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Daf-2
The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm ''Caenorhabditis elegans''. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging.〔Keyton, C. The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing. Philos Trans R Soc Lond B Biol Sci. 2011 January 12; 366(1561): 9–16. doi: 10.1098/rstb.2010.0276〕 DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens.〔Minaxi S Gami and Catherine A Wolkow (2006). "Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan". Aging Cell 5 (1): 31–7. doi:10.1111/j.1474-9726.2006.00188.x. PMC 1413578. PMID 16441841.〕 Mutations in DAF-2 have been shown by Cynthia Kenyon to double the lifespan of the worms.〔Jennie B. Dorman, Bella Albinder, Terry Shroyer & Cynthia Kenyon, "The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans," Genetics, volume 141, number 4, pages 1399-1406 (1995); and Javier Apfeld & Cynthia Kenyon, "Cell non-autonomy of C. elegans daf-2 function in the regulation of diapause and lifespan," Cell, v. 95, n.2, pp.199-210 (1998).〕 In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”〔Krulwich, R. (Performer) (2007, June 14). Mortality. Radiolab. (podcast ). Retrieved from http://www.radiolab.org/2007/jun/14/〕
== IGF-1 signal pathway ==
Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to mammals.〔Murphy,C.T., McCarroll, S.A., Bargmann,C.I, Fraser,A., Kamath, R.S., Ahringer, J., Li, H., Kenyon, C. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans.Nature, 424 (2003), pp. 277–283〕 DAF-2 is the only member of the insulin receptor family in ''C. elegans'' but it corresponds, in form and function, to multiple pathways in humans. The protein predicted from DAF-2's sequence is 35% identical to the human insulin receptor, which regulates metabolism; 34% identical to the IGF-1 receptor, which regulates growth; and 33% identical to the human insulin receptor–related receptor.〔Kimura, K. D., Tissenbaum, H. A., Liu, Y., & Ruvkun, G. (1997). daf-2 an insulin receptor-like gene that regulates longevity and diapause in caenorhabditis elegans. Science, 277(5328), 942946. doi:10.1126/science.277.5328.942〕〔Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120: 449–460.〕 In ''C. elegans'', the insulin/IGF-1/FOXO pathway is initiated by changes in IGF-1 levels which cause IGF-1 receptors to start a phosphorylation cascade that deactivates the FOXO transcription factor, DAF-16. When not phosphorylated, DAF-16 is active and present in the nucleus. DAF-16 is responsible for up-regulating transcription of about 100 genes that code for cell protecting products such as heat shock proteins and antioxidants.〔Hu, 2007 Hu, P.J. (2007). Dauer. In WormBook, The C. elegans Research Community, ed. 10.1895/wormbook.1.144.1, http://www.wormbook.org.〕 Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 knock-downs.〔Cynthia Kenyon The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing Phil. Trans. R. Soc. B January 12, 2011 366 1561 9-16; doi:10.1098/rstb.2010.0276 1471-2970 http://rstb.royalsocietypublishing.org/content/366/1561/9.full〕 By silencing DAF-16, activation of DAF-2 receptors can ultimately compromise a cell’s ability to mitigate harmful environmental conditions.〔 In most eukaryotes, insulin activates DAF-2 signaling. However, both human insulin and insulin coded for by orthologous genes in ''C. elegans'' inhibit DAF-2 receptors in ''C. elegans''.〔Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, Ferguson KC, Heller J, Platt DM, Pasquinelli AA, Liu LX, Doberstein SK, Ruvkun G (2001) Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev 15:672– 686.〕
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