Background: Age-related muscle decline (sarcopenia) is a major, unresolved societal health challenge. Repurposing existing prescription drugs represents a highly cost- and time-efficient approach to sarcopenia treatment discovery. For decades, bisphosphonates have been prescribed for osteoporosis treatment, however their potential as a sarcopenic therapy remain unclear. We examined the efficacy of bisphosphonates for preserving muscle health across the entire lifespan, using a C. elegans model of ageing muscle health.
Methods: Using zoledronic acid (ZA) as a potent, third-generation bisphosphonate, we assessed life/healthspan using a microfluidic device (‘NemaLife’). Wild-type C. elegans were treated with 100 nM – 500 µM ZA from larval stages (~300 animals per condition) and analysed for longevity and healthspan (total animal movement across the lifecourse). Muscle architecture was examined in response to ZA using transgenic animals expressing green fluorescent protein reporters for myofibres and mitochondria, until wild-type sarcopenic onset (~day 4-6 adulthood; ~60 animals / 300 muscle cells per condition/ time point). Pharmaco-genetic life/healthspan experiments of ZA + RNAi knockdown of muscle-bone crosstalk, and ZA-responsive genes were performed to establish potential mechanisms of ZA-mediated healthspan extension (~140 animals per condition/ time point).
Results: Higher ZA concentrations (100 and 500 μM) were lethal, and 10 µM had no effect on lifespan but reduced healthspan (P<0.01). Conversely, lower ZA doses of 100 nM, 500 nM and 1μM extended lifespan (median lifespan = 13-16 vs. 9 days post-adulthood in untreated controls, all P<0.0001) and preserved healthspan (AUC for movement rate across lifespan = 784-878 vs. 678 in untreated controls, all P<0.05). ZA (1 µM) also preserved muscle sarcomeric structure at day 6 post-adulthood (18% loss of sarcomeric arrays vs. 58% loss in untreated controls, P<0.05). Age-related mitochondrial fragmentation was not preserved by ZA (P=0.177). Of the five mechanistic candidates examined, agxt-2/ β-aminoisobutyric acid (BAIBA) was required for ZA-mediated healthspan preservation. Whilst healthspan extension was retained with ZA + sir-2.2/ sir-2.3 (mitochondrial sirtuins) or igdb-1 (FDNC5) knockdown, healthspan was not synergistically improved, putatively implicating ZA-induced healthspan acts via downregulation of these targets.
Conclusion: Low doses of bisphosphonates significantly improve lifespan, healthspan and preserves muscle integrity across age. Bisphosphonates might, therefore, hold significant potential as an immediately exploitable sarcopenia therapeutic.