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

Chen, Z., Cordero, J. , Alqarni, A. M., Slack, C., Zeidler, M. P. and Bellantuono, I. (2022) Zoledronate extends health span and survival via the mevalonate pathway in a FOXO-dependent manner. Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 77(8), pp. 1494-1502. (doi: 10.1093/gerona/glab172) (PMID:34137822) (PMCID:PMC9373971)

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.

• Item Type: Articles
• Additional Information: This work was supported by a University of Sheffield PhD studentship award.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cordero, Professor Julia
• Authors: Chen, Z., Cordero, J., Alqarni, A. M., Slack, C., Zeidler, M. P., and Bellantuono, I.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journals of Gerontology Series A: Biological Sciences and Medical Sciences
• Publisher: Oxford University Press
• ISSN: 1079-5006
• ISSN (Online): 1758-535X
• Published Online: 17 June 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Journals of Gerontology Series A: Biological Sciences and Medical Sciences 77(8): 1494-1502
• Publisher Policy: Reproduced under a Creative Commons License