EK, Powers T (2000) Mechanism of metabolic control: target of rapamycin signaling links nitrogen quality to the activity of the Rtg1 and Rtg3 transcription factors. J Cell Biol 151(4):863–878PubMedCrossRefGoogle Scholar
  86. Komili S, Farny NG, Roth FP, Silver PA (2007) Functional specificity among ribosomal proteins regulates gene expression. Cell 131(3):557–571PubMedCrossRefGoogle Scholar
  87. Korshunov SS, Skulachev VP, Starkov AA (1997) High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416(1):15–18PubMedCrossRefGoogle Scholar
  88. Lai CY, Jaruga E, Borghouts C, Jazwinski SM (2002) A mutation in the ATP2 gene abrogates the age asymmetry between mother and daughter cells of the yeast Saccharomyces cerevisiae. Genetics 162(1):73–87PubMedGoogle Scholar
  89. Lamming DW, Latorre-Esteves M, Medvedik O, Wong SN, Tsang FA, Wang C et al (2005) HST2 mediates SIR2-independent life-span extension by calorie restriction. Science 309(5742):1861–1864PubMedCrossRefGoogle Scholar
  90. Laun P, Pichova A, Madeo F, Fuchs J, Ellinger A, Kohlwein S et al (2001) Aged mother cells of Saccharomyces cerevisiae show markers of oxidative stress and apoptosis. Mol Microbiol 39(5):1166–1173PubMedCrossRefGoogle Scholar
  91. Laun P, Ramachandran L, Jarolim S, Herker E, Liang P, Wang J et al (2005) A comparison of the aging and apoptotic transcriptome of Saccharomyces cerevisiae. FEMS Yeast Res 5(12):1261–1272PubMedCrossRefGoogle Scholar
  92. Lee SE, Paques F, Sylvan J, Haber JE (1999) Role of yeast SIR genes and mating type in directing DNA double-strand breaks to homologous and non-homologous repair paths. Curr Biol 9(14):767–770PubMedCrossRefGoogle Scholar
  93. Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G (2003) A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 33(1):40–48PubMedCrossRefGoogle Scholar
  94. Lesur I, Campbell JL (2004) The transcriptome of prematurely aging yeast cells is similar to that of telomerase-deficient cells. Mol Biol Cell 15(3):1297–1312PubMedCrossRefGoogle Scholar
  95. Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289(5487):2126–2128PubMedCrossRefGoogle Scholar
  96. Lin SJ, Ford E, Haigis M, Liszt G, Guarente L (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 18(1):12–16PubMedCrossRefGoogle Scholar
  97. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC et al (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418(6895):344–348PubMedCrossRefGoogle Scholar
  98. Lin SS, Manchester JK, Gordon JI (2001) Enhanced gluconeogenesis and increased energy storage as hallmarks of aging in Saccharomyces cerevisiae. J Biol Chem 276(38):36000–36007PubMedCrossRefGoogle Scholar
  99. Lindstrom DL, Gottschling DE (2009) The mother enrichment program: a genetic system for facile replicative life span analysis in Saccharomyces cerevisiae. Genetics 183(2):413–422, 411SI–413SIPubMedCrossRefGoogle Scholar
  100. Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51(12):3075–3079PubMedGoogle Scholar
  101. Loeb LA, Loeb KR, Anderson JP (2003) Multiple mutations and cancer. Proc Natl Acad Sci USA 100(3):776–781PubMedCrossRefGoogle Scholar
  102. Longo VD, Ellerby LM, Bredesen DE, Valentine JS, Gralla EB (1997) Human Bcl-2 reverses survival defects in yeast lacking superoxide dismutase and delays death of wild-type yeast. J Cell Biol 137(7):1581–1588PubMedCrossRefGoogle Scholar
  103. Longo VD, Kennedy BK (2006) Sirtuins in aging and age-related disease. Cell 126(2):257–268PubMedCrossRefGoogle Scholar
  104. Ludovico P, Sousa MJ, Silva MT, Leao C, Corte-Real M (2001) Saccharomyces cerevisiae commits to a programmed cell death process in response to acetic acid. Microbiology 147(Pt 9):2409–2415PubMedGoogle Scholar
  105. Managbanag JR, Witten TM, Bonchev D, Fox LA, Tsuchiya M, Kennedy BK et al (2008) Shortest-path network analysis is a useful approach toward identifying genetic determinants of longevity. PLoS One 3(11):e3802PubMedCrossRefGoogle Scholar
  106. Martin DE, Hall MN (2005) The expanding TOR signaling network. Curr Opin Cell Biol 17(2):158–166PubMedCrossRefGoogle Scholar
  107. Martin SG, Laroche T, Suka N, Grunstein M, Gasser SM (1999) Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Cell 97(5):621–633PubMedCrossRefGoogle Scholar
  108. Matecic M, Smith DL, Pan X, Maqani N, Bekiranov S, Boeke JD et al (2010) A microarray-based genetic screen for yeast chronological aging factors. PLoS Genet 6(4):e1000921PubMedCrossRefGoogle Scholar
  109. Matsuura A, Anraku Y (1993) Characterization of the MKS1 gene, a new negative regulator of the Ras-cyclic AMP pathway in Saccharomyces cerevisiae. Mol Gen Genet 238(1–2):6–16PubMedGoogle Scholar
  110. McAinsh AD, Scott-Drew S, Murray JA, Jackson SP (1999) DNA damage triggers disruption of telomeric silencing and Mec1p-dependent relocation of Sir3p. Curr Biol 9(17):963–966PubMedCrossRefGoogle Scholar
  111. McIntosh KB, Warner JR (2007) Yeast ribosomes: variety is the spice of life. Cell 131(3):450–451PubMedCrossRefGoogle Scholar
  112. McMurray MA, Gottschling DE (2003) An age-induced switch to a hyper-recombinational state. Science 301(5641):1908–1911PubMedCrossRefGoogle Scholar
  113. Medvedik O, Lamming DW, Kim KD, Sinclair DA (2007) MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol 5(10):e261PubMedCrossRefGoogle Scholar
  114. Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B (2003) Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301(5638):1387–1391PubMedCrossRefGoogle Scholar
  115. Melov S, Hubbard A (2004) Microarrays as a tool to investigate the biology of aging: a retrospective and a look to the future. Sci Aging Knowledge Environ 2004(42):re7PubMedCrossRefGoogle Scholar
  116. Mills KD, Sinclair DA, Guarente L (1999) MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell 97(5):609–620PubMedCrossRefGoogle Scholar
  117. Morck C, Pilon M (2006) C. elegans feeding defective mutants have shorter body lengths and increased autophagy. BMC Dev Biol 6:39PubMedCrossRefGoogle Scholar
  118. Mortimer RK, Johnston JR (1959) Life span of individual yeast cells. Nature 183(4677):1751–1752PubMedCrossRefGoogle Scholar
  119. Muller I, Zimmermann M, Becker D, Flomer M (1980) Calendar life span versus budding life span of Saccharomyces cerevisiae. Mech Ageing Dev 12(1):47–52PubMedCrossRefGoogle Scholar
  120. Murakami C, Kaeberlein M (2009) Quantifying yeast chronological life span by outgrowth of aged cells. J Vis Exp 27:e1156. doi:10.3791/1156Google Scholar
  121. Murakami CJ, Burtner CR, Kennedy BK, Kaeberlein M (2008) A method for high-throughput quantitative analysis of yeast chronological life span. J Gerontol A Biol Sci Med Sci 63(2):113–121PubMedGoogle Scholar
  122. Murray AW, Szostak JW (1983) Pedigree analysis of plasmid segregation in yeast. Cell 34(3):961–970PubMedCrossRefGoogle Scholar
  123. Natarajan K, Meyer MR, Jackson BM, Slade D, Roberts C, Hinnebusch AG et al (2001) Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. Mol Cell Biol 21(13):4347–4368PubMedCrossRefGoogle Scholar
  124. Nestelbacher R, Laun P, Vondrakova D, Pichova A, Schuller C, Breitenbach M (2000) The influence of oxygen toxicity on yeast mother cell-specific aging. Exp Gerontol 35(1):63–70PubMedCrossRefGoogle Scholar
  125. Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273(7):3963–3966PubMedCrossRefGoogle Scholar
  126. Nowak MA, Komarova NL, Sengupta A, Jallepalli PV, Shih Ie M, Vogelstein B et al (2002) The role of chromosomal instability in tumor initiation. Proc Natl Acad Sci USA 99(25):16226–16231PubMedCrossRefGoogle Scholar
  127. Nystrom T (2005) Role of oxidative carbonylation in protein quality control and senescence. EMBO J 24(7):1311–1317PubMedCrossRefGoogle Scholar
  128. Oberdoerffer P, Michan S, McVay M, Mostoslavsky R, Vann J, Park SK et al (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135(5):907–918PubMedCrossRefGoogle Scholar
  129. Olsen B, Murakami CJ, Kaeberlein M (2010) YODA: software to facilitate high-throughput analysis of chronological life span, growth rate, and survival in budding yeast. BMC Bioinformatics 11:141PubMedCrossRefGoogle Scholar
  130. Pan KZ, Palter JE, Rogers AN, Olsen A, Chen D, Lithgow GJ et al (2007) Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6(1):111–119PubMedCrossRefGoogle Scholar
  131. Paradis S, Ruvkun G (1998) Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12(16):2488–2498PubMedCrossRefGoogle Scholar
  132. Patil CK, Li H, Walter P (2004) Gcn4p and novel upstream activating sequences regulate targets of the unfolded protein response. PLoS Biol 2(8):E246PubMedCrossRefGoogle Scholar
  133. Pedruzzi I, Dubouloz F, Cameroni E, Wanke V, Roosen J, Winderickx J et al (2003) TOR and PKA signaling pathways converge on the protein kinase Rim15 to control entry into G0. Mol Cell 12(6):1607–1613PubMedCrossRefGoogle Scholar
  134. Petes TD, Botstein D (1977) Simple Mendelian inheritance of the reiterated ribosomal DNA of yeast. Proc Natl Acad Sci USA 74(11):5091–5095PubMedCrossRefGoogle Scholar
  135. Philippsen P, Thomas M, Kramer RA, Davis RW (1978) Unique arrangement of coding sequences for 5 S, 58 S, 18 S and 25 S ribosomal RNA in Saccharomyces cerevisiae as determined by R-loop and hybridization analysis. J Mol Biol 123(3):387–404PubMedCrossRefGoogle Scholar
  136. Pierce MM, Maddelein ML, Roberts BT, Wickner RB (2001) A novel Rtg2p activity regulates nitrogen catabolism in yeast. Proc Natl Acad Sci USA 98(23):13213–13218PubMedCrossRefGoogle Scholar
  137. Piper PW, Harris NL, MacLean M (2006) Preadaptation to efficient respiratory maintenance is essential both for maximal longevity and the retention of replicative potential in chronologically ageing yeast. Mech Ageing Dev 127(9):733–740PubMedCrossRefGoogle Scholar
  138. Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20(2):174–184PubMedCrossRefGoogle Scholar
  139. Powers T (2007) TOR signaling and S6 kinase 1: yeast catches up. Cell Metab 6(1):1–2PubMedCrossRefGoogle Scholar
  140. Powers T, Dilova I, Chen CY, Wedaman K (2004) Yeast TOR signaling: a mechanism for metabolic regulation. Curr Top Microbiol Immunol 279:39–51PubMedCrossRefGoogle Scholar
  141. Que QQ, Winzeler EA (2002) Large-scale mutagenesis and functional genomics in yeast. Funct Integr Genomics 2(4–5):193–198PubMedCrossRefGoogle Scholar
  142. Riesen M, Morgan A (2009) Calorie restriction reduces rDNA recombination independently of rDNA silencing. Aging Cell 8(6):624–632PubMedCrossRefGoogle Scholar
  143. Rodriguez A, De la Cera T, Herrero P, Moreno F (2001) The hexokinase 2 protein regulates the expression of the GLK1, HXK1 and HXK2 genes of Saccharomyces cerevisiae. Biochem J 355:625–631PubMedGoogle Scholar
  144. Rusche LN, Kirchmaier AL, Rine J (2003) The establishment, inheritance, and function of silenced chromatin in Saccharomyces cerevisiae. Annu Rev Biochem 72:481–516PubMedCrossRefGoogle Scholar
  145. Rustchenko EP, Sherman F (1994) Physical constitution of ribosomal genes in common strains of Saccharomyces cerevisiae. Yeast 10(9):1157–1171PubMedCrossRefGoogle Scholar
  146. Scherens B, Goffeau A (2004) The uses of genome-wide yeast mutant collections. Genome Biol 5(7):229PubMedCrossRefGoogle Scholar
  147. Seichertova O, Beran K, Holan Z, Pokorny V (1973) The chitin-glucan complex of Saccharomyces cerevisiae. II. Location of the complex in the encircling region of the bud sear. Folia Microbiol (Praha) 18(3):207–211CrossRefGoogle Scholar
  148. Seo JG, Lai CY, Miceli MV, Jazwinski SM (2007) A novel role of peroxin PEX6: suppression of aging defects in mitochondria. Aging Cell 6(3):405–413PubMedCrossRefGoogle Scholar
  149. Sinclair DA (2005) Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev 126(9):987–1002PubMedCrossRefGoogle Scholar
  150. Sinclair DA, Guarente L (1997) Extrachromosomal rDNA circles – a cause of aging in yeast. Cell 91(7):1033–1042PubMedCrossRefGoogle Scholar
  151. Sloot PM, Van der Donk EH, Figdor CG (1988) Computer-assisted centrifugal elutriation. II. Multiparametric statistical analysis. Comput Methods Programs Biomed 27(1):37–46PubMedCrossRefGoogle Scholar
  152. Smeal T, Claus J, Kennedy B, Cole F, Guarente L (1996) Loss of transcriptional silencing causes sterility in old mother cells of S. cerevisiae. Cell 84(4):633–642PubMedCrossRefGoogle Scholar
  153. Smets B, De Snijder P, Engelen K, Joossens E, Ghillebert R, Thevissen K et al (2008) Genome-wide expression analysis reveals TORC1-dependent and -independent functions of Sch9. FEMS Yeast Res 8(8):1276–1288PubMedCrossRefGoogle Scholar
  154. Smith DL Jr, Li C, Matecic M, Maqani N, Bryk M, Smith JS (2009) Calorie restriction effects on silencing and recombination at the yeast rDNA. Aging Cell 8(6):633–642PubMedCrossRefGoogle Scholar
  155. Smith DL Jr, McClure JM, Matecic M, Smith JS (2007) Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins. Aging Cell 6(5):649–662PubMedCrossRefGoogle Scholar
  156. Smith ED, Kennedy BK, Kaeberlein M (2007) Genome-wide identification of conserved longevity genes in yeast and worms. Mech Ageing Dev 128(1):106–111PubMedCrossRefGoogle Scholar
  157. Smith ED, Tsuchiya M, Fox LA, Dang N, Hu D, Kerr EO et al (2008) Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res 18(4):564–570PubMedCrossRefGoogle Scholar
  158. Smith JS, Boeke JD (1997) An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev 11(2):241–254PubMedCrossRefGoogle Scholar
  159. Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK (2009) The TOR pathway comes of age. Biochim Biophys Acta 1790(10):1067–1074PubMedCrossRefGoogle Scholar
  160. Starkov AA (1997) “Mild” uncoupling of mitochondria. Biosci Rep 17(3):273–279PubMedCrossRefGoogle Scholar
  161. Steffen KK, Kennedy BK, Kaeberlein M (2009) Measuring replicative life span in the budding yeast. J Vis Exp 28:e1209. doi:10.3791/1209Google Scholar
  162. Steffen KK, MacKay VL, Kerr EO, Tsuchiya M, Hu D, Fox LA et al (2008) Yeast life span extension by depletion of 60 s ribosomal subunits is mediated by Gcn4. Cell 133(2):292–302PubMedCrossRefGoogle Scholar
  163. Steinkraus KA, Kaeberlein M, Kennedy BK (2008) Replicative aging in yeast: the means to the end. Annu Rev Cell Dev Biol 24:29–54PubMedCrossRefGoogle Scholar
  164. Swinnen E, Wanke V, Roosen J, Smets B, Dubouloz F, Pedruzzi I et al (2006) Rim15 and the crossroads of nutrient signalling pathways in Saccharomyces cerevisiae. Cell Div 1:3PubMedCrossRefGoogle Scholar
  165. ‘t Hoen PA, Ariyurek Y, Thygesen HH, Vreugdenhil E, Vossen RH, de Menezes RX et al (2008) Deep sequencing-based expression analysis shows major advances in robustness, resolution and inter-lab portability over five microarray platforms. Nucleic Acids Res 36(21):e141PubMedCrossRefGoogle Scholar
  166. Takeshige K, Baba M, Tsuboi S, Noda T, Ohsumi Y (1992) Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 119(2):301–311PubMedCrossRefGoogle Scholar
  167. Tamburini BA, Tyler JK (2005) Localized histone acetylation and deacetylation triggered by the homologous recombination pathway of double-strand DNA repair. Mol Cell Biol 25(12):4903–4913PubMedCrossRefGoogle Scholar
  168. Tate JJ, Cooper TG (2003) Tor1/2 regulation of retrograde gene expression in Saccharomyces cerevisiae derives indirectly as a consequence of alterations in ammonia metabolism. J Biol Chem 278(38):36924–36933PubMedCrossRefGoogle Scholar
  169. Tsuchiya M, Dang N, Kerr EO, Hu D, Steffen KK, Oakes JA et al (2006) Sirtuin-independent effects of nicotinamide on lifespan extension from calorie restriction in yeast. Aging Cell 5(6):505–514PubMedCrossRefGoogle Scholar
  170. Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O et al (2007) Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell 26(5):663–674PubMedCrossRefGoogle Scholar
  171. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F (2003) Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426(6967):620PubMedCrossRefGoogle Scholar
  172. Vilela C, McCarthy JE (2003) Regulation of fungal gene expression via short open reading frames in the mRNA 5’untranslated region. Mol Microbiol 49(4):859–867PubMedCrossRefGoogle Scholar
  173. Walsh RB, Clifton D, Horak J, Fraenkel DG (1991) Saccharomyces cerevisiae null mutants in glucose phosphorylation: metabolism and invertase expression. Genetics 128:521–527PubMedGoogle Scholar
  174. Walsh RB, Kawasaki G, Fraenkel DG (1983) Cloning of genes that complement yeast hexokinase and glucokinase mutants. J Bacteriol 154(2):1002–1004PubMedGoogle Scholar
  175. Wang CL, Landry J, Sternglanz R (2008) A yeast sir2 mutant temperature sensitive for silencing. Genetics 180(4):1955–1962PubMedCrossRefGoogle Scholar
  176. Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L et al (2008) Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet 4(1):e13PubMedCrossRefGoogle Scholar
  177. Wei M, Fabrizio P, Madia F, Hu J, Ge H, Li LM et al (2009) Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension. PLoS Genet 5(5):e1000467PubMedCrossRefGoogle Scholar
  178. Winzeler EA, Shoemaker DD, Astromoff A, Liang H, Anderson K, Andre B et al (1999) Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285(5429):901–906PubMedCrossRefGoogle Scholar
  179. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124(3):471–484PubMedCrossRefGoogle Scholar
  180. Zhang Z, Dietrich FS (2005) Identification and characterization of upstream open reading frames (uORF) in the 5’ untranslated regions (UTR) of genes in Saccharomyces cerevisiae. Curr Genet 48(2):77–87PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Department of PathologyUniversity of WashingtonSeattleUSA
  2. 2.Buck InstituteNovatoUSA
  3. 3.Department of Pathology and the Molecular and Cellular Biology ProgramUniversity of WashingtonSeattleUSA

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