Genetics of Life Span: Lessons from Model Organisms

  • José Marín-García
  • Michael J. Goldenthal
  • Gordon W. Moe


Life Span Caenorhabditis Elegans Werner Syndrome Extend Life Span Increase Life Span 


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  1. 1.
    Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. DAF-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997;277:942–946PubMedGoogle Scholar
  2. 2.
    Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature 1993;366:461–464PubMedGoogle Scholar
  3. 3.
    Apfeld J, Kenyon C. Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span. Cell 1998;95:199–210PubMedGoogle Scholar
  4. 4.
    Lin K, Dorman JB, Rodan A, Kenyon C. daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 1997;278:1319–1322PubMedGoogle Scholar
  5. 5.
    Lee RY, Hench J, Ruvkun G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr Biol 2001;11:1950–1957PubMedGoogle Scholar
  6. 6.
    Hsu AL, Murphy CT, Kenyon C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 2003;300:1142–1145PubMedGoogle Scholar
  7. 7.
    Morley JF, Morimoto RI. Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol Biol Cell 2004;15:657–664PubMedGoogle Scholar
  8. 8.
    Lin K, Hsin H, Libina N, Kenyon C. Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling. Nat Genet 2001;28:139–145PubMedGoogle Scholar
  9. 9.
    Apfeld J, O’Connor G, McDonagh T, DiStefano PS, Curtis R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 2004;18:3004–3009PubMedGoogle Scholar
  10. 10.
    Curtis R, O’Connor G, DiStefano PS. Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 2006;5:119–126PubMedGoogle Scholar
  11. 11.
    Dorman JB, Albinder B, Shroyer T, Kenyon C. The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 1995;141:1399–1406PubMedGoogle Scholar
  12. 12.
    Johnson TE, Tedesco PM, Lithgow GJ. Comparing mutants, selective breeding, and transgenics in the dissection of aging processes of Caenorhabditis elegans. Genetica 1993;91:65–77PubMedGoogle Scholar
  13. 13.
    Dillin A, Crawford DK, Kenyon C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 2002;298:830–834PubMedGoogle Scholar
  14. 14.
    Rouault JP, Kuwabara PE, Sinilnikova OM, Duret L, Thierry-Mieg D, Billaud M. Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN. Curr Biol 1999;9:329–332PubMedGoogle Scholar
  15. 15.
    Mihaylova VT, Borland CZ, Manjarrez L, Stern MJ, Sun H. The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Natl Acad Sci USA 1999;96:7427–7432PubMedGoogle Scholar
  16. 16.
    Solari F, Bourbon-Piffaut A, Masse I, Payrastre B, Chan AM, Billaud M. The human tumour suppressor PTEN regulates longevity and dauer formation in Caenorhabditis elegans. Oncogene 2005;24:20–27PubMedGoogle Scholar
  17. 17.
    McElwee J, Bubb K, Thomas JH. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2003;2:111–121PubMedGoogle Scholar
  18. 18.
    Lee SS, Kennedy S, Tolonen AC, Ruvkun G. DAF-16 target genes that control C. elegans life-span and metabolism. Science 2003;300:644–647PubMedGoogle Scholar
  19. 19.
    Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 2003;424:277–283PubMedGoogle Scholar
  20. 20.
    Walker GA, Lithgow GJ. Lifespan extension in C. elegans by a molecular chaperone dependent upon insulin-like signals. Aging Cell 2003;2:131–139PubMedGoogle Scholar
  21. 21.
    Kenyon C. The plasticity of aging: insights from long-lived mutants. Cell 2005;120:449–460PubMedGoogle Scholar
  22. 22.
    Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 2003;424:277–283PubMedGoogle Scholar
  23. 23.
    Rea S, Johnson TE. A metabolic model for life span determination in Caenorhabditis elegans. Dev Cell 2003;5:197–203PubMedGoogle Scholar
  24. 24.
    Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell 2005;120:483–495PubMedGoogle Scholar
  25. 25.
    McElwee JJ, Schuster E, Blanc E, Thornton J, Gems D. Diapause-associated metabolic traits reiterated in long-lived daf-2 mutants in the nematode Caenorhabditis elegans. Mech Ageing Dev 2006;127:458–472PubMedGoogle Scholar
  26. 26.
    Wadsworth WG, Riddle DL. Developmental regulation of energy metabolism in Caenorhabditis elegans. Dev Biol 1989;132:167–173PubMedGoogle Scholar
  27. 27.
    Holt SJ, Riddle DL. SAGE surveys C. elegans carbohydrate metabolism: evidence for an anaerobic shift in the long-lived dauer larva. Mech Ageing Dev 2003;124:779–800PubMedGoogle Scholar
  28. 28.
    Gems D, Sutton AJ, Sundermeyer ML, Albert PS, King KV, Edgley ML, Larsen PL, Riddle DL. Two pleiotropic classes of daf-2 mutation affect larval arrest, adult behavior, reproduction and longevity in Caenorhabditis elegans. Genetics 1998;150:129–155PubMedGoogle Scholar
  29. 29.
    Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 2001;292:107–110PubMedGoogle Scholar
  30. 30.
    Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 2001;292:104–106PubMedGoogle Scholar
  31. 31.
    Richardson A, Liu F, Adamo ML, Van Remmen H, Nelson JF. The role of insulin and insulin-like growth factor-I in mammalian ageing. Best Pract Res Clin Endocrinol Metab 2004;18:393–406PubMedGoogle Scholar
  32. 32.
    Hsieh CC, DeFord JH, Flurkey K, Harrison DE, Papaconstantinou J. Effects of the Pit1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse. Mech Ageing Dev 2002;123:1245–1255PubMedGoogle Scholar
  33. 33.
    Flurkey K, Papaconstantinou J, Miller RA, Harrison DE. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 2001;98:6736–6741PubMedGoogle Scholar
  34. 34.
    Coschigano KT, Clemmons D, Bellush LL, Kopchick JJ. Assessment of growth parameters and life span of GHR/BP gene-disrupted mice. Endocrinology 2000;141:2608–2613PubMedGoogle Scholar
  35. 35.
    Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 2003;421:125–126Google Scholar
  36. 36.
    Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 1998;2:559–569PubMedGoogle Scholar
  37. 37.
    Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 2000;289:2122–2125PubMedGoogle Scholar
  38. 38.
    Bluher M, Kahn BB, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 2003;299:572–574PubMedGoogle Scholar
  39. 39.
    Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P, Asico LD, Jose PA, Taylor SI, Westphal H. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet 1996;12:106–109PubMedGoogle Scholar
  40. 40.
    Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 1993;75:59–72PubMedGoogle Scholar
  41. 41.
    Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M. Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829–1833PubMedGoogle Scholar
  42. 42.
    Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997;390:45–51PubMedGoogle Scholar
  43. 43.
    Nabeshima Y. Toward a better understanding of Klotho. Sci Aging Knowledge Environ 2006;,v>2006:pe11Google Scholar
  44. 44.
    Mori K, Yahata K, Mukoyama M, Suganami T, Makino H, Nagae T, Masuzaki H, Ogawa Y, Sugawara A, Nabeshima Y, Nakao K. Disruption of klotho gene causes an abnormal energy homeostasis in mice. Biochem Biophys Res Commun 2000;278:665–667PubMedGoogle Scholar
  45. 45.
    Bartke A. Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging. Trends Endocrinol Metab 2006;17:33–35PubMedGoogle Scholar
  46. 46.
    Yamamoto M, Clark JD, Pastor JV, Gurnani P, Nandi A, Kurosu H, Miyoshi M, Ogawa Y, Castrillon DH, Rosenblatt KP, Kuro-o M. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 2005;280:38029–38034PubMedGoogle Scholar
  47. 47.
    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004;113:561–568PubMedGoogle Scholar
  48. 48.
    Razzaque MS, Sitara D, Taguchi T, St-Arnaud R, Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 2006;20:720–722PubMedGoogle Scholar
  49. 49.
    Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006;281:6120–6123PubMedGoogle Scholar
  50. 50.
    Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003;17:2393–2403PubMedGoogle Scholar
  51. 51.
    Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG. The beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 2005;310:490–493PubMedGoogle Scholar
  52. 52.
    Libina N, Berman JR, Kenyon C. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Cell 2003;115:489–502PubMedGoogle Scholar
  53. 53.
    Masse I, Molin L, Billaud M, Solari F. Lifespan and dauer regulation by tissue-specific activities of Caenorhabditis elegans DAF-18. Dev Biol 2005;286:91–101PubMedGoogle Scholar
  54. 54.
    Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 2004;429:562–566PubMedGoogle Scholar
  55. 55.
    Kloting N, Bluher M. Extended longevity and insulin signaling in adipose tissue. Exp Gerontol 2005;40:878–883PubMedGoogle Scholar
  56. 56.
    Feng J, Bussiere F, Hekimi S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev Cell 2001;1:633–644PubMedGoogle Scholar
  57. 57.
    Dillin A, Hsu AL, Arantes-Oliveira N, Lehrer-Graiwer J, Hsin H, Fraser AG, Kamath RS, Ahringer J, Kenyon C. Rates of behavior and aging specified by mitochondrial function during development. Science 2002;298:2398–2401PubMedGoogle Scholar
  58. 58.
    Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 2003;33:40–48PubMedGoogle Scholar
  59. 59.
    Anson RM, Hansford RG. Mitochondrial influence on aging rate in Caenorhabditis elegans. Aging Cell 2004;3:29–34PubMedGoogle Scholar
  60. 60.
    Lakowski B, Hekimi S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science 1996;272:1010–1013PubMedGoogle Scholar
  61. 61.
    Felkai S, Ewbank JJ, Lemieux J, Labbe JC, Brown GG, Hekimi S. CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans. EMBO J 1999;18:1783–1792PubMedGoogle Scholar
  62. 62.
    Ewbank JJ, Barnes TM, Lakowski B, Lussier M, Bussey H, Hekimi S. Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science 1997;275:980–983PubMedGoogle Scholar
  63. 63.
    Braeckman BP, Houthoofd K, Brys K, Lenaerts I, De Vreese A, Van Eygen S, Raes H, Vanfleteren JR. No reduction of energy metabolism in Clk mutants. Mech Ageing Dev 2002;123:1447–1456PubMedGoogle Scholar
  64. 64.
    Kayser EB, Sedensky MM, Morgan PG, Hoppel CL. Mitochondrial oxidative phosphory-lation is defective in the long-lived mutant clk-1. J Biol Chem 2004;279:54479–54486PubMedGoogle Scholar
  65. 65.
    Asencio C, Rodriguez-Aguilera JC, Ruiz-Ferrer M, Vela J, Navas P. Silencing of ubiquinone biosynthesis genes extends life span in Caenorhabditis elegans. FASEB J 2003;17:1135–1137PubMedGoogle Scholar
  66. 66.
    Larsen PL, Clarke CF. Extension of life-span in Caenorhabditis elegans by a diet lacking coenzyme Q. Science 2002;295:120–123PubMedGoogle Scholar
  67. 67.
    Rodriguez-Aguilera JC, Gavilan A, Asencio C, Navas P. The role of ubiquinone in Caenorhabditis elegans longevity. Ageing Res Rev 2005;4:41–53PubMedGoogle Scholar
  68. 68.
    Shibata Y, Branicky R, Landaverde IO, Hekimi S. Redox regulation of germline and vulval development in Caenorhabditis elegans. Science 2003;302:1779–1782PubMedGoogle Scholar
  69. 69.
    Vajo Z, King LM, Jonassen T, Wilkin DJ, Ho N, Munnich A, Clarke CF, Francomano CA. Conservation of the Caenorhabditis elegans timing gene clk-1 from yeast to human: a gene required for ubiquinone biosynthesis with potential implications for aging. Mamm Genome 1999;10:1000–1004PubMedGoogle Scholar
  70. 70.
    Takahashi M, Asaumi S, Honda S, Suzuki Y, Nakai D, Kuroyanagi H, Shimizu T, Honda Y, Shirasawa T. Mouse coq7/clk-1 orthologue rescued slowed rhythmic behavior and extended life span of clk-1 longevity mutant in Caenorhabditis elegans. Biochem Biophys Res Commun 2001;286:534–540PubMedGoogle Scholar
  71. 71.
    Nakai D, Shimizu T, Nojiri H, Uchiyama S, Koike H, Takahashi M, Hirokawa K, Shirasawa T. coq7/clk-1 regulates mitochondrial respiration and the generation of reactive oxygen species via coenzyme Q. Aging Cell 2004;3:273–281PubMedGoogle Scholar
  72. 72.
    Levavasseur F, Miyadera H, Sirois J, Tremblay ML, Kita K, Shoubridge E, Hekimi S. Ubiquinone is necessary for mouse embryonic development but is not essential for mitochondrial respiration. J Biol Chem 2001;276:46160–46164PubMedGoogle Scholar
  73. 73.
    Liu X, Jiang N, Hughes B, Bigras E, Shoubridge E, Hekimi S. Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes Dev 2005;19:2424–2434PubMedGoogle Scholar
  74. 74.
    Ishii N, Takahashi K, Tomita S, Keino T, Honda S, Yoshino K, Suzuki K. A methyl viologen-sensitive mutant of the nematode Caenorhabditis elegans. Mutat Res 1990;237:165–171PubMedGoogle Scholar
  75. 75.
    Honda S, Ishii N, Suzuki K, Matsuo M. Oxygen-dependent perturbation of life span and aging rate in the nematode. J Gerontol 1993;48:B57–B61PubMedGoogle Scholar
  76. 76.
    Ishii N, Fujii M, Hartman PS, Tsuda M, Yasuda K, Senoo-Matsuda N, Yanase S, Ayusawa D, Suzuki K. A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes. Nature 1998;394:694–697PubMedGoogle Scholar
  77. 77.
    Senoo-Matsuda N, Yasuda K, Tsuda M, Ohkubo T, Yoshimura S, Nakazawa H, Hartman PS, Ishii N. A defect in the cytochrome b large subunit in complex II causes both superoxide anion overproduction and abnormal energy metabolism in Caenorhabditis elegans. J Biol Chem 2001;276:41553–41558PubMedGoogle Scholar
  78. 78.
    Senoo-Matsuda N, Hartman PS, Akatsuka A, Yoshimura S, Ishii N. A complex II defect affects mitochondrial structure, leading to ced-3- and ced-4-dependent apoptosis and aging. J Biol Chem 2003;278:22031–22036PubMedGoogle Scholar
  79. 79.
    Hartman P, Ponder R, Lo HH, Ishii N. Mitochondrial oxidative stress can lead to nuclear hypermutability. Mech Ageing Dev 2004;125:417–420PubMedGoogle Scholar
  80. 80.
    Ishii N, Senoo-Matsuda N, Miyake K, Yasuda K, Ishii T, Hartman PS, Furukawa S. Coenzyme Q10 can prolong C. elegans lifespan by lowering oxidative stress. Mech Ageing Dev 2004;125:41–46PubMedGoogle Scholar
  81. 81.
    Kayser EB, Morgan PG, Sedensky MM. GAS-1: a mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans. Anesthesiology 1999;90:545–554PubMedGoogle Scholar
  82. 82.
    Kayser EB, Sedensky MM, Morgan PG. The effects of complex I function and oxidative damage on lifespan and anesthetic sensitivity in Caenorhabditis elegans. Mech Ageing Dev 2004;125:455–464PubMedGoogle Scholar
  83. 83.
    Kayser EB, Morgan PG, Hoppel CL, Sedensky MM. Mitochondrial expression and function of GAS-1 in Caenorhabditis elegans. J Biol Chem 2001;276:20551–20558PubMedGoogle Scholar
  84. 84.
    Kondo M, Senoo-Matsuda N, Yanase S, Ishii T, Hartman PS, Ishii N. Effect of oxidative stress on translocation of DAF-16 in oxygen-sensitive mutants, mev-1 and gas-1 of Caenorhabditis elegans. Mech Ageing Dev 2005;126:637–641PubMedGoogle Scholar
  85. 85.
    Napoli E, Taroni F, Cortopassi GA. Frataxin, iron-sulfur clusters, heme, ROS, and aging. Antioxid Redox Signal 2006;8:506–516PubMedGoogle Scholar
  86. 86.
    Ventura N, Rea S, Henderson ST, Condo I, Johnson TE, Testi R. Reduced expression of frataxin extends the lifespan of Caenorhabditis elegans. Aging Cell 2005;4:109–112PubMedGoogle Scholar
  87. 87.
    Vazquez-Manrique RP, Gonzalez-Cabo P, Ros S, Aziz H, Baylis HA, Palau F. Reduction of Caenorhabditis elegans frataxin increases sensitivity to oxidative stress, reduces life-span, and causes lethality in a mitochondrial complex II mutant. FASEB J 2006; 20:172–174PubMedGoogle Scholar
  88. 88.
    Thierbach R, Schulz TJ, Isken F, Voigt A, Mietzner B, Drewes G, von Kleist-Retzow JC, Wiesner RJ, Magnuson MA, Puccio H, Pfeiffer AF, Steinberg P, Ristow M. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Hum Mol Genet 2005;14:3857–3864PubMedGoogle Scholar
  89. 89.
    Herndon LA, Schmeissner PJ, Dudaronek JM, Brown PA, Listner KM, Sakano Y, Paupard MC, Hall DH, Driscoll M. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 2002;419:808–814PubMedGoogle Scholar
  90. 90.
    Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 2003;33:40–48PubMedGoogle Scholar
  91. 91.
    Hamilton B, Dong Y, Shindo M, Liu W, Odell I, Ruvkun G, Lee SS. A systematic RNAi screen for longevity genes in C. elegans. Genes Dev 2005;19:1544–1555PubMedGoogle Scholar
  92. 92.
    Hansen M, Hsu AL, Dillin A, Kenyon C. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet 2005;1:119–128PubMedGoogle Scholar
  93. 93.
    Apfeld J, Kenyon C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 1999;402:804–809PubMedGoogle Scholar
  94. 94.
    Hekimi S, Lakowski B, Barnes TM, Ewbank JJ. Molecular genetics of life span in C. elegans: how much does it teach us? Trends Genet 1998;14:14–20PubMedGoogle Scholar
  95. 95.
    Kennedy BK, Austriaco NR Jr, Zhang J, Guarente L. Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae. Cell 1995;80:485–496PubMedGoogle Scholar
  96. 96.
    Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 1999;13:2570–2580PubMedGoogle Scholar
  97. 97.
    Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 2001;410:227–230PubMedGoogle Scholar
  98. 98.
    Rine J, Herskowitz I. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics 1987;116:9–22PubMedGoogle Scholar
  99. 99.
    Sinclair DA, Guarente L. Extrachromosomal rDNA circles – a cause of aging in yeast. Cell 1997;91:1033–1042PubMedGoogle Scholar
  100. 100.
    Lin SJ, Ford E, Haigis M, Liszt G, Guarente L. Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 2004;18:12–16PubMedGoogle Scholar
  101. 101.
    Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L. Mammalian SIRT1 represses forkhead transcription factors. Cell 2004;116:551–563PubMedGoogle Scholar
  102. 102.
    Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;303:2011–2015PubMedGoogle Scholar
  103. 103.
    Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M, Nakajima T, Fukamizu A. Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci USA 2004;101:10042–10047PubMedGoogle Scholar
  104. 104.
    Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y, Nemoto S, Finkel T, Gu W, Cress WD, Chen J. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 2006;8:1025–1031PubMedGoogle Scholar
  105. 105.
    Nemoto S, Fergusson MM, Finkel T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J Biol Chem 005;280:16456–16460Google Scholar
  106. 106.
    Bouras T, Fu M, Sauve AA, Wang F, Quong AA, Perkins ND, Hay RT, Gu W, Pestell RG. SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem 2005;280:10264–10276PubMedGoogle Scholar
  107. 107.
    Yang T, Fu M, Pestell R, Sauve AA. SIRT1 and endocrine signaling. Trends Endocrinol Metab 2006;17:186–911PubMedGoogle Scholar
  108. 108.
    Kaeberlein M, Kirkland KT, Fields S, Kennedy BK. Sir2-independent life span extension by calorie restriction in yeast. PLoS Biol 2004;2:E296PubMedGoogle Scholar
  109. 109.
    Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 2002;8;418:344–348Google Scholar
  110. 110.
    Kaeberlein M, Hu D, Kerr EO, Tsuchiya M, Westman EA, Dang N, Fields S, Kennedy BK. Increased life span due to calorie restriction in respiratory-deficient yeast. PLoS Genet 2005;1:e69PubMedGoogle Scholar
  111. 111.
    Rogina B, Helfand SL. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci USA 2004;101:15998–16003PubMedGoogle Scholar
  112. 112.
    Chen D, Steele AD, Lindquist S, Guarente L. Increase in activity during calorie restriction requires Sirt1. Science 2005;310:1641PubMedGoogle Scholar
  113. 113.
    Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 2004;429:771–776Google Scholar
  114. 114.
    Kaeberlein M, Powers RW 3rd, Steffen KK, Westman EA, Hu D, Dang N, Kerr EO, Kirkland KT, Fields S, Kennedy BK. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 2005;310:1193–1196PubMedGoogle Scholar
  115. 115.
    Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 2004;14:885–890PubMedGoogle Scholar
  116. 116.
    Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003;426:620PubMedGoogle Scholar
  117. 117.
    Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 2004;131:3897–3906PubMedGoogle Scholar
  118. 118.
    Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 2006;20:174–184PubMedGoogle Scholar
  119. 119.
    Desai BN, Myers BR, Schreiber SL. FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc Natl Acad Sci USA 2002;99:4319–4324PubMedGoogle Scholar
  120. 120.
    Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002;110:163–175PubMedGoogle Scholar
  121. 121.
    Tokunaga C, Yoshino K, Yonezawa K. mTOR integrates amino acid- and energy-sensing pathways. Biochem Biophys Res Commun 2004;313:443–446PubMedGoogle Scholar
  122. 122.
    Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K, Hara K, Tanaka N, Avruch J, Yonezawa K. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem 2003;278:15461–15464PubMedGoogle Scholar
  123. 123.
    Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, Finkel T. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 2006;281:27643–27652PubMedGoogle Scholar
  124. 124.
    Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 2004;113:1535–1549PubMedGoogle Scholar
  125. 125.
    Khan S, Salloum F, Das A, Xi L, Vetrovec GW, Kukreja RC. Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. J Mol Cell Cardiol 2006;41:256–264PubMedGoogle Scholar
  126. 126.
    Liu Z, Butow RA. Mitochondrial retrograde signaling. Annu Rev Genet 2006;40:159–185PubMedGoogle Scholar
  127. 127.
    Butow RA, Avadhani NG. Mitochondrial signaling: the retrograde response. Mol Cell 2004;14:1–15PubMedGoogle Scholar
  128. 128.
    Grotewiel MS, Martin I, Bhandari P, Cook-Wiens E. Functional senescence in Drosophila melanogaster. Ageing Res Rev 2005;4:372–397PubMedGoogle Scholar
  129. 129.
    Ballard JW. Drosophila simulans as a novel model for studying mitochondrial metabolism and aging. Exp Gerontol 2005;40:763–773PubMedGoogle Scholar
  130. 130.
    Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, Bodmer R. Insulin regulation of heart function in aging fruit flies. Nat Genet 2004;36:1275–1281PubMedGoogle Scholar
  131. 131.
    Paternostro G, Vignola C, Bartsch DU, Omens JH, McCulloch AD, Reed JC. Age-associated cardiac dysfunction in Drosophila melanogaster. Circ Res 2001;88:1053–1058PubMedGoogle Scholar
  132. 132.
    Mourikis P, Hurlbut GD, Artavanis-Tsakonas S. Enigma, a mitochondrial protein affecting lifespan and oxidative stress response in Drosophila. Proc Natl Acad Sci USA 2006;103:1307–1312PubMedGoogle Scholar
  133. 133.
    Wang MC, Bohmann D, Jasper H. JNK signaling confers tolerance to oxidative stress and extends lifespan in Drosophila. Dev Cell 2003;5:811–816PubMedGoogle Scholar
  134. 134.
    Wang MC, Bohmann D, Jasper H. JNK extends life span and limits growth by antago-nizing cellular and organism-wide responses to insulin signaling. Cell 2005;121:115–125PubMedGoogle Scholar
  135. 135.
    Lin YJ, Seroude L, Benzer S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 1998;282:943–946PubMedGoogle Scholar
  136. 136.
    Cvejic S, Zhu Z, Felice SJ, Berman Y, Huang XY. The endogenous ligand Stunted of the GPCR Methuselah extends lifespan in Drosophila. Nat Cell Biol 2004;6:540–546PubMedGoogle Scholar
  137. 137.
    Wang HD, Kazemi-Esfarjani P, Benzer S. Multiple-stress analysis for isolation of Drosophila longevity genes. Proc Natl Acad Sci USA 2004;101:12610–12615PubMedGoogle Scholar
  138. 138.
    Morrow G, Samson M, Michaud S, Tanguay RM. Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J 2004;18:598–599PubMedGoogle Scholar
  139. 139.
    Rogina B, Reenan RA, Nilsen SP, Helfand SL. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science 2000;290:2137–2140PubMedGoogle Scholar
  140. 140.
    Fridell YW, Sanchez-Blanco A, Silvia BA, Helfand SL. Targeted expression of the human uncoupling protein 2 (hUCP2) to adult neurons extends life span in the fly. Cell Metab 2005;1:145–152PubMedGoogle Scholar
  141. 141.
    Padalko VI. Uncoupler of oxidative phosphorylation prolongs the lifespan of Drosophila. Biochemistry (Mosc) 2005;70:986–989Google Scholar
  142. 142.
    Miwa S, Riyahi K, Partridge L, Brand MD. Lack of correlation between mitochondrial reactive oxygen species production and life span in Drosophila. Ann N Y Acad Sci 2004;1019:388–391PubMedGoogle Scholar
  143. 143.
    Bayne AC, Mockett RJ, Orr WC, Sohal RS. Enhanced catabolism of mitochondrial superoxide/hydrogen peroxide and aging in transgenic Drosophila. Biochem J 2005;391:277–284PubMedGoogle Scholar
  144. 144.
    Magwere T, West M, Riyahi K, Murphy MP, Smith RA, Partridge L. The effects of exogenous antioxidants on lifespan and oxidative stress resistance in Drosophila melanogaster. Mech Ageing Dev 2006;127:356–370PubMedGoogle Scholar
  145. 145.
    Walker DW, Muffat J, Rundel C, Benzer S. Overexpression of a Drosophila homolog of apolipoprotein d leads to increased stress resistance and extended lifespan. Curr Biol 2006;16:674–679PubMedGoogle Scholar
  146. 146.
    Arking R, Buck S, Hwangbo DS, Lane M. Metabolic alterations and shifts in energy allocations are corequisites for the expression of extended longevity genes in Drosophila. Ann N Y Acad Sci 2002;959:251–262PubMedGoogle Scholar
  147. 147.
    Aigaki T, Ohsako T, Toba G, Seong K, Matsuo T. The gene search system: its application to functional genomics in Drosophila melanogaster. J Neurogenet 2001;15:169–178PubMedGoogle Scholar
  148. 148.
    Seong KH, Ogashiwa T, Matsuo T, Fuyama Y, Aigaki T. Application of the gene search system to screen for longevity genes in Drosophila. Biogerontology 2001;2:209–217PubMedGoogle Scholar
  149. 149.
    Aigaki T, Seong KH, Matsuo T. Longevity determination genes in Drosophila melanogaster. Mech Ageing Dev 2002;123:1531–1541PubMedGoogle Scholar
  150. 150.
    Bauer JH, Goupil S, Garber GB, Helfand SL. An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc Natl Acad Sci USA 2004;101:12980–12985PubMedGoogle Scholar
  151. 151.
    Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 1999;402:309–313PubMedGoogle Scholar
  152. 152.
    Trinei M, Giorgio M, Cicalese A, Barozzi S, Ventura A, Migliaccio E, Milia E, Padura IM, Raker VA, Maccarana M, Petronilli V, Minucci S, Bernardi P, Lanfrancone L, Pelicci PG. A p53–p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis. Oncogene 2002;21:3872–3878PubMedGoogle Scholar
  153. 153.
    Migliaccio E, Mele S, Salcini AE, Pelicci G, Lai KM, Superti-Furga G, Pawson T, Di Fiore PP, Lanfrancone L, Pelicci PG. Opposite effects of the p52shc/p46shc and p66shc splicing isoforms on the EGF receptor-MAP kinase-fos signalling pathway. EMBO J 1997;16:706–716PubMedGoogle Scholar
  154. 154.
    Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D, Martin-Padura I, Pelliccia G, Trinei M, Bono M, Puri C, Tacchetti C, Ferrini M, Mannucci R, Nicoletti I, Lanfrancone L, Giorgio M, Pelicci PG. The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem 2004;279:25689–25695PubMedGoogle Scholar
  155. 155.
    Nemoto S, Finkel T. Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 2002;295:2450–2452PubMedGoogle Scholar
  156. 156.
    Giorgio M, Migliaccio E, Orsini F, Paolucci D, Moroni M, Contursi C, Pelliccia G, Luzi L, Minucci S, Marcaccio M, Pinton P, Rizzuto R, Bernardi P, Paolucci F, Pelicci PG. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 2005;122:221–233PubMedGoogle Scholar
  157. 157.
    Wang J, Silva JP, Gustafsson CM, Rustin P, Larsson NG. Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc Natl Acad Sci USA 2001;98:4038–4043PubMedGoogle Scholar
  158. 158.
    Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 2004;429:417–423PubMedGoogle Scholar
  159. 159.
    Trifunovic A, Hansson A, Wredenberg A, Rovio AT, Dufour E, Khvorostov I, Spelbrink JN, Wibom R, Jacobs HT, Larsson NG. Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production. Proc Natl Acad Sci USA 2005;102:17993–17998PubMedGoogle Scholar
  160. 160.
    Ku HH, Brunk UT, Sohal RS. Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radic Biol Med 1993;15:621–627PubMedGoogle Scholar
  161. 161.
    Sohal RS, Toy PL, Allen RG. Relationship between life expectancy, endogenous antioxidants and products of oxygen free radical reactions in the housefly, Musca domestica. Mech Ageing Dev 1986;36:71–77PubMedGoogle Scholar
  162. 162.
    Munkres K, Rana RS. Antioxidants prolong life span and inhibit the senescence-dependent accumulation of fluorescent pigment (lipofuscin) in clones, of Podospora anserina. Mech Ageing Dev 1978;7:407–415PubMedGoogle Scholar
  163. 163.
    Orr WC, Sohal RS. Extension of life-span by overexpression of superoxide dismutase and catalase in Drosophila melanogaster. Science 1994;263:1128–1130PubMedGoogle Scholar
  164. 164.
    Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, Wallace DC, Malfroy B,Doctrow SR, Lithgow GJ. Extension of life-span with superoxide dismutase/catalase mimetics. Science 2000;289:1567–1569Google Scholar
  165. 165.
    Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne G. Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet 1998;19:171–174PubMedGoogle Scholar
  166. 166.
    Sun J, Tower J. FLP recombinase-mediated induction of Cu/Zn-superoxide dismutase transgene expression can extend the life span of adult Drosophila melanogaster flies. Mol Cell Biol 1999;19:216–228PubMedGoogle Scholar
  167. 167.
    Sun J, Folk D, Bradley TJ, Tower J. Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Genetics 2002;161:661–672PubMedGoogle Scholar
  168. 168.
    Orr WC, Sohal RS. Does overexpression of Cu, Zn-SOD extend life span in Drosophila melanogaster? Exp Gerontol 2003;38:227–230PubMedGoogle Scholar
  169. 169.
    Orr WC, Mockett RJ, Benes JJ, Sohal RS. Effects of overexpression of copper-zinc and manganese superoxide dismutases, catalase, and thioredoxin reductase genes on longevity in Drosophila melanogaster. J Biol Chem 2003;278:26418–26422PubMedGoogle Scholar
  170. 170.
    Huang TT, Carlson EJ, Gillespie AM, Shi Y, Epstein CJ. Ubiquitous overexpression of CuZn superoxide dismutase does not extend life span in mice. J Gerontol A Biol Sci Med Sci 2000;55:B5–B9PubMedGoogle Scholar
  171. 171.
    Gallagher IM, Jenner P, Glover V, Clow A. CuZn-superoxide dismutase transgenic mice: no effect on longevity, locomotor activity and 3H-mazindol and 3H-spiperone binding over 19 months. Neurosci Lett 2000;289:221–223PubMedGoogle Scholar
  172. 172.
    Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 2003;16:29–37PubMedGoogle Scholar
  173. 173.
    Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA 1988;85:6465–6467PubMedGoogle Scholar
  174. 174.
    Takasawa M, Hayakawa M, Sugiyama S, Hattori K, Ito T, Ozawa T. Age-associated damage in mitochondrial function in rat hearts. Exp Gerontol 1993;28:269–280PubMedGoogle Scholar
  175. 175.
    Hayakawa M, Torii K, Sugiyama S, Tanaka M, Ozawa T. Age-associated accumulation of 8-hydroxydeoxyguanosine in mitochondrial DNA of human diaphragm. Biochem Biophys Res Commun 1991;179:1023–1029PubMedGoogle Scholar
  176. 176.
    Hayakawa M, Hattori K, Sugiyama S, Ozawa T. Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts. Biochem Biophys Res Commun 1992;189:979–985PubMedGoogle Scholar
  177. 177.
    Mecocci P, MacGarvey U, Kaufman AE, Koontz D, Shoffner JM, Wallace DC, Beal MF. Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain. Ann Neurol 1993;34:609–616PubMedGoogle Scholar
  178. 178.
    Richter C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int J Biochem Cell Biol 1995;27:647–653PubMedGoogle Scholar
  179. 179.
    Stuart JA, Bourque BM, de Souza-Pinto NC, Bohr VA. No evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA. Free Radic Biol Med 2005;38:737–745PubMedGoogle Scholar
  180. 180.
    Huang TT, Carlson EJ, Kozy HM, Mantha S, Goodman SI, Ursell PC, Epstein CJ. Genetic modification of prenatal lethality and dilated cardiomyopathy in Mn superoxide dismutase mutant mice. Free Radic Biol Med 2001;31:1101–1110PubMedGoogle Scholar
  181. 181.
    Van Remmen H, Qi W, Sabia M, Freeman G, Estlack L, Yang H, Mao Guo Z, Huang TT, Strong R, Lee S, Epstein CJ, Richardson A. Multiple deficiencies in antioxidant enzymes in mice result in a compound increase in sensitivity to oxidative stress. Free Radic Biol Med 2004;36:1625–1634PubMedGoogle Scholar
  182. 182.
    Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, Coskun PE, Ladiges W, Wolf N, Van Remmen H, Wallace DC, Rabinovitch PS. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 2005;308:1909–1911PubMedGoogle Scholar
  183. 183.
    Andziak B, O’Connor TP, Buffenstein R. Antioxidants do not explain the disparate longevity between mice and the longest-living rodent, the naked mole-rat. Mech Ageing Dev 2005;126:1206–1212PubMedGoogle Scholar
  184. 184.
    Buffenstein R. The naked mole-rat: a new long-living model for human aging research. J Gerontol A Biol Sci Med Sci 2005;60:1369–1377PubMedGoogle Scholar
  185. 185.
    Yu CE, Oshima J, Wijsman EM, Nakura J, Miki T, Piussan C, Matthews S, Fu YH, Mulligan J, Martin GM, Schellenberg GD. Mutations in the consensus helicase domains of the Werner syndrome gene. Werner’s Syndrome Collaborative Group. Am J Hum Genet 1997;60:330–341PubMedGoogle Scholar
  186. 186.
    Shen J, Loeb LA. Unwinding the molecular basis of the Werner syndrome. Mech Ageing Dev 2001;122:921–944PubMedGoogle Scholar
  187. 187.
    Szekely AM, Chen YH, Zhang C, Oshima J, Weissman SM. Werner protein recruits DNA polymerase delta to the nucleolus. Proc Natl Acad Sci USA 2000;97:11365–11370PubMedGoogle Scholar
  188. 188.
    Watt PM, Hickson ID, Borts RH, Louis EJ. SGS1, a homologue of the Bloom’s and Werner’s syndrome genes, is required for maintenance of genome stability in Saccharomyces cerevisiae. Genetics 1996;144:935–945PubMedGoogle Scholar
  189. 189.
    Sinclair DA, Mills K, Guarente L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 1997;277:1313–1316PubMedGoogle Scholar
  190. 190.
    Myung K, Datta A, Chen C, Kolodner RD. SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homologous recombination. Nat Genet 2001;27:113–116PubMedGoogle Scholar
  191. 191.
    Johnson FB, Marciniak RA, McVey M, Stewart SA, Hahn WC, Guarente L. The Saccharomyces cerevisiae WRN homolog Sgs1p participates in telomere maintenance in cells lacking telomerase. EMBO J 2001;20:905–913PubMedGoogle Scholar
  192. 192.
    Cohen H, Sinclair DA. Recombination-mediated lengthening of terminal telomeric repeats requires the Sgs1 DNA helicase. Proc Natl Acad Sci USA 2001;98:3174–3179PubMedGoogle Scholar
  193. 193.
    Lee SJ, Yook JS, Han SM, Koo HS. A Werner syndrome protein homolog affects C. elegans development, growth rate, life span and sensitivity to DNA damage by acting at a DNA damage checkpoint. Development 2004;131:2565–2575PubMedGoogle Scholar
  194. 194.
    Lebel M, Leder P. A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc Natl Acad Sci USA 1998;95:13097–13102PubMedGoogle Scholar
  195. 195.
    Lombard DB, Beard C, Johnson B, Marciniak RA, Dausman J, Bronson R, Buhlmann JE, Lipman R, Curry R, Sharpe A, Jaenisch R, Guarente L. Mutations in the WRN gene in mice accelerate mortality in a p53-null background. Mol Cell Biol 2000;20:3286–3291PubMedGoogle Scholar
  196. 196.
    Chang S. A mouse model of Werner Syndrome: what can it tell us about aging and cancer? Int J Biochem Cell Biol 2005;37:991–999PubMedGoogle Scholar
  197. 197.
    Chang S, Multani AS, Cabrera NG, Naylor ML, Laud P, Lombard D, Pathak S, Guarente L, DePinho RA. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat Genet 2004;36:877–882PubMedGoogle Scholar
  198. 198.
    Du X, Shen J, Kugan N, Furth EE, Lombard DB, Cheung C, Pak S, Luo G, Pignolo RJ, DePinho RA, Guarente L, Johnson FB. Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes. Mol Cell Biol 2004;24:8437–8446Google Scholar
  199. 199.
    Opresko PL, von Kobbe C, Laine JP, Harrigan J, Hickson ID, Bohr VA. Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J Biol Chem 2002;277:41110–41119PubMedGoogle Scholar
  200. 200.
    Machwe A, Xiao L, Orren DK. TRF2 recruits the Werner syndrome (WRN) exonuclease for processing of telomeric DNA. Oncogene 2004;23:149–156PubMedGoogle Scholar
  201. 201.
    Opresko PL, Otterlei M, Graakjaer J, Bruheim P, Dawut L, Kolvraa S, May A, Seidman MM, Bohr VA. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol Cell 2004;14:763–774PubMedGoogle Scholar
  202. 202.
    Massip L, Garand C, Turaga RV, Deschenes F, Thorin E, Lebel M. Increased insulin, triglycerides, reactive oxygen species, and cardiac fibrosis in mice with a mutation in the helicase domain of the Werner syndrome gene homologue. Exp Gerontol 2006;41:157–168PubMedGoogle Scholar
  203. 203.
    Szekely AM, Bleichert F, Numann A, Van Komen S, Manasanch E, Ben Nasr A, Canaan A, Weissman SM. Werner protein protects nonproliferating cells from oxidative DNA damage. Mol Cell Biol 2005;25:10492–10506PubMedGoogle Scholar
  204. 204.
    Von Kobbe C, May A, Grandori C, Bohr VA. Werner syndrome cells escape hydrogen peroxide-induced cell proliferation arrest. FASEB J 2004;18:1970–1972Google Scholar
  205. 205.
    von Kobbe C, Harrigan JA, May A, Opresko PL, Dawut L, Cheng WH, Bohr VA. Central role for the Werner syndrome protein/poly(ADP-ribose) polymerase 1 complex in the poly(ADP-ribosyl)ation pathway after DNA damage. Mol Cell Biol 2003;23:8601–8613Google Scholar
  206. 206.
    Pagano G, Zatterale A, Degan P, d’Ischia M, Kelly FJ, Pallardo FV, Kodama S. Multiple involvement of oxidative stress in Werner syndrome phenotype. Biogerontology 2005;6:233–243PubMedGoogle Scholar
  207. 207.
    Deschenes F, Massip L, Garand C, Lebel M. In vivo misregulation of genes involved in apoptosis, development and oxidative stress in mice lacking both functional Werner syndrome protein and poly(ADP-ribose) polymerase-1. Hum Mol Genet 2005;14:3293–3308PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • José Marín-García
    • 1
  • Michael J. Goldenthal
    • 2
  • Gordon W. Moe
    • 3
  1. 1.The Molecular Cardiology and Neuromuscular InstituteHighland Park
  2. 2.The Molecular Cardiology and Neuromuscular InstituteHighland Park
  3. 3.University of TorontoTorontoCanada

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