Direct Inhibition of the Longevity-Promoting Factor SKN-1 by Insulin-like Signaling in C. elegans

Abstract

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.

Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans

“…Tullet et al . (2008) indicated that the transcription network regulated by SKN‐1 promotes longevity and is an important direct target of IIS. SKN‐1 represents a connection between the development of the digestive system and one of its most basic functions – resistance to oxidative and xenobiotic stresses.…”

“…The skn‐1 mutant of C. elegans shows decreased resistance to oxidative stress and a shortened lifespan. In contrast, C. elegans mutants overexpressing SKN‐1, which constitutively localizes to the nuclei of intestinal cells, show increased resistance to oxidative stress and increased longevity (An & Blackwell, 2003; An et al ., 2005; Tullet et al ., 2008). …”

“…The chosen alleles were skn‐1 (zu135), which contains a premature stop codon in the SKN‐1 DNA‐binding domain, and skn‐1 (zu67), which lacks the regions encoding the SKN‐1A and SKN‐1C isoforms (Bowerman et al ., 1992; Bishop & Guarente, 2007; Johns et al ., 2007; Tullet et al ., 2008). We did not confirm that zu67 produces functional SKN‐1b/c and that this stop codon mutation within the other isoforms does not affect b/c transcription.…”

Movement decline across lifespan of Caenorhabditis elegans mutants in the insulin/insulin‐like signaling pathway

“…All mutants had previously been reported to extend lifespan (Friedman & Johnson, 1988; Hertweck, Gobel, & Baumeister, 2004; Kenyon et al., 1993; McElwee, Bubb, & Thomas, 2003; Murphy, Lee, & Kenyon, 2007; Paradis, Ailion, Toker, Thomas, & Ruvkun, 1999; Tullet et al., 2008; Zhang et al., 2008). However, the sgk‐1 mutant has been observed to have variable lifespan (Chen, Guo, Dumas, Ashrafi, & Hu, 2013; Mizunuma, Neumann‐Haefelin, Moroz, Li, & Blackwell, 2014; Xiao et al., 2013).…”

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…Thus, NHR‐49 and SKN‐1 are both important in stress conditions and in long‐lived glp‐1 mutants, but partner with MDT‐15 to coordinate expression of distinct gene sets that may be more important under particular conditions. For example, in long‐lived daf‐2 /insulin receptor mutants, where skn‐1 is important, but nhr‐49 dispensable for the increase in lifespan (Ratnappan et al., 2014; Tullet et al., 2008), the requirement for mdt‐15 may exclusively reflect MDT‐15's function as a SKN‐1 coregulator (Goh et al., 2014). …”