A number of studies have established a correlation between increased resistance to cell stress and extended life span. The interplay between cell metabolism and signaling pathways involved in stress responses is an important area of research into the causes of aging. For example, a reduction in insulin-like signaling mediated by DAF-16, a homolog of the transcription factor FOXO, is associated with increased life span in Caenorhabditis elegans. DAF-16-responsive genes include those involved in the response to oxidative stress. Tullet et al. examined the role of insulin-like signaling in the regulation of another transcription factor, SKN-1, which activates genes involved in the detoxification response. A transgenic fusion protein of green fluorescent protein (GFP) and SKN-1 was detectable in the intestinal nuclei of C. elegans with mutant daf-2, the worm homolog of the insulin receptor, which was not the case in wild-type transgenic animals. Animals with mutant daf-2 also had longer life spans than did control animals. RNAi-mediated knockdown of AKT and SGK kinases, which are activated following DAF-2 stimulation, resulted in increased nuclear localization of SKN-1:GFP compared with that in control animals. Western blotting analysis showed the direct phosphorylation of SKN-1 by these kinases, and quantitative polymerase chain reaction assays demonstrated DAF-2-dependent inhibition of the expression of SKN-1 target genes. Whereas mutation of skn-1 decreased the extended life spans observed in daf-2 mutant worms, worms in which skn-1 was overexpressed had increased life spans compared with wild-type worms, which was independent of DAF-16. Together, these data suggest that SKN-1 makes a critical, DAF-16-independent contribution to stress responses and longevity that are associated with decreased insulin-like signaling. As Jasper discusses in commentary, establishing whether insulin signaling interacts similarly with the SKN-1 homolog Nrf2 in humans is an important next step in understanding the mechanisms of aging.
J. M. A. Tullet, M. Hertweck, J. H. An, J. Baker, J. Y. Hwang, S. Liu, R. P. Oliveira, R. Baumeister, T. K. Blackwell, Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132, 1025-1038 (2008). [PubMed]
H. Jasper, SKNy worms and long life. Cell 132, 915-916 (2008). [PubMed]