Elsevier, Cell, 6(132), p. 1025-1038, 2008
DOI: 10.1016/j.cell.2008.01.030
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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 lifespan 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.