Exercise And Weekly Sirolimus (Rapamycin) In Older Adults: RAPA-EX-01 Randomised, Double-Blind, Placebo-Controlled Trial
Research Summary
A randomised, double-blind, placebo-controlled exploratory trial testing the ‘cycling hypothesis’ – that alternating mTORC1 activation with exercise and mTORC1 inhibition on rest days could preserve or amplify training gains – in sedentary older adults starting a home exercise programme.
Who Or What Was Studied?
40 community-dwelling, sedentary adults aged 65 to 85 years (mean 72.2 years, 47.5% female), randomised 1:1 to sirolimus 6 mg or matched placebo once weekly for 13 weeks. Both groups did the same home-based programme three times a week: 30-second chair stands with progressive density training, plus a magnetic-resistance exercycle progressing from 10 to 25 minutes. The drug was taken on day 6 of each training week, about 24 hours after the last session. The primary outcome was the change in 30-second chair-stand repetitions; secondary outcomes were 6-minute walk distance, grip strength, SF-36 scores, C-reactive protein and four epigenetic clocks.
What Did The Research Show?
- Both groups improved, but the primary intention-to-treat analysis showed an adjusted difference of -2.13 chair-stand repetitions for sirolimus versus placebo (95% CI -4.61 to 0.34; p = 0.089); the prespecified complete-case analysis gave -2.46 repetitions (95% CI -4.87 to -0.06; p = 0.045) and the per-protocol analysis -3.44 repetitions (95% CI -5.86 to -0.99; p = 0.007).
- Secondary functional outcomes pointed the same way but were not statistically significant: 6-minute walk distance -4.87 m (p = 0.706), grip strength -1.19 kg (p = 0.344) and SF-36 physical component score -2.76 points (p = 0.376).
- Four epigenetic clocks (PCGrimAge, SystemsAge, OMICmAge, DunedinPACE) and C-reactive protein showed no significant between-group differences.
- Adverse events were more frequent with sirolimus: 99 events versus 63 (rate ratio 1.57, 95% CI 0.86-2.87; p = 0.14), events judged possibly or probably drug-related in 35% versus 15% of participants, and one serious event (community-acquired pneumonia) in the sirolimus arm.
- Laboratory shifts in the sirolimus arm included HbA1c +1.74 mmol/mol (p = 0.030), LDL cholesterol +0.32 mmol/L (p = 0.036) and a lower mean corpuscular volume (-2.9 fL, p < 0.001).
Limitations And Interpretation
- Small exploratory trial (n = 40) sized to detect a large effect: the primary intention-to-treat result was not statistically significant, and the significant findings come from the sensitivity analyses.
- Only 13 weeks and a single dose (6 mg once weekly); with a terminal half-life of about 62 hours the drug may still have been active during training days, but no drug levels or muscle biopsies were measured, so the mechanism is inferred rather than shown.
- Home-based body-weight training has a lower ceiling for maximal strength than loaded gym training, which may limit the size of any signal.
- The trial was funded by crowdfunding via Lifespan.io and VitaDAO, and it tested exercise plus drug: the findings apply to this combination in sedentary older adults, not to rapamycin alone.
Summary prepared from the published paper (abstract and full text where accessible). This is not medical advice — always consult the original publication.