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Gene Review

daf-16  -  Protein DAF-16

Caenorhabditis elegans

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Disease relevance of daf-16

  • We find that loss-of-function mutations in any of three genes (daf-16, daf-18, or daf-12) not only reduce or abolish the ability to form dauers but also block the hormetic response increasing life span following sub-lethal heat stress [1].

Psychiatry related information on daf-16


High impact information on daf-16

  • The lifespan-extending effect of long telomeres was dependent on daf-16 [3].
  • In particular, DAF-16 activity in the intestine, which is also the animal's adipose tissue, completely restores the longevity of daf-16(-) germline-deficient animals, and increases the lifespans of daf-16(-) insulin/IGF-1-pathway mutants substantially [4].
  • Genetic analysis indicates that the sir-2.1 transgene functions upstream of daf-16 in the insulin-like signalling pathway [5].
  • Downregulation of this pathway activates a forkhead transcription factor (daf-16), which may regulate targets that promote dauer formation in larvae and stress resistance and longevity in adults [5].
  • Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation. daf-2 and daf-16 provide entry points into understanding how lifespan can be extended [6].

Biological context of daf-16

  • In mammals, AKT/PKB regulates cell survival by modulating the activity of several apoptotic proteins, including p53 . In Caenorhabditis elegans, akt-1 and akt-2 regulate development in response to environmental cues by controlling the FOXO transcription factor daf-16, but the role of these genes in regulating p53-dependent apoptosis is not known [7].
  • In contrast, akt-1(mg247) and pdk-1(mg261) did not affect lifespan or stress resistance, while both daf-16 alleles fully suppressed these phenotypes [8].
  • These theories were tested in the nematode Caenorhabditis elegans by examining the consequences of eliminating either apoptosis or the daf-16, daf-18 or sir-2.1 genes that promote longevity of postmitotic somatic cells [9].
  • These results suggest that chemosensory neurons are a target of oxidative stress and influence longevity dependent on the daf-16 signaling in C. elegans [10].
  • Other developmental events such as cell migration, cell fusion, and expression of the microRNA lin-4, a temporal regulator of post-embryonic development, are also observed in starved daf-16/FOXO mutants [11].

Anatomical context of daf-16

  • The life-span extension caused by daf-2 mutations requires the activity of the gene daf-16. daf-16 appears to play a unique role in life-span regulation and encodes a member of the hepatocyte nuclear factor 3 (HNF-3)/forkhead family of transcriptional regulators [12].
  • We show that DAF-16 is required for transcription of the cyclin-dependent kinase inhibitor cki-1 in stem cells in response to starvation, accounting for the failure of daf-16/FOXO mutants to arrest cell division during L1 arrest [11].

Associations of daf-16 with chemical compounds


Regulatory relationships of daf-16


Other interactions of daf-16

  • Three genes, daf-16, daf-18 and daf-20, may affect downstream steps in a branched part of the pathway [18].
  • Positive regulation by DAF-2 on dao-1, dao-4 and dao-8 was mediated by DAF-16, whereas daf-16 mediates only part of DAF-2 signaling for dao-2 and dao-9 [19].
  • Mutation in the transcription factor daf-16 suppressed the Age and ATP phenotypes, but not the reduction of respiration rate imparted by mutation in clk-1 [20].
  • The daf-16 phenotype resembles that of mev-1 showing a short life and oxygen sensitivity [21].
  • Adaptive responses to oxidative damage in three mutants of Caenorhabditis elegans (age-1, mev-1 and daf-16) that affect life span [21].

Analytical, diagnostic and therapeutic context of daf-16

  • Both RT-PCR and analysis of an OLD-1::GFP tag suggest that old-1 expression is dependent on daf-16 [22].
  • Microarray analysis reveals increased transcript levels of daf-16 and downstream targets and past experiments demonstrate that DAF-16 (FOXO) acting on downstream targets can influence all of the phenotypes we see altered in maintenance medium [23].


  1. Hormesis in Caenorhabditis elegans dauer-defective mutants. Cypser, J.R., Johnson, T.E. Biogerontology. (2003) [Pubmed]
  2. daf-16 protects the nematode Caenorhabditis elegans during food deprivation. Henderson, S.T., Bonafè, M., Johnson, T.E. J. Gerontol. A Biol. Sci. Med. Sci. (2006) [Pubmed]
  3. Long lifespan in worms with long telomeric DNA. Joeng, K.S., Song, E.J., Lee, K.J., Lee, J. Nat. Genet. (2004) [Pubmed]
  4. Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan. Libina, N., Berman, J.R., Kenyon, C. Cell (2003) [Pubmed]
  5. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Tissenbaum, H.A., Guarente, L. Nature (2001) [Pubmed]
  6. A C. elegans mutant that lives twice as long as wild type. Kenyon, C., Chang, J., Gensch, E., Rudner, A., Tabtiang, R. Nature (1993) [Pubmed]
  7. AKT-1 Regulates DNA-Damage-Induced Germline Apoptosis in C. elegans. Quevedo, C., Kaplan, D.R., Derry, W.B. Curr. Biol. (2007) [Pubmed]
  8. Activated AKT/PKB signaling in C. elegans uncouples temporally distinct outputs of DAF-2/insulin-like signaling. Gami, M.S., Iser, W.B., Hanselman, K.B., Wolkow, C.A. BMC Dev. Biol. (2006) [Pubmed]
  9. Uncoupling of pathways that promote postmitotic life span and apoptosis from replicative immortality of Caenorhabditis elegans germ cells. Ahmed, S. Aging Cell (2006) [Pubmed]
  10. Mutations in chemosensory cilia cause resistance to paraquat in nematode Caenorhabditis elegans. Fujii, M., Matsumoto, Y., Tanaka, N., Miki, K., Suzuki, T., Ishii, N., Ayusawa, D. J. Biol. Chem. (2004) [Pubmed]
  11. DAF-16/FOXO regulates transcription of cki-1/Cip/Kip and repression of lin-4 during C. elegans L1 arrest. Baugh, L.R., Sternberg, P.W. Curr. Biol. (2006) [Pubmed]
  12. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Lin, K., Dorman, J.B., Rodan, A., Kenyon, C. Science (1997) [Pubmed]
  13. A defect in the activity of Delta6 and Delta5 desaturases may be a factor predisposing to the development of insulin resistance syndrome. Das, U.N. Prostaglandins Leukot. Essent. Fatty Acids (2005) [Pubmed]
  14. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Viswanathan, M., Kim, S.K., Berdichevsky, A., Guarente, L. Dev. Cell (2005) [Pubmed]
  15. daf-2, daf-16 and daf-23: genetically interacting genes controlling Dauer formation in Caenorhabditis elegans. Gottlieb, S., Ruvkun, G. Genetics (1994) [Pubmed]
  16. An insulin-like signaling pathway affects both longevity and reproduction in Caenorhabditis elegans. Tissenbaum, H.A., Ruvkun, G. Genetics (1998) [Pubmed]
  17. The p38 signal transduction pathway participates in the oxidative stress-mediated translocation of DAF-16 to Caenorhabditis elegans nuclei. Kondo, M., Yanase, S., Ishii, T., Hartman, P.S., Matsumoto, K., Ishii, N. Mech. Ageing Dev. (2005) [Pubmed]
  18. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Vowels, J.J., Thomas, J.H. Genetics (1992) [Pubmed]
  19. DAF-16-dependent and independent expression targets of DAF-2 insulin receptor-like pathway in Caenorhabditis elegans include FKBPs. Yu, H., Larsen, P.L. J. Mol. Biol. (2001) [Pubmed]
  20. Apparent uncoupling of energy production and consumption in long-lived Clk mutants of Caenorhabditis elegans. Braeckman, B.P., Houthoofd, K., De Vreese, A., Vanfleteren, J.R. Curr. Biol. (1999) [Pubmed]
  21. Adaptive responses to oxidative damage in three mutants of Caenorhabditis elegans (age-1, mev-1 and daf-16) that affect life span. Yanase, S., Yasuda, K., Ishii, N. Mech. Ageing Dev. (2002) [Pubmed]
  22. The OLD-1 positive regulator of longevity and stress resistance is under DAF-16 regulation in Caenorhabditis elegans. Murakami, S., Johnson, T.E. Curr. Biol. (2001) [Pubmed]
  23. Delayed development and lifespan extension as features of metabolic lifestyle alteration in C. elegans under dietary restriction. Szewczyk, N.J., Udranszky, I.A., Kozak, E., Sunga, J., Kim, S.K., Jacobson, L.A., Conley, C.A. J. Exp. Biol. (2006) [Pubmed]
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