However, these experiments were confounded by the fact that naphthoquinone toxicity was significantly higher in the presence of heat-killed bacteria . There are several explanations for this result. One is that bacteria were protective against naphthoquinone toxicity which was necessary to unmask the hormetic Axitinib manufacturer effects in C. elegans. Thus, growth on heat-killed bacteria could have shifted the hormetic dose range to doses that were much lower than those we tested. An alternative explanation is that bacteria enzymatically converted the naphthoquinones into products with hormetic activity in C. elegans. We did not further investigate these possibilities. We found that naphthazarin and oxoline, but not menadione, could extend C. elegans lifespan. At doses between 100�C500 mM, naphthazarin treatment was associated with increased mean and maximum lifespan . For oxoline, a 500 mMdose extended mean lifespan by 13�C15% in 3 of 4 trials and increased maximum lifespan by at least 10% in all 4 trials. 1 mM oxoline was also associated with significant increases in mean and maximum lifespan . Comparison of relative Pgst-4::GFP fluorescence and lifespan indicated that beneficial concentrations of naphthazarin, oxoline and plumbagin were associated with 50�C150% increased Pgst-4::GFP Tasocitinib expression . However, Pgst-4::GFP expression was not strictly correlated with lifespan extension, as menadione, which also induced Pgst-4::GFP within this range, had no effect on lifespan at low concentrations and was toxic at high concentrations . This may reflect additional toxic effects of menadione in vivo. Our findings and those of previous studies suggest that interventions activating stress response pathways can reduce cellular damage, thereby slowing aging and increasing lifespan. Phytochemicals that exert cytoprotective effects, such as curcumin and sulforaphane , do so by inducing the Phase 2 detoxification response via NF-E2 transcription factors. Here, we characterized the ability of three naphthoquinones, plumbagin, naphthazarin and oxoline, to extend C. elegans lifespan through stress hormesis pathways linked to the antioxidant response. In our study, lifespan extension by plumbagin and naphthazarin was dependent on skn-1 activity. In the absence of skn-1 activity, the hormetic benefits of plumbagin were lost. In C. elegans, lifespan extension from stress hormesis by thermal stress and jugloneinduced oxidative stress also require daf-16 . Lifespan extension by plumbagin was weaker and more variable in daf-16 mutants than in wildtype animals, suggesting that daf-16 is a component of the hormetic pathway induced by plumbagin.