{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T05:10:25Z","timestamp":1792559425747,"version":"4.5.0"},"reference-count":38,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Preclinical models suggest alternating activation and inhibition of mechanistic target of rapamycin complex 1 (mTORC1) could enhance adaptation to exercise (\u2018cycling hypothesis\u2019). Whether this concept translates to older adults is unknown. This exploratory trial assessed whether once\u2010weekly sirolimus (rapamycin) 6\u2009mg enhances or inhibits functional gains from a home\u2010based exercise programme.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this randomised, double\u2010blind, placebo\u2010controlled trial, 40 sedentary adults aged 65\u201385\u2009years (mean 72.2\u2009years; 47.5% female) were assigned (1:1) to sirolimus (rapamycin) 6\u2009mg or matched placebo once weekly for 13\u2009weeks. Both groups performed a standardised home\u2010based resistance (chair\u2010stands) and endurance (exercycle) programme three times\/week. The primary outcome was the change in 30\u2010s chair\u2010stand repetitions at 13\u2009weeks (intention\u2010to\u2010treat; ANCOVA adjusted for baseline performance, age stratum and sex). Complete\u2010case (CC) and per\u2010protocol (PP) analyses were prespecified sensitivity analyses. Secondary outcomes included grip strength, 6\u2010min walk distance, SF\u201036 physical and mental component scores, C\u2010reactive protein and several epigenetic age measures. Safety was assessed through adverse\u2010event monitoring and laboratory tests.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both groups improved chair\u2010stand performance. The primary intention\u2010to\u2010treat analysis showed an adjusted mean difference (sirolimus\u2013placebo) of \u22122.13 repetitions (95% CI \u22124.61 to 0.34;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.089). Sensitivity analyses favoured placebo and reached statistical significance: complete\u2010case analysis (16 sirolimus, 19 placebo) showed a difference of \u22122.46 repetitions (95% CI \u22124.87 to \u22120.06;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.045) and per\u2010protocol analysis (15 sirolimus, 16 placebo) showed \u22123.44 repetitions (95% CI \u22125.86 to \u22120.99;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.007). Secondary functional outcomes also favoured placebo but were not statistically significant: the adjusted mean difference for 6MWD was \u22124.87\u2009m (95% CI \u221228.97 to 19.71;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.706) and for grip strength was \u22121.13\u2009kg (95% CI \u22123.52 to 1.18;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.344). SF\u201036 scores showed small, non\u2010significant differences favouring placebo. Quality\u2010of\u2010life scores showed small, non\u2010significant differences favouring placebo. Seventeen participants (85%) in each arm reported \u2265\u20091 adverse event, but the total burden was higher with sirolimus (99 vs. 63 events), including one possibly drug\u2010related serious adverse event (pneumonia).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In this exploratory trial, once\u2010weekly sirolimus (rapamycin) 6\u2009mg did not enhance, and in sensitivity analyses, it may have modestly attenuated short\u2010term functional improvements from a home exercise programme in older adults. The regimen also increased the burden of minor adverse events and may have contributed to one serious infection. Future trials with longer treatment duration or less frequent\/lower dosing are needed to determine whether a favourable benefit\u2013risk profile can be achieved.<\/jats:p>\n                    <jats:p>\n                      <jats:bold>Trial Registration:<\/jats:bold>\n                      ACTRN12624000790549\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.70274","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T23:39:45Z","timestamp":1776296385000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA\u2010EX\u201001 Randomised, Double\u2010Blind, Placebo\u2010Controlled Trial"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1004-2039","authenticated-orcid":false,"given":"Brad","family":"Stanfield","sequence":"first","affiliation":[{"name":"Royal New Zealand College of General Practitioners  Wellington New Zealand"},{"name":"University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Leroux","sequence":"additional","affiliation":[{"name":"University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Kaeberlein","sequence":"additional","affiliation":[{"name":"University of Washington  Seattle Washington USA"},{"name":"Optispan Inc.  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Jones","sequence":"additional","affiliation":[{"name":"BioValeo  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Lucas","sequence":"additional","affiliation":[{"name":"BioValeo  Wellington New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"e_1_2_9_2_1","first-page":"11","article-title":"Human Aging, Muscle Mass, and Fiber Type Composition","volume":"50","author":"Lexell J.","year":"1995","journal-title":"Journals of Gerontology. 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