Reduced neuronal expression of ribose‐5‐phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila

Summary Aging and age‐related diseases can be viewed as the result of the lifelong accumulation of stress insults. The identification of mutant strains and genes that are responsive to stress and can alter longevity profiles provides new therapeutic targets for age‐related diseases. Here we reported that a Drosophila strain with reduced expression of ribose‐5‐phosphate isomerase (rpi), EP2456, exhibits increased resistance to oxidative stress and enhanced lifespan. In addition, the strain also displays higher levels of NADPH. The knockdown of rpi in neurons by double‐stranded RNA interference recapitulated the lifespan extension and oxidative stress resistance in Drosophila. This manipulation was also found to ameliorate the effects of genetic manipulations aimed at creating a model for studying Huntington’s disease by overexpression of polyglutamine in the eye, suggesting that modulating rpi levels could serve as a treatment for normal aging as well as for polyglutamine neurotoxicity.