Zoledronate extends healthspan and survival via the mevalonate pathway in a FOXO-dependent manner

Increased longevity has not been paralleled by extended healthspan, resulting in more years spent with multiple diseases in older age. As such, interventions to improve healthspan are urgently required. Zoledronate is a nitrogen containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase (FPPS) enzyme, central to the mevalonate pathway. It is already used clinically to prevent fractures in osteoporotic patients, who have been reported to derive unexpected and unexplained survival benefits. In this study we show that zoledronate has beneficial effects on both lifespan and healthspan using Drosophila as a model. We found that zoledronate extended lifespan, improved climbing activity and reduced intestinal epithelial dysplasia and permeability in aged flies. Mechanistic studies showed that zoledronate conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of FPPS. Moreover, zoledronate inhibited pAKT in the mTOR pathway and functioned via dFOXO, a molecule associated with increased longevity, downstream of the mevalonate pathway. Taken together, our work indicates that zoledronate, a drug already widely used and dosed only once a year to prevent osteoporosis, modulates important mechanisms of ageing. Its repurposing holds great promise as a treatment to improve healthspan.