Abstract
Over recent decades, increased longevity has not been paralleled by extended health span, resulting in more years spent with multiple diseases in older age. As such, interventions to improve health span are urgently required. Zoledronate (Zol) is a nitrogen-containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase 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. Using Drosophila as a model we determined the effects of Zol on life span, parameters of health span (climbing ability and intestinal dysplasia), and the ability to confer resistance to oxidative stress using a combination of genetically manipulated Drosophila strains and Western blotting. Our study shows that Zol extended life span, improved climbing activity, and reduced intestinal epithelial dysplasia and permeability with age. Mechanistic studies showed that Zol conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of farnesyl pyrophosphate synthase. Moreover, Zol was associated with inhibition of phosphorylated AKT in the mammalian traget of rapamycin pathway downstream of the mevalonate pathway and required dFOXO for its action, both molecules associated with increased longevity. Taken together, our work indicates that Zol, a drug already widely used to prevent osteoporosis and dosed only once a year, modulates important mechanisms of aging. Its repurposing holds great promise as a treatment to improve health span.
Highlights
It has been estimated that by 2050, Europe, North America, and eight countries across the other continents will have more than 30% of their population over the age of 60(1)
In this study we examined whether Zol is able to extend lifespan and healthspan independent of its effect on bone using Drosophila, a model widely used for ageing studies
While wDah pre-treated with Zol showed a significant increase in lifespan, Drosophila have a single FOXO gene (dFOXO) Δ94/+ flies treated in the same way did not show any beneficial effect (Fig. 4E), suggesting dFOXO is required for Zol action on survival
Summary
It has been estimated that by 2050, Europe, North America, and eight countries across the other continents will have more than 30% of their population over the age of 60(1). T RESULTS ip Zol increases lifespan in Drosophila r To determine whether Zol might have beneficial effects on the lifespan of Drosophila, both male and c female wDah flies were maintained on standard fly food supplemented with 1μM or 10μM Zol from s day 4 of adult life onwards (Fig. 1 A&B and eFig.1).
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call