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Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans.

Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS.

Pubmed ID: 18358814


  • Tullet JM
  • Hertweck M
  • An JH
  • Baker J
  • Hwang JY
  • Liu S
  • Oliveira RP
  • Baumeister R
  • Blackwell TK



Publication Data

March 21, 2008

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 2 R01 GM062891
  • Agency: NIGMS NIH HHS, Id: 5 F32 GM070088-02
  • Agency: NIGMS NIH HHS, Id: R01 GM062891
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-05
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-06
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-07
  • Agency: NIGMS NIH HHS, Id: R01 GM062891-08
  • Agency: NIDDK NIH HHS, Id: T32 DK07260

Mesh Terms

  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Gene Regulatory Networks
  • Insulin
  • Insulin-Like Growth Factor I
  • Intestines
  • Longevity
  • Oxidative Stress
  • Phosphorylation
  • Receptor, Insulin
  • Signal Transduction
  • Transcription Factors