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][4] In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”^[5]

IGF-1 signal pathway

Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to mammals.^[6] 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.^[7][8] 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.^[9] Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 knock-downs.^[10] By silencing DAF-16, activation of DAF-2 receptors can ultimately compromise a cell’s ability to mitigate harmful environmental conditions.^[6] 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.^[11]

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.^[9] Disabling DAF-2 arrests development in the dauer stage which increases longevity, delays senescence and prevents reproductive maturity.^[11]

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.^[12]

References

1. ↑ Keyton, C (January 2011). "The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing". Philos Trans R Soc Lond B Biol Sci. 366 (1561): 9–16. PMC 3001308 . PMID 21115525. doi:10.1098/rstb.2010.0276. 
2. ↑ Gami, Minaxi S; Wolkow, Catherine A (2006). "Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan". Aging Cell. 5 (1): 31–7. PMC 1413578 . PMID 16441841. doi:10.1111/j.1474-9726.2006.00188.x. 
3. ↑ Dorman, Jennie B.; Albinder, Bella; Shroyer, Terry; Kenyon, Cynthia (1995). "The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans". Genetics. 141 (4): 1399–1406. 
4. ↑ Apfeld, Javier; Kenyon, Cynthia (1998). "Cell non-autonomy of C. elegans daf-2 function in the regulation of diapause and lifespan". Cell. 95 (2): 199–210. doi:10.1016/s0092-8674(00)81751-1. 
5. ↑ Krulwich, R. (Performer) (2007, June 14). Mortality. Radiolab. [Audio podcast]. Retrieved from http://www.radiolab.org/2007/jun/14/
6. 1 2 Murphy, C.T.; McCarroll, S.A.; Bargmann, C.I; Fraser, A.; Kamath, R.S.; Ahringer, J.; Li, H.; Kenyon, C. (2003). "Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans". Nature. 424: 277–283. PMID 12845331. doi:10.1038/nature01789. 
7. ↑ 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. 
8. ↑ Kenyon, C (2005). "The plasticity of aging: insights from long-lived mutants". Cell. 120: 449–460. doi:10.1016/j.cell.2005.02.002. 
9. 1 2 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.
10. ↑ Kenyon, Cynthia (2011). "The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing". Phil. Trans. R. Soc. B. 366 (1561): 9–16. PMC 3001308 . PMID 21115525. doi:10.1098/rstb.2010.0276. 
11. 1 2 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. PMC 312654 . PMID 11274053. doi:10.1101/gad.867301. 
12. ↑ 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. PMC 2887095 . PMID 19883616. doi:10.1016/j.cmet.2009.10.003.