In Caenorhabditis elegans, sublethal thermal stress can extend adult lifespan, suggesting that thermal stress responses overlap with prolongevity pathways in this organism . Chemical stress can induce heat shock protein expression and thermotolerance in Saccharomyces cerevisiae . Cultured cells and whole organisms are protected from oxidative stress by pretreatments with hyperbaric oxygen or low levels of free-radical generators such as paraquat or juglone . In addition, mild oxidative stress from low concentrations of juglone extended C. elegans lifespan, suggesting that oxidative stress response pathways also overlap with prolongevity pathways in C. elegans . The close link between stress and aging suggests that interventions harnessing hormetic mechanisms may extend lifespan or delay age-associated functional decline. However, challenges for developing hormetic mechanisms into anti-aging therapies include the relatively small dose range providing protective benefits and the toxic effects of higher doses. Therefore, studies are R428 needed to determine the feasibility of modifying hormetic agents to extend the beneficial dose range and minimize toxicity. Here, we report that hormetic chemicals can be modified to optimize beneficial effects and minimize toxicity in C. elegans, a model for studying aging in whole organisms. C. elegans is wellsuited to this problem due to the short lifespan, ease of genetic manipulation and transparent anatomy. First, we examined whether lifespan extension is common among biological toxins with various chemical structures and mechanisms of action. In a small screen of natural phytochemicals, we identified two ROS generating compounds, plumbagin and juglone, which extended lifespan at subtoxic doses. Mean lifespan extension by plumbagin was dependent on SKN-1, a cap��n��collar transcription 537049-40-4 factor that promotes antioxidant gene expression in response to oxidative stress . We further screened a collection of six plumbagin analogs, identifying three additional naphthoquinones that activated expression of a skn-1 target. One of these could extend lifespan over a larger range of doses than plumbagin, demonstrating the utility of stress hormesis mechanisms as promising prolongevity intervention. The other compounds had differing effects on longevity, possibly reflecting structure-specific alterations in stability and toxicity. This work highlights C. elegans as an experimental approach for identifying lead compounds with the potential to act on conserved targets.