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.[1] DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens.[2] Mutations in DAF-2 have been shown by Cynthia Kenyon to double the lifespan of the worms.[3] In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”[4]

IGF-1 signal pathway

Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to mammals.[5] 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.[6][7] 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.[8] Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 knock-downs.[9] By silencing DAF-16, activation of DAF-2 receptors can ultimately compromise a cell’s ability to mitigate harmful environmental conditions.[5] 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.[10]

Role in C. elegans developmental stages

Caenorhabditis elegans, which progresses through a series of larval stages into a final reproductive adult, may instead enter a less metabolically active dauer diapause stage if food scarcity or overcrowding occurs before reaching adulthood.[8] Disabling DAF-2 arrests development in the dauer stage which increases longevity, delays senescence and prevents reproductive maturity.[10]

Diet’s interaction with the IGF-1 pathway

Research into the interaction between diet and the insulin/IGF-1 pathway has shown sugar intake to be negatively correlated with DAF-16 activity and longevity. One study found that glucose ingestion reduced the rate of dauer formation and shortened the life-spans of DAF-2 knock-downs to resemble that of normal C. elegans, suggesting that DAF-16 mediated gene expression associated with longevity is suppressed by glucose ingestion Wild type C. elegans fed a diet that included 2% glucose showed reduced Daf-16 activity and lifespan was shortened by 20% compared to worms fed on glucose-free media. These findings raise the possibility that a low-sugar diet might have beneficial effects on life span in higher organisms..[11]

References

  1. ↑ 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
  2. ↑ 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.
  3. ↑ 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).
  4. ↑ Krulwich, R. (Performer) (2007, June 14). Mortality. Radiolab. [Audio podcast]. Retrieved from http://www.radiolab.org/2007/jun/14/
  5. ↑ 5.0 5.1 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
  6. ↑ 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
  7. ↑ Kenyon C (2005) The plasticity of aging: insights from long-lived mutants. Cell 120: 449–460.
  8. ↑ 8.0 8.1 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.
  9. ↑ 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
  10. ↑ 10.0 10.1 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.
  11. ↑ Lee, S. J., Murphy, C. T., & Keyon, C. (2009). Glucose shortens the life span of c. elegans by downregulating daf-16/foxo activity and aquaporin gene expression. Cell metabolism, 10(5), 379–391. doi: http://dx.doi.org/10.1016/j.cmet.2009.10.003