I didn’t know that everolimus was available? Can doctors prescribe it? Generic?
Some are bringing up bodybuilders in response. Yes, most of us are not bodybuilders, not trying to be Schwarzenegger. But one huge problem with aging is muscle loss, sarcopenia, frailty. So in being concerned about healthspan, healthy aging, I think one has to consider muscular effect?
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But rapa dosing protocols are very speculative to begin with? For example, why do most take it once weekly? Is there any science behind that? (In animal studies, didn’t the animals receive it every day?)
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Absolutely. It’s arbitrary. There is a variety of dosages and protocols, sometimes based on specific goals (like in transplant patients). The once a week at 6mg protocol is based on the famous Joan Mannick study, where a variety of dosages and protocols of everolimus (a close, though not identical rapalogue) were used in elderly subjects to test the effect on immunity. Based on effectiveness and side effect profile, 5mg once a week seemed most favorable. Based on that the 6mg once a week rapamycin was implemented by among others Dr. Green who had a lot of people taking rapamycin for longevity purposes - from this patient cohort Dr. Green developed a lot of clinical experience with rapamycin, and the 6mg once a week was the most popular option. Since then a lot of people in the longevity space experimented with rapamycin with a variety of dosages and protocols, and a lot of experience was gathered. The 6mg once a week remained the most popular option.
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I had previously shifted from once per week to once every two weeks and the study just made me a little more confident in that decision. I’m not trying to build any more muscle though.
I had considered monthly dosing but it’s likely that isn’t enough for optimal lifespan extension. Once every two weeks probably isn’t enough either but I’ll take suboptimal with lower chances of side effects.
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A few questions worth considering if thinking about stopping rapamycin because of loss of muscle building. (1) why do you want more muscle? If you are frail, then more muscle is a lifesaver. If you are muscular but want more muscle, be sure to think about what you aren’t doing to build / maintain physical capacity: cardio (endurance), HIIT (max heart rate), mobility/ balance (full range of motion), coordination (hand-eye, running fast, eye tracking), fast reaction speed (rough ground, reacting to opponent). (2) if you are not building muscle despite effort to do so (assuming you are not at your genetic limit), make sure you are working hard enough, often enough, eating enough (protein), and sleeping enough. It’s probably not the rapamycin, in my opinion.
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This protocol is actually rooted in pharmacokinetics. Trough concentrations exceeding 15 μg/L correlate with adverse reactions—primarily thrombocytopenia and hyperlipidemia. Since a 5mg dose in kidney transplant patients yields a trough level of 13.6 μg/L, the 6mg figure was selected. Consequently, you can see why this dosing regimen is highly questionable.
The once-weekly frequency is driven by the drug’s prolonged half-life, as chronic mTOR inhibition can trigger rebound hyperactivation.
https://onlinelibrary.wiley.com/doi/10.1111/jcpt.13753
An approved sirolimus dosing regimen (kidney transplant recipients) consists of 6 mg oral loading dose followed by 2 mg once daily. The recommended target trough concentration is 4–12 μg/L when combined with cyclosporine and 12–20 μg/L following cyclosporine discontinuation. Given sirolimus long half-life, the whole blood levels should be measured at least 5 days after the last dosing adjustment when new steady-state has already been reached. The recommendations for sirolimus dosage individualization are summarized in Table 1.
My view ia that a low (~zero) trough needs to be maintained for a material period of time