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Exercise and Weekly Sirolimus (Rapamycin) in Older Adults: RAPA‐EX‐01 Randomised, Double‐Blind, Placebo‐Controlled Trial

15 April 2026

Stanfield Brad, Leroux Brian, Kaeberlein Matt, Jones Julie, Lucas Ruth

Summary

  1. Plain-language summary of what the study found: This study explored whether taking a weekly dose of sirolimus (rapamycin) could improve the benefits of a home-based exercise program in older adults. Contrary to expectations, the drug did not enhance exercise gains, and in some analyses, it seemed to slightly reduce them, while also increasing minor side effects.

  2. Key findings:

    • Both groups improved physical function from their exercise program (chair-stands, 6-minute walk, grip strength).
    • The sirolimus group generally showed less improvement in physical function compared to the placebo group.
    • Sensitivity analyses for the primary outcome (chair-stand repetitions) indicated that sirolimus modestly attenuated (reduced) the gains from exercise.
    • Participants taking sirolimus experienced a higher total number of minor adverse events and one serious infection possibly related to the drug.

  3. Practical takeaways for someone interested in nutrition and longevity: For individuals interested in longevity and healthy aging, this study suggests that adding weekly sirolimus (rapamycin) to an exercise routine in older adults is not beneficial for enhancing physical improvements and carries increased risks of side effects. Focus should remain on consistent exercise and a healthy lifestyle, as the 'cycling hypothesis' for sirolimus-enhanced exercise did not translate positively in this trial.

  4. Study limitations: This was an exploratory trial with a relatively small number of participants and a short duration (13 weeks), limiting the generalizability and conclusive nature of the findings.

Abstract

ABSTRACT Background Preclinical models suggest alternating activation and inhibition of mechanistic target of rapamycin complex 1 (mTORC1) could enhance adaptation to exercise (‘cycling hypothesis’). Whether this concept translates to older adults is unknown. This exploratory trial assessed whether once‐weekly sirolimus (rapamycin) 6 mg enhances or inhibits functional gains from a home‐based exercise programme. Methods In this randomised, double‐blind, placebo‐controlled trial, 40 sedentary adults aged 65–85 years (mean 72.2 years; 47.5% female) were assigned (1:1) to sirolimus (rapamycin) 6 mg or matched placebo once weekly for 13 weeks. Both groups performed a standardised home‐based resistance (chair‐stands) and endurance (exercycle) programme three times/week. The primary outcome was the change in 30‐s chair‐stand repetitions at 13 weeks (intention‐to‐treat; ANCOVA adjusted for baseline performance, age stratum and sex). Complete‐case (CC) and per‐protocol (PP) analyses were prespecified sensitivity analyses. Secondary outcomes included grip strength, 6‐min walk distance, SF‐36 physical and mental component scores, C‐reactive protein and several epigenetic age measures. Safety was assessed through adverse‐event monitoring and laboratory tests. Results Both groups improved chair‐stand performance. The primary intention‐to‐treat analysis showed an adjusted mean difference (sirolimus–placebo) of −2.13 repetitions (95% CI −4.61 to 0.34; p  = 0.089). Sensitivity analyses favoured placebo and reached statistical significance: complete‐case analysis (16 sirolimus, 19 placebo) showed a difference of −2.46 repetitions (95% CI −4.87 to −0.06; p  = 0.045) and per‐protocol analysis (15 sirolimus, 16 placebo) showed −3.44 repetitions (95% CI −5.86 to −0.99; p  = 0.007). Secondary functional outcomes also favoured placebo but were not statistically significant: the adjusted mean difference for 6MWD was −4.87 m (95% CI −28.97 to 19.71; p  = 0.706) and for grip strength was −1.13 kg (95% CI −3.52 to 1.18; p  = 0.344). SF‐36 scores showed small, non‐significant differences favouring placebo. Quality‐of‐life scores showed small, non‐significant differences favouring placebo. Seventeen participants (85%) in each arm reported ≥ 1 adverse event, but the total burden was higher with sirolimus (99 vs. 63 events), including one possibly drug‐related serious adverse event (pneumonia). Conclusion In this exploratory trial, once‐weekly sirolimus (rapamycin) 6 mg did not enhance, and in sensitivity analyses, it may have modestly attenuated short‐term 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–risk profile can be achieved. Trial Registration: ACTRN12624000790549
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