Zoledronate Extends Health Span and Survival via the Mevalonate Pathway in a FOXO-dependent Manner
| Autor: | Zhengqi Chen, Cathy Slack, Adel M Alqarni, Julia B. Cordero, Martin P. Zeidler, Ilaria Bellantuono |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Aging
DNA damage media_common.quotation_subject medicine.medical_treatment Farnesyl pyrophosphate Mevalonic Acid Pharmacology medicine.disease_cause Zoledronic Acid chemistry.chemical_compound Cell Line Tumor Medicine Animals Drosophila Proteins PI3K/AKT/mTOR pathway media_common Mammals business.industry Longevity Imidazoles Forkhead Transcription Factors Bisphosphonate chemistry Ageing Drosophila Mevalonate pathway Geriatrics and Gerontology business Oxidative stress |
| Zdroj: | The journals of gerontology. Series A, Biological sciences and medical sciences. 77(8) |
| ISSN: | 1758-535X 1079-5006 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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