Maybe they were testing the hypothesis that the chronically activated MTOR signal in the elderly was actually what impaired their ability to put on muscle? If it turned out that it actually increased muscle building in the elderly then it immediately becomes a solution to one of the most common age-related health conditions out there.
Unfortunately the results just sort of show that rapamycin isn’t entirely a free lunch, and if trying to counteract sarcopenia is your top priority then it makes sense to give the rapa a rest.
Not agreeing with you on this one. As @desertshores noted above (n=1 though but reliable IMO) RAPA seems to counter sarcopenia. Most people in old age are not looking to gain muscle, but preserve muscle and RAPA may? (and “does” according to @desertshores ) help preserve muscle. I as an example would not want to gain any muscle whatsoever, while would love to preserve (as long as possible) what I have so not worried about Rapa not matching my goals. To me the bigger surprise was the fact that even the rapa population actually were able to gain muscle, and that is a BIG plus IMO as I was of the opinion that Rapa does not allow/help gain muscle but rather may help preserve muscle. So as far as I’m concerned, this study did nothing to change my mind on RAPA nor to even change my RAPA regimen.
Certainly dont want to fall victim to any sort of confirmation bias but how do we extrapolate these rather important findings to people in their fifties recognizing ageing isnt a linear process and rather dramatic molecular sgifts happen at cresting points as 44, 60 etc. May be that should be the some kind of primary endpoint of younger cohort. Are the upsides or downsides cumulative?
Just typing out loud here but since we saw some pretty impressive results in the study for the older folks (aged 70-76) folks who took 1mg daily on health parameters, I wonder if the 6mg bolus dose explains why we saw these negative results in Brad’s trial.
I know the endpoints were different for both trials (cardiovascular vs anabolism) but what if instead of focusing on dosing frequency needing to be more spread out, we actually would be better off taking daily 1mg micro doses that might not actually worsen muscle benefits or even side effects like worse immunity, A1C, LDL, and ALP since it’s a lower dose.
Well, first 1mg its’s not much of a micro dose since that is the dose transplant patients take, and I kind of like the idea of doing 1mg daily for 5 days per week and see how it feels.
We do have a person in here @LaraPo that has been taking daily (?) Rapa for a long time.
If I remember correctly, she had once said she is very healthy and feels and looks better than her age group. Maybe she’ll chime in again with some info because she’s a really good N=1 example since she’s been doing it for a long time (over 10 years if I remember correctly) plus she is in relatively mature age, early 70’s (if I remember correctly) and if she is free of pains and aches and other old age maladies then maybe Rapa might have had a positive effect.
Yes but it’s a micro dose compared to the large intermittent doses people have done for anti aging. Maybe just small daily doses would be enough to get the benefits without the side effects of the intermittent dosing. It’s too bad that study didn’t measure the same outcomes that Brad’s study did because that would’ve given us a lot of information.
After all, pretty much everything else we take is in daily doses
Well, it has been 16 years since I started Rapamycin after kidney transplant. It had been working well for me - my kidney is working well and I’m still alive. 1 mg per day is definitely not a micro dose because it accumulates quickly and produces a kind of a permanent trough level between 3 and 5, which leads to mTOR2 inhibition with all expected and well described side effects. To avoid that negative side of Rapa it seems we need breaks. Nobody knows how often and how long. I prefer my trough not to fall under 1 and never cross 5. When it’s close to 1, I restart the 1 mg/day cycle till my trough reaches 4.5 - 5, and so on. I don’t think that those who take it for longevity should follow my transplant schedule. If not my transplant I would have longer breaks.
At 71 I feel pretty good. Have good energy, walk and jog daily, and still occasionally skate. No pains besides recently developed pain and stiffness in both thumbs. It started as a side effect of Lipitor. Pain went away after I stopped it but after starting Repatha it returned. Decrease in cholesterol definitely affects it. It’s the only thing that bothers me.
About the looks, it’s difficult to say if it’s Rapa or fillers and other cosmetic procedures. But after 70 I noticed that my skin elasticity changed. Fillers stopped working aa effectively as before. Now I need more frequent applications. It happened rather suddenly.
Another problem I have is inability to gain weight no matter how much or how often I eat. My weight got stuck on 110-112 lbs (5’3” height). Seems that Rapa created a permanent starvation mode for me and my body responds accordingly.
To play devil’s advocate against myself, this study last year showed 1mg daily might have worsened Alzheimer’s disease and inflammatory biomarkers in a small study of ten people. Very small study though so not sure how much merit to put into it.
Thanks for your detailed explanation. I know everyone is different and there’s different variables such as age, sex, and weight etc but do you mind sharing how long does it take you to reach trough of 4.5-5 (doing 1mg per day) and then how many days you have to usually rest to see it go back to about 1. Thanks,
If you have Alzheimer’s…dementia…it might push it back some… (once diseased …cells stop playing by the rules). If you don’t have Alzheimer’s… you wont get it.
Preventing it is better than treating, post disease.
Thanks @LaraPo. Great info. Lately (and surprisingly) I’ve been getting mouth sores and the cold symptoms (more often) from my weekly dose of 6mg, so given what I know now, I have decided to try 1mg daily for 7-10 days and then rest for 20. Basically, do 1mg first 7-10 of each month and rest the next 20 days. Clearly, we are experimenting and the weekly high doses was a guess (maybe a good one?), but what the heck might as well try other regimens also especially given the return of the side effects on my weekly regimen.
I thought the results were in a while ago. Unless I’m missing something there have been over 50 messages from various people in this thread about the same one, no?.
Clinical Peer Review: mTORC1 Inhibition vs. Exercise-Induced Adaptation (Stanfield et al., 2026)
I. Executive Summary
The analyzed data (Stanfield et al., 2026, Journal of Cachexia, Sarcopenia and Muscle) presents a critical challenge to the “longevity culture” surrounding off-label Rapamycin (Sirolimus) use. While Rapamycin is the undisputed gold standard for lifespan extension in diverse animal models—consistently extending life by 10–15% in rodents—this high-quality, preregistered human Randomized Controlled Trial (RCT) reveals a significant translational gap regarding skeletal muscle.
The study investigated whether a “cycling” protocol (6mg weekly, dosed 24 hours post-exercise) could overcome age-related anabolic resistance by inhibiting hyperactive basal mTORC1 and promoting autophagy, while leaving a window for exercise-induced growth. The results “floored” the investigators: Rapamycin did not enhance exercise gains; instead, it blunted them. In the most rigorous sensitivity analyses (Per-Protocol and Case-Complete), the placebo group significantly outperformed the Rapamycin group in functional metrics like the 30-second chair-stand test.
Furthermore, the trial identified specific safety signals that suggest 6mg/week may be too high for older populations. These include a statistically significant (though clinically modest) rise in HbA1c and a serious adverse event of pneumonia, highlighting the drug’s inherent immunosuppressive risk. The trial essentially confirms that the “building mode” (mTORC1 activation) required for exercise adaptation is functionally incompatible with the “maintenance mode” (mTORC1 inhibition) triggered by Rapamycin at this frequency. Future research must pivot toward significantly longer dosing intervals (e.g., every 3–6 weeks) to allow for homeostatic recovery.
II. Insight Bullets
Direct Blunting: 6mg/week of Rapamycin significantly attenuated functional strength gains from a 12-week exercise program in adults aged 65–85.
Cycling Failure: Dosing 24 hours after the final weekly exercise session was insufficient to prevent anabolic interference.
Half-Life Persistence: While serum levels may clear within 7 days, the 62-hour terminal half-life suggests Rapamycin remains in tissues (muscle/liver) during subsequent exercise sessions.
Anabolic Tension: There is a “real biological tension” between mTORC1 as a longevity target (inhibition) and its role as the master regulator of muscle protein synthesis (activation).
Placebo Superiority: Placebo groups consistently showed greater improvement in the 30-second chair-stand test across all sensitivity analyses.
Sensitivity Analysis Significance: When excluding non-compliant participants, the divergence between groups became statistically significant (favoring placebo).
Immunosuppression Risk: One participant developed community-acquired pneumonia requiring hospitalization after a single dose; causality cannot be excluded.
Glycemic Variability: A statistically significant rise in HbA1c was observed in the Rapamycin arm, confirming metabolic side effects even at intermittent doses.
Anabolic Resistance Hypothesis: The trial was designed to test if clearing “cellular trash” via autophagy could restore muscle sensitivity; this was not supported by the 12-week data.
Bioavailability Variance: The study used brand-name Rapamune (Pfizer) to ensure 100% bioavailability, unlike the earlier “PEARL” trial which used compounded pills with ~30% effective dosing.
CRP Outliers: Higher average inflammation in the Rapamycin group was driven by two extreme outliers; once removed, no significant anti-inflammatory effect was noted.
No Quality of Life Gain: SF-36 questionnaires showed no statistical difference in subjective health-related quality of life between groups.
Suboptimal Frequency: A once-weekly 6mg dose is likely too frequent for older adults looking to maintain or build muscle mass.
Tissue Specificity: The “optimal” dose for the brain or heart may be higher and more frequent than the optimal dose for skeletal muscle.
Trial Cost/Rigor: The study cost ~$724,000 and was crowdfunded to ensure total independence from pharmaceutical influence.
Nadir Levels: Preliminary data from other studies (University of Arizona) suggests most individuals clear Rapamycin from serum before the next weekly dose, but cellular levels likely persist.
Muscle vs. Lifespan: While muscle gains were blunted, the study does not rule out Rapamycin’s benefits for other longevity hallmarks (e.g., senescent cell clearance).
Exercise Interaction: Rapamycin may block the ERK1/2 and MNK1 signaling pathways required for contraction-induced protein synthesis.
Short-Term vs. Long-Term: Matt Kaeberlein hypothesizes that while short-term gains are blunted, a 12-month study might show the Rapamycin group eventually catching up or exceeding placebo.
Lack of PD Markers: The study did not perform muscle biopsies to confirm the actual degree of mTORC1 inhibition in the tissue (a noted limitation).
III. Adversarial Claims & Evidence Table
Claim from Video
Speaker’s Evidence
Scientific Reality (Current Data)
Evidence Grade
Verdict
Rapamycin blunts exercise adaptation in humans.
Stanfield Trial results (2026).
Confirmed in this study and supported by acute protein synthesis data Drummond et al., 2009.
B
Strong Support
mTORC1 is hyperactivated in aged human muscle.
Cited as rationale for the study.
Evidence in rodents is strong; human data is mixed, often showing blunted activation post-exercise Francaux et al., 2016.
C
Speculative
Rapamycin is safe at 6mg weekly.
Preliminary clinical experience.
Study found HbA1c rise and a serious pneumonia case. FDA safety warnings for Sirolimus include immunosuppression, dose dependent FDA PI.
B
FDA General Safety Warning
Intermittent dosing (once/week) prevents side effects.
Cultural consensus in longevity community.
Blunted muscle gains and glycemic changes suggest 6mg weekly dosing is still “too much” for homeostasis Stanfield et al., 2026.
B
Unsupported
Rapamycin improves body composition (Lean Mass).
Referenced “PEARL” trial.
PEARL trial showed gains in women but used compounded drug with low bioavailability Moel et al., 2025. Results are inconsistent.
B
Plausible
IV. Actionable Protocol (Prioritized)
High Confidence Tier (Protocol Changes Based on Evidence)
Decouple Rapamycin from Hypertrophy: Do not initiate Rapamycin if the primary goal is gaining functional strength or muscle mass via a new exercise program.
Monitor Glycemic Markers: Anyone on off-label Rapamycin should monitor HbA1c and fasting insulin quarterly, as even 6mg/week can perturb glucose homeostasis.
Experimental Tier (Refined Dosing Hypotheses)
Extend Dosing Intervals: To avoid the “blunting” effect seen in this trial, explore dosing every 14, 21, or even 42 days. This mimics “transient” inhibition seen in animal models that successfuly reversed aging phenotypes.
Wash-out Periods: Implement an 8-week “on” / 8-week “off” cycle to allow for muscle adaptation during the “off” phase while capturing geroprotective benefits during the “on” phase.
Red Flag Zone (Safety Data Absent)
Avoid Compounded Rapamycin: Bioavailability is unreliable. Only use FDA-approved, enteric-coated formulations if participating in clinical research.
Acute Infection Protocol: Stop all Rapamycin immediately at the first sign of bacterial or viral infection (fever, cough), given the hospitalization case noted in the trial.
V. Technical Mechanism Breakdown
The primary mechanism at play is the mTORC1-S6K1 Pathway.
Anabolic Signaling: In healthy muscle, resistance exercise activates mTORC1 via the mechanotransduction pathway and IGF-1/PI3K signaling. This leads to the phosphorylation of p70S6K and 4E-BP1, which are the master switches for mRNA translation and new protein synthesis.
The “Volume Dial” Conflict: Rapamycin functions as an allosteric inhibitor of mTORC1 by binding to FKBP12. Stanfield’s data suggests that at 6mg/week, the “volume” of mTORC1 is turned down so low—or for so long—that the muscle cannot respond to the mechanical stimulus of exercise.
Autophagy vs. Synthesis: The “Cycling Hypothesis” aimed to promote autophagy (cellular cleanup via Lysosomal degradation) during the “off” days. However, if mTORC1 remains inhibited, the cell remains in a “catabolic/maintenance” state, preventing the “anabolic/growth” state necessary for the hypertrophy seen in the placebo group.
mTORC2 Inhibition: Chronic or high-dose Rapamycin can also inhibit mTORC2, which regulates insulin sensitivity and the cytoskeleton. The rise in HbA1c observed in the trial is a classic indicator of potential mTORC2 interference or reduced glucose uptake in the muscle.
