Stress Resistance Screen in a Human Primary Cell Line Identifies Small Molecules That Affect Aging Pathways and Extend Caenorhabditis elegans' Lifespan

Increased resistance to environmental stress at the cellular level is correlated with the longevity of long-lived mutants and wild-animal species. Moreover, in experimental organisms, screens for increased stress resistance have yielded mutants that are long-lived. To find entry points for small molecules that might extend healthy longevity in humans, we screened ∼100,000 small molecules in a human primary-fibroblast cell line and identified a set that increased oxidative-stress resistance. Some of the hits fell into structurally related chemical groups, suggesting that they may act on common targets. Two small molecules increased C. elegans9 stress resistance, and at least 9 extended their lifespan by ∼10-50%. We also looked into potential mechanism of action for a chalcone that produced relatively large effects on lifespan and were able to implicate the activity of stress-response regulators NRF2/skn-1 and SESN/sesn-1 in its mechanism of action. Taken together, screening for increased stress resistance in human cells can enrich for compounds with promising pro-longevity effects. Further characterization of these compounds may elucidate new ways to extend healthy human lifespan.