Off-Patent Osteoporosis Drug Also Found to Extend Lifespan

Zoledronate is a biophosphonate, a drug used to strengthen bones and reduce the risk of osteoporosis-related bone fractures. It is well-absorbed into the bones, so it only needs to be administered through infusion once a year.

A 2010 study had found that people who were given zoledronate after experiencing hip fractures showed slightly reduced all-cause mortality compared to a control group. Patients who took the drug were at significantly lower risk for heart arrhythmias and pneumonia.

As this is a drug that is already being given to people, the choice to go back to genetically modified fruit flies, a much simpler model of aging, may seem counterintuitive. The team chose to test these insects for two principal reasons. The first is that Drosophila flies are a common subject of studies on basic aging pathways, which the researchers wished to explore. The second is simpler: Drosophila flies lack bones, making the bone-affecting properties of zoledronate irrelevant to the study.

Giving the drug in moderate doses to middle-aged flies and found that this late administration increased lifespan in both males and females, increasing male lifespan by roughly 5% and female lifespan by 16%, and the team notes that these results are similar to rapamycin. High doses is bad.

Journals of Gerontology – Zoledronate extends healthspan and survival via the mevalonate pathway in a FOXO-dependent manner

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.

SOURCES- lifespan.io, Journal of Gerontology
Written By Brian Wang, Nextbigfuture.com