Protection of nuclear DNA by lifespan-extending compounds in the yeast Saccharomyces cerevisiae

Highlights: • Rapamycin and spermidine decreased CAN1 mutation rates in yeast. • Dinitrophenol, metformin, and resveratrol decreased EMS-induced mutations. • Spermidine sensitized cells to H₂O₂ insult. • Only spermidine increased lifespan in cells growth-arrested with hydroxyurea. DNA damage has been hypothesized to be a driving force of the aging process. At the same time, there exists multiple compounds that can extend lifespan in model organisms, such as yeast, worms, flies, and mice. One possible mechanism of action for these compounds is a protective effect against DNA damage. We investigated whether five of these lifespan-extending compounds, dinitrophenol, metformin, rapamycin, resveratrol, and spermidine, could protect nuclear DNA in the yeast Saccharomyces cerevisiae at the same doses under which they confer lifespan extension. We found that rapamycin and spermidine were able to decrease the spontaneous mutation rate at the CAN1 locus, whereas dinitrophenol, metformin, and resveratrol were able to protect yeast against CAN1 mutations induced by ethyl methanesulfonate (EMS). We also tested whether these compounds could enhance survival against EMS, ultraviolet (UV) light, or hydrogen peroxide (H₂O₂) insult. All five compounds conferred a protective effect against EMS, while metformin and spermidine protected yeast against UV light. Somewhat surprisingly, none of the compounds were able to afford a significant protection against H₂O₂, with spermidine dramatically sensitizing cells. We also examined the ability of these compounds to increase lifespan when growth-arrested by hydroxyurea; only spermidine was found to have a positive effect. Overall, our results suggest that lifespan-extending compounds may act in part by protecting nuclear DNA.