Zoledronate Extends Health Span 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.

In vitroandin vivoeffects of zoledronate on senescence and senescence-associated secretory phenotype markers

“…Our findings in mice are also consistent with recent findings in Drosophila demonstrating that zoledronate treatment was associated with an extension of lifespan and improved climbing ability, which is analogous to assessment of grip strength in mice [62]. This study also linked the known inhibition of farnesyl pyrophosphate synthetase (FPPS) by zoledronate to a reduction in the accumulation of DNA damage, which is a key trigger of cellular senescence [10].…”

Bisphosphonates attenuate age‐related muscle decline inCaenorhabditis elegans

“…Growing pre‐clinical 17–19 and human 20 evidence suggest that bisphosphonates not only preserve bone integrity but also exert muscle promoting effects across a variety of conditions. A recent study in fruit flies suggest similar effects might extend to the ageing process, where bisphosphonate treatment prolonged lifespan and animal healthspan 21 . We provide the first in vivo evidence for a direct role of chronic bisphosphonate administration in delaying age‐related muscle structural decline.…”

“…In fruit flies, bisphosphonates increase lifespan through inhibition of the mevalonate metabolic pathway and downstream FOXO activation 21 . We extend this by implicating the mevalonate‐FOXO system as necessary for bisphosphonate‐mediated health improvements across the life course.…”

“…Retrospective analysis of osteoporosis patients prescribed ZA for 3 years also exhibit significant increases in total lean muscle mass, compared with a loss of muscle mass in untreated controls 20 . In the ageing context, ZA‐treated fruit flies displayed increased survival and improved climbing ability across the life course, suggesting improved neuromuscular ageing 21 . However, the direct anti‐sarcopenic efficacy of ZA has not been established.…”

How zoledronic acid improves osteoporosis by acting on osteoclasts

“…Excessive amounts of FPP and GGPP lead to protein prenylation impairment, this is a potential pathological feature of osteoporosis ( Zameer et al, 2018 ). ZA is known as the gold standard for the treatment of osteoporosis because of its recognized role in attenuating bone resorption and osteoclast apoptosis by inhibiting FPPS in the mevalonate pathway ( Figure 2 ) ( Tang et al, 2017 ; Zameer et al, 2018 ; Chandra and Rajawat, 2021 ; Chen et al, 2021 ; Munoz et al, 2021 ). Targeted inhibition of FPPS by ZA blocks the synthesis of FPP and the downstream product GGPP, which prevents the prenylation of Rab GTPases (e.g., members of the Ras superfamily) and their binding proteins ( Kimachi et al, 2011 ; Zameer et al, 2018 ; Soysa and Alles, 2019 ).…”