Stress resistance has been associated with longevity in C. elegans and other species. The Phase 2 detoxification mechanism, which scavenges free radicals and reactive xenobiotics, defends against oxidative stress. In mammals this stress response can be induced by the isothiocyanate sulforaphane (SFN), which is derived from broccoli sprouts, and by CDDO-Imidazolide (CDDO-Im), a synthetic triterpenoid. We have explored how these indirect antioxidants influence stress resistance and longevity in C. elegans, in which the SKN-1 transcription factor induces Phase 2 gene expression in the intestine. We show that treatment with either SFN or CDDO-Im induces SKN-1 to accumulate in intestinal cell nuclei and upregulates Phase 2 gene expression in a
skn-1- and
p38-dependent manner. We have also shown for the first time that these compounds induce the stress response factor FOXO/DAF-16 to accumulate in nuclei and activate target gene expression, in both C. elegans and cultured mammalian cells. In C. elegans, SFN increases glutathione levels, dependent upon
skn-1,
daf-16, and
p38 signaling. Transient treatment with either SFN or CDDO-Im also dramatically enhances C. elegans oxidative stress resistance, through the Phase 2 and also other stress defense mechanisms. Importantly, transient SFN treatment significantly prolongs C. elegans lifespan, independently of any effects on pathogenesis. This longevity increase is not fully dependent upon either
skn-1 or
daf-16 but, surprisingly, is abolished by lack of
p38 signaling. Preliminary results indicate that CDDO-Im also increases C. elegans life span. We conclude that these chemoprotective agents induce the SKN-1 and FOXO/DAF-16 stress responses in a wide variety of animals, and provide robust organismal defense against oxidative and xenobiotic stress, and thereby have the potential to increase longevity. Our findings also implicate
p38 signaling as being important for responses to SFN, and central to its pro-longevity effects.