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The daf‐2 gene network for longevity regulates oxidative stress resistance and Mn‐superoxide dismutase gene expression in Caenorhabditis elegans

Longevity is regulated by the daf‐2 gene network in Caenorhabditis elegans. Mutations in the daf‐2 gene, which encodes a member of the insulin receptor family, confer the life extension (Age) phenotype and the constitutive dauer (a growth‐arrested larval form specialized for dispersal) formation phenotype. The Age phenotype is mutually potentiated by two life extension mutations in the daf‐2 gene and the clk‐1 gene, a homologue of yeast CAT5/COQ7 known to regulate ubiquinone biosynthesis. In this study, we demonstrated that the daf‐2 mutation also conferred an oxidative stress resistance (Oxr) phenotype, which was also enhanced by the clk‐1 mutation. Similar to the Age phenotype, the Oxr phenotype was regulated by the genetic pathway of insulin‐like signaling from daf‐2 to the daf‐16 gene, a homologue of the HNF‐3/forkhead transcription factor. These findings led us to examine whether the insulin‐like signaling pathway regulates the gene expression of antioxidant defense enzymes. We found that the mRNA level of the sod‐3 gene, which encodes Mn‐superoxide dismutase (SOD), was much higher in daf‐2 mutants than in the wild type. Moreover, the increased sod‐3 gene expression phenotype is regulated by the insulin‐like signaling pathway. Although the clk‐1 mutant itself did not display Oxr and the increased sod‐3 expression phenotypes, the clk‐1 mutation enhanced them in the daf‐2 mutant, suggesting that clk‐1 is involved in longevity in two ways: clk‐1 composes the original clk‐1 longevity program and the daf‐2 longevity program. These observations suggest that the daf‐2 gene network controls longevity by regulating the Mn‐SOD‐associated antioxidant defense system. This system appears to play a role in efficient life maintenance at the dauer stage.—Honda, Y., Honda, S. The daf‐2 gene network for longevity regulates oxidative stress resistance and Mn‐superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 13, 1385–1393 (1999)