One User Trying Very High Doses of Rapamycin, and Negative Adverse Events / Results

This seems like an unwise test of the highest doses of rapamycin I’ve heard of anyone taking. It comes from a doctor on Twitter who (it sounds like) is working with the patient (or at least seeing the patient when he has problems), which seems lucky given the problematic results at the higher dosages with the combination of the vaccine (when he had the vaccine the day after he took the 20mg dose of rapamycin).

The patient first tried an 80mg dose of rapamycin in 2020 (I think this same patient was earlier mentioned as taking 20mg on a weekly basis without problems), but then in November 2021 he tried 104mg over 6 hours, and 144mg over 36 hours.

The take-home message seems to be work closely with your doctor and don’t do radical dose experimentation by yourself. And, be extra careful to give yourself a washout period before getting a vaccination shot.

What’s the highest dose you have tried?

Note: Dyspepsia is indigestion / gastro-intestinal upset. Inotropy is when you have an increase or decrease in muscular contractions (see inotrope)

Summary: This patient took 20 mg sirolimus the night before [no 2 week washout as was done in Mannick study] a morning half-dose Moderna booster shot. The patient had an Extreme overnight vaccine reaction: shaking chills / fever / myalgia (muscle aches and pains) etc. They did a laboratory test that measures the presence and amount of antibodies in blood and the result was >2500.0 u/mL.

Link from above tweet:

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Thanks for sharing this! Would be a shame if this “dose escalation competition” gets out of hand, somebody gets hurt, the news media gets ahold of it and next thing you know there’s some kind of rapamycin/sirolimus crackdown.:roll_eyes:

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Right now, with COVID, I agree that there is too much risk. The interesting thing is that, in males at least (mice) the higher the dose used (so far) the longer the lifespan of the mice. In female mice they reached the peak at 2mg/kg, and 8mg/kg the lifespan was actually not increased at all (so back to zero lifespan increase at 8mg/kg) (source).

So its likely the optimal dose for longevity is higher than the 3mg to 10mg/week that most people seem to be using right now - but its also likely to vary by person, and there is that ever-present risk as you go very high, and more frequent, of inhibiting mTORc2 and the resulting immune system suppression.

It seems like it wouldn’t be too expensive to do a dose optimization / side effect minimization clinical study with 50 to 250 people monitoring of TREGs (Regulatory T-cells) to see if there is any immune system suppression, when it starts, how much it varies by person, etc…

Ultimately, Blagosklonny may be right - but the clinical testing and dose optimization needs to be done:

And the most recent NIA ITP program study (in mice) looked at dosing quite closely - with some interesting results:

"Initiation of Rapa at 42 ppm (from 20 months until death) increased survival significantly in both male and female mice. Exposure to Rapa for a 3-month period led to significant longevity benefit in males only. Protocols in which each month of Rapa treatment was followed by a month without Rapa exposure (from 20 months until death) were also effective in both sexes, though this approach was less effective than continuous exposure in female mice. "

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Personally, I would love to see a human Rapamycin / Rapalog dosing clinical trial that looked at:

  • Everolimus
  • Sirolimus
  • Temsirolimus

and

  • Dosing from 5mg/week to 50mg/week (or equivalent for other rapalogs), also a 2 week dosing schedule (and perhaps one at 3 or 4 weeks at higher doses), with regular blood testing for TREGs and Blood/Sirolimus Levels (as well as all other standards CBC blood test parameters)
  • Dosing with medication alone, or with drugs like Ketocanazole that increase bioavailability of sirolimus (with perhaps lower side effects)

Different sex and race, and age groups of people:

  • 30 to 40 years
  • 41 to 50 years
  • 51 to 60 years
  • 61 to 70 years
  • 71 to 80 years

Then, I’d also like to see some combination drug human clinical trials:

  • Rapaycin with Acarbose
  • Rapamycin with Canagliflozin
  • Rapamycin with 17-alpha estradiol

The one thing I wonder with this type of clinical study is whether a study like the one outlined above would be cheaper and faster, and just as valuable if it was done in dogs.

Another strategy to lower cost on a human dosing clinical study like the above would be to do it in a 3rd world country where costs are lower and things can proceed faster.

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Brian Kennedy in his video claimed his Delos Phama has compounds only inhibits TORC1 and not TORC2, if his drug works, high dosage would be safe.

True - but any new drug in development right now still has to go through Phase 1, 2 and 3 clinical trials, so likely 5 to 10 years away from any possible commercial availability… and of course any new drug is going to be priced like a new drug.

Everolimus in the USA prior to going generic was something like $15,000 per month - see link here (if not covered by insurance). I suspect that any new mTOR inhibitor will be priced similarly (and for anti-aging purposes won’t be covered by insurance). So then the calculus has to be is the marginal benefit of the new mTOR inhibitor worth the marginal cost (an extra $15,000/month) to you over the older mTOR inhibitors…

And, of course, it will take many years of animal clinical studies to prove that any new mTOR inhibitor works as well in animal lifespan extension as rapamycin. Each mouse study takes at least 3 or 4 years, so it will be 10 or 15 years before we really know if a new drug is as good as rapamycin.

And there are other mTOR startups out there besides Delos … David Sabatini is involved with 2 or three mTOR-focused startups, and Dudley Lamming another (not sure if there is overlap or not).

So until then, we need to figure out how to optimize things with rapamycin and rapalogs.

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i am concerned about the high dose effect on mTORC2, as this quoted in 2012 report by Lamming et. al.

“We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that
mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further,
decreased mTORC1 signaling was sufficient to extend lifespan independently from changes in
glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited
decreased mTORC1 activity and extended lifespan, but had normal glucose tolerance and insulin
sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in
vivo.”.

But Dudley Lamming @lwd2000 and others have also correctly pointed out that its longterm “Continual dosing” (and by that they mean daily dosing) that causes mTORC2 inhibition - so thats the key issue. Details here:

Conclusion: Here, we identified an intermittent rapamycin dosing schedule with minimal effects on
glucose tolerance, and we find that this schedule has a reduced impact on pyruvate tolerance, fasting glucose and insulin levels, beta cell function, and the immune system compared to daily rapamycin treatment. Further, we find that the FDAapproved rapamycin analogs everolimus and temsirolimus efficiently inhibit mTORC1 while having a reduced impact on glucose and pyruvate tolerance. Our results suggest that many of the negative side effects of rapamycin treatment can be mitigated through intermittent dosing or the use of rapamycin analogs.

What I find confusing is that Dudley Lamming and team suggest above that rapalogs (i.e. everolimus) seems to be better than sirolimus in terms of glucose and pyruvate impact, but at the same time this other study cited below seems to suggest that everolimus is worse (i.e. more significant effects) in terms of inhibiting mTORC2.

In his rapamycin / muscle human clinical trial, Dr. Brad Stanfield suggests:

It is important to note that the lifespan-enhancing effects of mTOR inhibitors have been linked to mTORC1 inhibition, whereas inhibition mTORC2 might even be detrimental, because mTORC2 controls insulin-mediated suppression of hepatic gluconeogenesis [28]. Therefore for this proposed trial, Sirolimus is the preferred rapamycin analogue as it does not inhibit mTORC2 to the same extent as Everolimus.

These two research papers cited above seem to contradict each other. @lwd2000 or @mkaeberlein any comments on this apparent contradiction in the two above mentioned studies?

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I’m pretty sure rapamycin is highly specific for mTORC1 and does not inhibit mTORC2 directly, even at high doses; rather, the effect on mTORC2 is indirect as a result of chronic continuous inhibition of mTORC1, as some sort of compensatory mechanism. I believe Kaeberlein said in the Attia podcast that he theorizes the insulin resistance from chronic rapamycin may even be a result of the body using a greater proportion of fat vs glucose for fuel, similar to the insulin resistance that’s seen during ketosis/fasting.

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Yes, exactly correct. Dudley’s work in mice is very good, but the whole mTORC1 “good”, mTORC2 “bad” thing is probably overly simplistic and still only a model. Peter and I discussed this in some detail in his podcast. I don’t really know of any compelling evidence to favor everolimus over rapamycin (sirolimus) or vice versa at this point. Everolimus (RAD001) is what was used in the Mannick studies, but rapamycin/sirolimus is what has been used in all of the mouse studies showing LS extension and numerous healthspan benefits.

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Welcome to the forum, Dr. Kaeberlein! My dog and I are huge fans. If you have time (and I understand if you don’t), I’d love to see your thoughts on the “rapamycin and muscle inhibition” thread. The overarching question is, during the 2+ day weekly window of maximal mTOR inhibition after taking rapamycin, does high intensity exercise interfere with the otherwise-beneficial long-term effects of rapamycin on muscle tissue, either by partially reversing mTOR inhibition or by stimulating pathways of protein synthesis that counteract autophagy and/or other beneficial effects of rapamycin. Thanks!
-David

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It’s a great question and I really don’t know of any directly relevant data, so it’s just an educated guess. To make matters worse, the muscle people have been completely wrong about the effects of rapamycin on muscle maintenance up to this point. They kept saying it would make sarcopenia worse, but it appears to be just the opposite (at least in mice and rats). So… personally unless you are doing heavy resistance training for muscle growth I wouldn’t worry about it very much. If you are doing heavy resistance training, you might want to schedule your rapa dosing to coincide with a rest day or two-day rest. E.g. if you do something like Stronglifts 5x5 and taking rapa 1x per week, you could dose at the beginning of the 2 day rest each week. But again, that’s just a guess.

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Thanks! That’s actually what I’ve been doing. Rapa on Sunday morning, and Sunday/Monday I just do light cardio (zone 2), dog walks, stretching, etc. Back to resistance training on Tuesday-Saturday. Now I just wonder if the rapa interferes with recovery from the resistance training (if so, I give up!:laughing:)

It also seems (intuitively, at least?) that going light on calories/carbs/protein on those 2 days might be additive/synergistic in taking max advantage of that “mTOR suppression window”. (also likely pure speculation, I know)

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Thanks Matt! This is insightful and useful. It looks like you prefer approach 2 in this thread: https://www.reddit.com/r/rapagains/comments/ogw7bt/organizing_work_outs_and_diet_around_a_rapamycin/

If one is not resting or lifting weights on the days of rapa dosage, do you have opinions on what kind of exercise would be most beneficial? Endurance v.s. Cardio v.s. HIIT? Do you expect to see detrimental effects on these exercises similar to those from metformin, or do you think that’s comparing apples to oranges?

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Some good cautionary advice for dose upmanship

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