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 and also Age-1 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]

abnormal dauer formation protein 2
Identifiers
Organism	Caenorhabditis elegans
Symbol	daf-2
Entrez	175410
RefSeq (mRNA)	NM_065249.5
RefSeq (Prot)	NP_497650.4
UniProt	Q968Y9
Other data
Chromosome	III: 2.99 - 3.03 Mb
Search for Structures Swiss-model Domains InterPro

Long-lived mutants

Long-lived DAF-2 C. elegans mutants are resistant to the oxidizing agent paraquat and to UV light.^[6] DAF-2 mutants also have a higher DNA repair capability than wild-type C. elegans.^[6] Knockdown of the nucleotide excision repair gene Xpa-1 increases sensitivity to UV and reduces the life span of the long-lived mutants. These findings support the hypothesis that DNA damage has a significant role in the aging process.^[6]

IGF-1 signal pathway

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

See also

• Unfolded protein response
• Genetics of aging

References

1. Kenyon 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. doi:10.1098/rstb.2010.0276. PMC 3001308. PMID 21115525.
2. Gami MS, Wolkow CA (February 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. Dorman JB, Albinder B, Shroyer T, Kenyon C (December 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. doi:10.1093/genetics/141.4.1399. PMC 1206875. PMID 8601482.
4. Apfeld J, Kenyon C (October 1998). "Cell nonautonomy of C. elegans daf-2 function in the regulation of diapause and life span". Cell. 95 (2): 199–210. doi:10.1016/s0092-8674(00)81751-1. PMID 9790527.
5. Krulwich, R. (Performer) (2007, June 14). Mortality. Radiolab. [Audio podcast]. Retrieved from http://www.radiolab.org/2007/jun/14/
6. Hyun M, Lee J, Lee K, May A, Bohr VA, Ahn B (March 2008). "Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans". Nucleic Acids Research. 36 (4): 1380–9. doi:10.1093/nar/gkm1161. PMC 2275101. PMID 18203746.
7. Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, et al. (July 2003). "Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans". Nature. 424 (6946): 277–83. Bibcode:2003Natur.424..277M. doi:10.1038/nature01789. PMID 12845331. S2CID 4424249.
8. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (August 1997). "daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans". Science. 277 (5328): 942–6. doi:10.1126/science.277.5328.942. PMID 9252323.
9. Kenyon C (February 2005). "The plasticity of aging: insights from long-lived mutants". Cell. 120 (4): 449–60. doi:10.1016/j.cell.2005.02.002. PMID 15734678.
10. 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.
11. Pierce SB, Costa M, Wisotzkey R, Devadhar S, Homburger SA, Buchman AR, et al. (March 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 & Development. 15 (6): 672–86. doi:10.1101/gad.867301. PMC 312654. PMID 11274053.
12. Lee SJ, Murphy CT, Kenyon C (November 2009). "Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression". Cell Metabolism. 10 (5): 379–91. doi:10.1016/j.cmet.2009.10.003. PMC 2887095. PMID 19883616.