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

Abstract

Over recent decades, 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. Using Drosophila as a model we determined the effects of Zoledronate on lifespan, parameters of healthspan (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 Zoledronate extended lifespan, improved climbing activity and reduced intestinal epithelial dysplasia and permeability with age. 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 was associated with inhibition of pAKT in the mTOR pathway downstream of the mevalonate pathway and required dFOXO for its action, both molecules associated with increased longevity. Taken together, our work indicates that Zoledronate, a drug already widely used to prevent osteoporosis and dosed only once a year, modulates important mechanisms of ageing. Its repurposing holds great promise as a treatment to improve healthspan.

Publication DOI: https://doi.org/10.1093/gerona/glab172
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
Additional Information: © The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Funding: University of Sheffield PhD studentship award.
Uncontrolled Keywords: Ageing,lifespan,bisphosphonates,DNA damage,Drosophila
Full Text Link:
Related URLs: https://academi ... glab172/6301579 (Publisher URL)
PURE Output Type: Article
Published Date: 2021-06-17
Published Online Date: 2021-06-17
Accepted Date: 2021-06-01
Submitted Date: 2020-12-16
Authors: Chen, Zhengqi
Cordero, Julia
Alqarni, Adel M
Slack, Cathy (ORCID Profile 0000-0002-7949-4079)
Zeidler, Martin P
Bellantuono, Ilaria

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