Regulation of C.elegans Life Span by Insulin-Like Signaling

  • Gary Ruvkun
Part of the Research and Perspectives in Endocrine Interactions book series (RPEI)


An insulin signaling pathway couples feeding and nutritional status in mammals to the tempo and mode of metabolism in most tissues of the animal (Kahn 1994; Kahn and Weir 1994). Insulin secretion by the pancreas is regulated by nutritional and autonomic neural inputs, and this endocrine signal of metabolic status is detected by target tissues to regulate the activities of metabolic enzymes that synthesize or break down glucose, amino acids, fat, etc. We have shown that an insulin-like signaling pathway regulates longevity and metabolism in C. elegans (Kimura et al. 1997). This regulation may be mechanistically related to the longevity increase caused by caloric restriction in mammals. Our genetic analysis has also revealed outputs of C. elegans insulin -like signaling. We identified human homologs of many of these components in genome databases; many of these homologs have now been shown to transduce insulin and insulin-like signaling in humans.


Caenorhabditis Elegans Reproductive Life Span PIP3 Signal Insulin Superfamily Insulin Response Sequence 
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  1. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15: 6541–6551PubMedGoogle Scholar
  2. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PRJ, Reese CB, Cohen P (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B. Current Biol 7: 261–269CrossRefGoogle Scholar
  3. Apfeld J, Kenyon C (1998) Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span. Cell 95: 199–210PubMedCrossRefGoogle Scholar
  4. Blundell TL, Humbel RE (1980) Hormone families: pancreatic hormones and homologous growth factors. Nature 287: 781–787PubMedCrossRefGoogle Scholar
  5. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D, Kahn CR (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289: 2122–2125PubMedCrossRefGoogle Scholar
  6. Dorman JB, Albinder B, Shroyer T, Kenyon C (1995) The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 14: 1399–1406Google Scholar
  7. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275: 661–665Google Scholar
  8. Durham SK, Suwanichkul A, Scheimann AO, Yee D, Jackson JG, Barr FG Powell DR (1999) FKHR binds the insulin response element in the insulin-like growth factor binding protein-1 promoter. Endocrinology 140: 3140–3146PubMedCrossRefGoogle Scholar
  9. Esteban J, Rosen DR, Bowling AC, Sapp P, McKenna-Yasek D, O’Regan JP, Beal MF, Horvitz HR, Brown RH Jr (1994) Identification of two novel mutations and a new polymorphism in the gene for Cu/Zn superoxide dismutase in patients with amyotrophic lateral sclerosis. Human Mol Genet 3: 997–998CrossRefGoogle Scholar
  10. Estevez,M, Attisano L,Wrana JL, Albert PS, Massague J, Riddle DL (1993) The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development. Nature 365: 644–649CrossRefGoogle Scholar
  11. Georgi LL, Albert PS, Riddle DL (1990) daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase. Cell 61: 635–645Google Scholar
  12. Golden JW, Riddle DL (1984) A pheromone-induced developmental switch in Caenorhabditis elegans: Temperature-sensitive mutants reveal a wild-type temperature-dependent process. Proc. Natl. Acad. Sci. USA 81: 819–823Google Scholar
  13. Gottlieb S, Ruvkun G (1994) daf-2, daf-16, and daf-23: genetically interacting genes controlling dauer formation in Caenorhabditis elegans. Genetics 137: 107–120Google Scholar
  14. Granner D, Andreone T, Sasaki K, Beale E (1983) Inhibition of transcription of the phosphoenolpyruvate carboxykinase gene by insulin. Nature 305: 549–551PubMedCrossRefGoogle Scholar
  15. Guo S, Rena G, Cichy S, He X, Cohen P, Uterman T (1999) Phosphorylation of serine 256 by proteiun kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Cheml74: 17184–17192Google Scholar
  16. Hall RK, Yamasaki T, Kucera T, Waltner-Law,M, Obrien R,Granner DK (2000) Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteins. J Biol Chem 275: 30169–30175Google Scholar
  17. Hobert 0, Mori I, Yamashita Y, Honda H, Ohshima Y, Liu Y, Ruvkun G (1997) Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 LIM homeobox gene. Neuron 19: 345–357PubMedCrossRefGoogle Scholar
  18. Honda Y, Honda S (1999) The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J13 (:1385–1393)Google Scholar
  19. Inoue T, Thomas JH (2000) Targets of TGF-beta signaling in Caenorhabditis elegans dauer formation. Dev Biol 217: 192–204PubMedCrossRefGoogle Scholar
  20. Kahn CR (1994) Insulin action, diabetogenes, and the cause of Type II Diabetes. Diabetes 43: 1066–1084PubMedCrossRefGoogle Scholar
  21. Kahn CR, Weir GC (eds) (1994) Joslin’s Diabetes Mellitus. 13th Edition. Lea FebigerGoogle Scholar
  22. Kenyon C, Chang J, Gensch E, Rudner A, Tabtlang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366: 461–464PubMedCrossRefGoogle Scholar
  23. Kimura K, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277: 942–946Google Scholar
  24. Klass M (1983) A method for the isolation of longevity mutants in the nematode C. elegans and initial results. Mech Ageing Dev 22: 279–286PubMedCrossRefGoogle Scholar
  25. Kulik G, Klippel A, Weber MJ (1997) Antiapoptotic signalling by the insulin-like growth factor I receptor, phophatidylinositol 3-kinase, and Akt. Mol Cell Biol 17: 1595–1606PubMedGoogle Scholar
  26. Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR (1999) Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes.Cell 96: 329Google Scholar
  27. Larsen P (1993) Aging and resistance to oxidative damage in Caenorhabditis elegans. Proc Natl Acad Sci USA 90: 8905–8909PubMedCrossRefGoogle Scholar
  28. Larsen PL, Albert PS, Riddle DL (1995) Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139: 1567–1583PubMedGoogle Scholar
  29. Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phsophatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhavditis elegans. Nature 382: 536–539PubMedCrossRefGoogle Scholar
  30. Nakae J, Park BC Accili D (1999) Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive patheway. J Biol Chem 274: 15982–15985PubMedCrossRefGoogle Scholar
  31. Nasrin N, Ogg S, Cahill C, Biggs W, Nui S, Dore J, Calvo D, ShiY, Ruvkun G, Alexander-Bridges M (2000) DAF-16 recruits the CBP co-activator to the IGFBP-1 promoter in HepG2 cells. Proc Natl Acad Sci USA97: 10412–10417Google Scholar
  32. Ogg S,Ruvkun G (1998) The C. elegans PTEN homolog daf-18 acts in the insulin receptor-like metabolic signaling pathway. Mol Cell 2: 887–893CrossRefGoogle Scholar
  33. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, RuvkunG (1997) The Fork head Transcription factor DAF-16 transduces insulin-like metabolic and longevity singals in C. elegans. Nature 389: 994–999Google Scholar
  34. Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G (1999) A PDK1 homolog is Necessary and Sufficient to Transduce AGE-1 PI3 Kinase Signals that Regulate Diapause in C. elegans Genes Devel 13: 1438–1452Google Scholar
  35. Parkes TL, Elia AJ, Dickinson D, Hilliker AJ, Phillips JP, Boulianne GL Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. Nat Genet 19: 171Google Scholar
  36. Patterson G, Koweek A, Wong A, Liu Y, Ruvkun G (1997) The DAF-3 Smad protein antagonizes TGF-beta-related receptor signaling in the Caenorhabditis elegans dauer pathway. Genes Dev 11: 2679–2690PubMedCrossRefGoogle Scholar
  37. Perls TT, Alpert L, Fretts RC (1997) Middle-aged mothers live longer. Nature 389: 133PubMedCrossRefGoogle Scholar
  38. Rena G, Guo S, Cichy SC, Unterman TG, Cohen P (1999) Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem 274: 17179–17183PubMedCrossRefGoogle Scholar
  39. Ren g Lim CS, Johnsen R, Albert PS, Pilgrim D, Riddle DL (1996) Control of C. elegans larval development by neuronal expression of a TGF-beta homolog. Science 274: 1389–1392CrossRefGoogle Scholar
  40. Rubin GM,Yandell MD, Wortman JR, Gabor Miklos GL, Nelson CR, Hariharan IK, Fortini ME, Li PW, Apweiler R, Fleischmann W, Cherry JM, Henikoff S, Skupski MP, Misra S, Ashburner M, Birney E, Boguski MS, Brody T, Brokstein P, Celniker SE, Chervitz SA, Coates D, Cravchik A, Gabrielian A, Galle RF, Gelbart WM, George RA, Goldstein LS, Gong F, Guan P, Harris NL, Hay BA, Hoskins RA, Li J, Li Z, Hynes RO, Jones SJ, Kuehl PM, Lemaitre B, Littleton JT, Morrison DK, Mungall C, O’Farrell PH, Pickeral OK, Shue C, Vosshall LB, Zhang J, Zhao Q, Zheng XH, Lewis S (2000). Comparative genomics of the eukaryotes. Science 287: 2204–2215CrossRefGoogle Scholar
  41. Schackwitz WS, Inoue T, Thomas JH (1996) Chemosensory neurons function in parallel to mediate a pheromone response in C. elegans. Neuron 17: 719–728PubMedCrossRefGoogle Scholar
  42. Schmoll D, Walker KS, Alessi DR, Grempler R, Burchell A, Guo S, Walther R, Unterman TG (2000) Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR: Evidence for insulin response unit ( IRU)-dependent and independent effects of insulin on promoter activity. J Biol Chem 275: 36324–36333Google Scholar
  43. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake Nature 404: 661Google Scholar
  44. Tauber MJ, Tauber CA, Masaki S (1986) Seasonal adaptation of insects. Oxford University Press, New YorkGoogle Scholar
  45. Taub J, Lau JF, Ma C, Hahn JH, Hogue R, Rothblatt J, Chalfie M (1999) A cytosolic catalase is needed to extend adult lifespan in C. elegans dauer constitutive and clk-1 mutants. Nature 399: 162–166PubMedCrossRefGoogle Scholar
  46. Thomas JH, Birnby DA, Vowels JJ (1993) Evidence for parallel processing of sensory information controlling dauer formation in Caenorhabditis elegans. Genetics 134: 1005–1117Google Scholar
  47. Tang ED, Nunez G, Barr FG, Guan KL (1999) Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem 274 (24): 16741–16746PubMedCrossRefGoogle Scholar
  48. Thacker C, Peters K, Srayko M, Rose AM (1995) The bli-4 locus of Caenorhabditis elegans encodes structurally distinct kex2/subtilisin-like endoproteases essential for early development and adult morphology. Genes Devel 9: 956–971PubMedCrossRefGoogle Scholar
  49. Tomizawa M, Kumar A, Perrot V, Nakae J, Accili D, Rechler MM, Kumaro A (2000) Insulin inhibits the activation of transcription by a C-terminal fragment of the forkhead transcription factor FKHR. A mechanism for insulin inhibition of insulin-like growth factor-binding protein-1 transcription. J Biol Chem 275: 7289–7295PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2004

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  • Gary Ruvkun

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