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Drugs that counter sarcopenia without harmful side effects are lacking, and repurposing existing pharmaceuticals could expedite realistic clinical options. Recent studies suggest bisphosphonates promote muscle health; however, the efficacy of bisphosphonates as an anti\u2010sarcopenic therapy is currently unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using<jats:styled-content style=\"fixed-case\"><jats:italic>Caenorhabditis elegans<\/jats:italic><\/jats:styled-content>as a sarcopenia model, we treated animals with 100\u00a0nM, 1, 10, 100 and 500\u00a0\u03bcM zoledronic acid (ZA) and assessed lifespan and healthspan (movement rates) using a microfluidic chip device. The effects of ZA on sarcopenia were examined using GFP\u2010tagged myofibres or mitochondria at days 0, 4 and 6 post\u2010adulthood. Mechanisms of ZA\u2010mediated healthspan extension were determined using combined ZA and targeted RNAi gene knockdown across the life\u2010course.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found 100\u00a0nM and 1\u00a0\u03bcM ZA increased lifespan (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and healthspan [954\u00a0\u00b1\u00a053 (100\u00a0nM) and 963\u00a0\u00b1\u00a048 (1\u00a0\u03bcM) vs. 834\u00a0\u00b1\u00a059% (untreated) population activity AUC,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05]. 10\u00a0\u03bcM ZA shortened lifespan (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) but not healthspan (758.9\u00a0\u00b1\u00a037 vs. 834\u00a0\u00b1\u00a059,<jats:italic>P<\/jats:italic>\u00a0&gt;\u00a00.05), whereas 100 and 500\u00a0\u03bcM ZA were larval lethal. ZA (1\u00a0\u03bcM) significantly improved myofibrillar structure on days 4 and 6 post\u2010adulthood (83 and 71% well\u2010organized myofibres, respectively, vs. 56 and 34% controls,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001) and increased well\u2010networked mitochondria at day 6 (47 vs. 16% in controls,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Genes required for ZA\u2010mediated healthspan extension included<jats:italic>fdps\u20101<\/jats:italic>\/FDPS\u20101 (278\u00a0\u00b1\u00a09 vs. 894\u00a0\u00b1\u00a017% population activity AUC in knockdown\u00a0+\u00a01\u00a0\u03bcM ZA vs. untreated controls, respectively,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.0001),<jats:italic>daf\u201016<\/jats:italic>\/FOXO (680\u00a0\u00b1\u00a016 vs. 894\u00a0\u00b1\u00a017%,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and<jats:italic>agxt\u20102<\/jats:italic>\/BAIBA (531\u00a0\u00b1\u00a023 vs. 552\u00a0\u00b1\u00a08%,<jats:italic>P<\/jats:italic>\u00a0&gt;\u00a00.05). Life\/healthspan was extended through knockdown of<jats:italic>igdb\u20101<\/jats:italic>\/FNDC5 (635\u00a0\u00b1\u00a010 vs. 523\u00a0\u00b1\u00a010% population activity AUC in gene knockdown vs. untreated controls,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and<jats:italic>sir\u20102.3<\/jats:italic>\/SIRT\u20104 (586\u00a0\u00b1\u00a010 vs. 523\u00a0\u00b1\u00a010%,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), with no synergistic improvements in ZA co\u2010treatment vs. knockdown alone [651\u00a0\u00b1\u00a012 vs. 635\u00a0\u00b1\u00a010% (<jats:italic>igdb\u20101<\/jats:italic>\/FNDC5) and 583\u00a0\u00b1\u00a09 vs. 586\u00a0\u00b1\u00a010% (<jats:italic>sir\u20102.3<\/jats:italic>\/SIRT\u20104), both<jats:italic>P<\/jats:italic>\u00a0&gt;\u00a00.05]. Conversely,<jats:italic>let\u2010756<\/jats:italic>\/FGF21 and<jats:italic>sir\u20102.2<\/jats:italic>\/SIRT\u20104 were dispensable for ZA\u2010induced healthspan [630\u00a0\u00b1\u00a06 vs. 523\u00a0\u00b1\u00a010% population activity AUC in knockdown\u00a0+\u00a01\u00a0\u03bcM ZA vs. untreated controls,<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01 (<jats:italic>let\u2010756<\/jats:italic>\/FGF21) and 568\u00a0\u00b1\u00a09 vs. 523\u00a0\u00b1\u00a010%,<jats:italic>P\u00a0&lt;<\/jats:italic>\u00a00.05 (<jats:italic>sir\u20102.2<\/jats:italic>\/SIRT\u20104)].<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Despite lacking an endoskeleton, ZA delays<jats:styled-content style=\"fixed-case\"><jats:italic>Caenorhabditis elegans<\/jats:italic><\/jats:styled-content>sarcopenia, which translates to improved neuromuscular function across the life course. Bisphosphonates might, therefore, be an immediately exploitable anti\u2010sarcopenia therapy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13335","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T01:23:53Z","timestamp":1695086633000},"page":"2613-2622","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Bisphosphonates attenuate age\u2010related muscle decline in<scp><i>Caenorhabditis elegans<\/i><\/scp>"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7660-7392","authenticated-orcid":false,"given":"Luke","family":"Slade","sequence":"first","affiliation":[{"name":"University of Exeter Medical School Exeter UK"},{"name":"Faculty of Health and Life Sciences University of Exeter Exeter UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby E.","family":"Bollen","sequence":"additional","affiliation":[{"name":"Centre of Metabolism, 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