Daf-2

Long-lived DAF-2 C. elegans mutants are resistant to the oxidizing agent paraquat and to UV light.{{cite journal | vauthors = Hyun M, Lee J, Lee K, May A, Bohr VA, Ahn B | title = Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans | journal = Nucleic Acids Research | volume = 36 | issue = 4 | pages = 1380–9 | date = March 2008 | pmid = 18203746 | pmc = 2275101 | doi = 10.1093/nar/gkm1161 }} DAF-2 mutants also have a higher DNA repair capability than wild-type C. elegans. 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.

Insulin/IGF-1-like signaling is well-conserved evolutionarily across animal phyla, from single celled organisms to mammals.{{cite journal | vauthors = Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C | display-authors = 6 | title = Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans | journal = Nature | volume = 424 | issue = 6946 | pages = 277–83 | date = July 2003 | pmid = 12845331 | doi = 10.1038/nature01789 | bibcode = 2003Natur.424..277M | s2cid = 4424249 }} 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.{{cite journal | vauthors = Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G | title = daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans | journal = Science | volume = 277 | issue = 5328 | pages = 942–6 | date = August 1997 | pmid = 9252323 | doi = 10.1126/science.277.5328.942 }}{{cite journal | vauthors = Kenyon C | title = The plasticity of aging: insights from long-lived mutants | journal = Cell | volume = 120 | issue = 4 | pages = 449–60 | date = February 2005 | pmid = 15734678 | doi = 10.1016/j.cell.2005.02.002 | doi-access = free }} 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. 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.{{cite journal | vauthors = 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 | display-authors = 6 | title = 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 | journal = Genes & Development | volume = 15 | issue = 6 | pages = 672–86 | date = March 2001 | pmid = 11274053 | pmc = 312654 | doi = 10.1101/gad.867301 }}

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

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.{{cite journal | vauthors = Lee SJ, Murphy CT, Kenyon C | title = Glucose shortens the life span of C. elegans by downregulating DAF-16/FOXO activity and aquaporin gene expression | journal = Cell Metabolism | volume = 10 | issue = 5 | pages = 379–91 | date = November 2009 | pmid = 19883616 | pmc = 2887095 | doi = 10.1016/j.cmet.2009.10.003 }}

• Unfolded protein response
• Genetics of aging

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{{Dauer larva}}

Category:Caenorhabditis elegans genes

Category:Aging-related genes