What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity?

Rapamycin Dosing Level and Timing

Here are the common dosing variables that I see people considering when they start dosing rapamycin for anti-aging (from an August, 2022 user poll here on our site):

Note: Most users taking rapamycin for anti-aging, take between 3mg and 10mg per week, on a once-weekly dosing schedule. Our forum software doesn’t accommodate conditional branching in these surveys, but most of the doses above 10mg are likely people who are dosing once every 10 days or 2 weeks, so an effective weekly dose of between 5 and 10mg per week. A few people are trying much higher dosing levels.

1. Starting Dose and Ramping Up the Dose:
I started at 1mg per week, then each week increased by 1mg until I reached my target dose of 6mg/week. Most people, working with their doctor, seem to end up taking between 3mg and 10mg of rapamycin in a single weekly dose. (see recent poll results above)

In my case, many months after I plateaued at 6m per week, I slowly increased to my current dose of 10mg/week. This has worked well for me, with only one time when I got a canker sore (which cleared up by itself after a few days). Other people ramp up more quickly - for example 3mg/week, then 6 mg a week… Generally I seem to see more side effects the faster the ramp up in dose.

Patient’s of Dr Green say he recommends taking rapamycin in the morning as it can be stimulative.

Patient’s of Dr. Green have conveyed that he has the following blood tests ordered before the initial visit, to get a baseline of information:

  • Insulin
  • CBC (Complete Blood Count)
  • CMP (Comprehensive Metabolic Panel
  • Ferritin
  • Lipid Panel
  • Hemoglobin A1C

People also say Dr. Green also strongly recommends people get their DNA sequenced (e.g. 23andMe), primarily to look for the APOE variants which are suggestive of increased risk for Alzheimers.

Other people look at additional blood tests for additional information:

A consideration for what food to take with/before taking the rapamycin: How to Improve Bioavailability, Lower the Cost, of Rapamycin

2. Timing of the Dose (weekly, every two weeks, etc.)
Most people taking rapamycin for anti-aging seem to have settled on a weekly dose, largely because that was the dosing frequency originally used in the Mannick 2014 Study of the rapalog everolimus. That study used a weekly dose and saw only minor side effects over the period of the study.

Other people are looking at the research on the half-life of rapamycin (typically cited as somewhere between 62 and 80+ hours - and seems to vary by age and ethnicity) and then evaluating their dose and weight and determining when their blood sirolimus levels are at a trough level that they consider safe enough for the next dose. For some people this is 10 or 12 days. As you can see in the graph below tracking blood sirolimus levels over time, there is a quick initial peak about 1 hour after taking the medicine, and then it decreases by about 50% every 65 to 85 hours (source).

Recently the Life Extension Foundation Lab services has started offering a low cost blood test for blood sirolimus levels via Labcorp. testing services. They sent this email to me recently:

After re-evaluating current pricing for test 716712, we are able to offer it at a price of $95 going forward. Please call us if you would like to place an order. Thank you for your support and interest in our lab testing services. Life Extension Customer Support, (800) 678-8989.

More details on $95 Sirolimus Blood test from Life Extension Corp.

This may be a good way to make sure your dosing schedule is working in terms of minimizing risk of MTORC2 inhibition.

Lately, some people have started taking higher doses (e.g. 20mg) with a once every two weeks dosing schedule. This has been adopted by Dr. Mikhail Blagosklonny because he believes that the higher intial dose may help penetrate the blood brain barrier (see tweet here).

On Twitter, on Aging-focused Doctor has mentioned a patient who is using 20mg rapamycin every week: (sources here and here)

Case report, unpublished: 20 mg rapamycin once a week (~0.36 mg/kg!) anecdotally associated with insulin<1, fasting BG in the 70s-80s, perfect lipids and other biomarkers. Cmin is below immunosuppressive transplant range, and patient doing great with subjectively better immunity despite not washing out (ie, MTORC2 feedback inhibition) between doses. ( from details posted by https://twitter.com/agingdoc1)

That’s no typo: 20 mg, every week. Cmax peaks/Cmin troughs to prove it. Contrary to hypothesis, BG went down rather than up (this ideal BMI subject had a bit of dawn phenomenon - i.e. high morning glucose levels - that only disappeared following dose escalation to this level.

While we are addressing important issues in other model systems, what is the potential for translational work with rapamycin RCTs at such high-dose periodic regimens?

The closest thing to that is Joan Mannick’s everolimus work @ 20 mg ( and 5mg) weekly, but rapamycin is a lot more affordable, has vastly more model organism literature, and based on the clinical data we have so far (including case series in the several hundred by Dr. Alan Green, who monitors lipid panel & HOMA-IR in every patient every visit with rare material biomarker perturbations[unpublished data]) it appears very safe with the weekly dosing despite the longer half-life compared with everolimus.

I see some trials at various stages at clinicaltrials.gov , esp. for Covid but only at much lower doses than the 20 mg/week ( allometric scaling and pharmacokinetics suggest doses in the 20-40mg range for humans based on the ITP results). Moreover these trials are based on either short-term or continuous dosage as opposed to long term pulsed therapy akin to work by Anisimov, & separately by Mannick (w/ raplog everolimus).

Rapamycin is serious business with real risks (& potential/theoretical benefits yet to be confirmed), so less anarchy and the cultivation of more systematic approaches - carefully weighing risks versus benefits as clinically appropriate to that situation - would be a good thing…

4. Rapamycin Vacations
We don’t yet know what the optimal doses, or dosing schedules, are for anti-aging, but the current theory that many of the rapamycin researchers think may be true is that the higher the dose, (and more frequent the dose) and the longer the use of rapamycin, the greater the risk of potentially blocking the MTORC2 pathway, which can lead to reduced immune system function and risk of increased infections and other issues. We have not see this issue much at all in this user group, on the weekly or every two week dosing schedules. Given the lack of any issues related to immune function that we’ve seen, most people today do not do “rapamycin vacations”, but some still do. So, to make sure they are not blocking MTORC2 some people are taking periodic “vacations” from rapamycin (of a few weeks or longer), so as to be sure that the MTORC2 pathway is not excessively inhibited, and is allowed to return to normal function.

There is no research yet on the details of how much time is the right amount of time-off from rapamycin to allow this, so its all guess work right now.

In Peter Attia’s podcast interview with Joan Mannick and Nir Barzelai he mentioned his dosing protocol and the rationale behind it:

  • Joan’s paper suggested 5 mg once a week was a pretty good place to start
  • Peter triangulated that data with data from Matt Kaeberlein’s dogs
  • He settled on 6 mg once a week
  • What still remains unclear for Peter is how to cycle it
    • Current protocol is—on for 8 weeks, off for 5 weeks
    • But, truthfully, without more advanced testing, I’m really making it up and therefore I don’t like talking about it like I just did .”

More Reading:

Pharmacokenetics and Safety of a Single Dose of Rapamycin (sirolimus) in Healthy Males
10.1097@00007691-200010000-00006-3.pdf (163.8 KB)

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Do we know if weekly R at 1-10mg does blocks MTORC2 significantly?

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Hi, welcome to the site. Good question. We “sort” of know it - but I believe it likely varies by cell type and by person. We know from the scientific literature that rapamycin binds very specifically to mTORC1, and indirectly to mTORC2:

It is well established that rapamycin directly inhibits mTORC1 through a noncompetitive mechanism by establishing a three-way interaction with mTOR and FKBP12 (Liang et al ., 1999). While rapamycin binds mTORC1 directly, it does not bind the mTORC2 complex. Instead, it is proposed that rapamycin inhibits the assembly of the mTORC2 complex in a manner requiring FKBP12.

from here (but more generally in many papers).

The general operating model that the researchers are using is that mTORC1 inhibition drives the benefits that we see (anti-aging) but the mTORC2 inhibition drives the negative side effects. This is not proven completely - but its the general model that the researchers say they are working on.

We also know that to get the immune system modulation (which for us would be a negative side effect, but is their goal) that the organ transplant patients get when they take high dosages of rapamycin can require much higher dosages, for longer periods of time.

Anecdotally at a personal level we see most people taking and you can see the benefits they are suggesting at these levels, and the side effects (which all seem pretty benign):

But what we don’t know is how the doses impact (or will impact) any given individual - both from a blood level response, and a side effect (or benefits in detail) perspective.

The research is still early in anti-aging, and very little has been done on rapamycin in generally healthy individuals (as opposed to really sick people - cancer… organ transplantation, etc. and who are typically taking many different medications in addition to rapamycin.

So - its complex.

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although this paper didn’t seem to quantify the degree of inhibition of MTORC2, the photo figures showed a strong response. It does seem wise to take some time off of R to let any inhibited metabolism return to normal for a while.

Agreed… its probably wise to take periodic “vacations” from rapamycin to pause any possible mTORC2 inhibition. Of course - the big issue is when and for how long?

I wonder if there are any potential leading indicators that your mTORC2 is getting too inhibited? I also wonder if it matters (in humans) where (in what organs and tissues) and when the mTORC2 inhibition is taking place? And if that might be revealed in any way short of tissue biopsies.

From that same paper first referenced above:

" As expected, inhibition of the phosphorylation of the mTORC1 substrate, S6 (S240/244), was seen in every tissue tested, but mTORC2 inhibition, measured by the phosphorylation of Akt (S473), was only seen to differing degrees in a subset of tissues including heart, soleus muscle, gastrocnemius muscle, pancreas, liver, lung, visceral fat, and spleen (Figs​(Figs6A6A,​,BB,​,CC and S3)"

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Obviously, much more research needs to be done on the mTORC2 inhibition issue, and how pulse dosing may or may not inhibit mTORC2 over weeks, months and years. All the literature talks about the need for “chronic” and typically “high” dosing of rapamycin to inhibit mTORC2 - but the exact definitions of “chronic” seems to lack experimental evidence in healthy humans especially related to periodic schedules.

acel0014-0265-f7

In some tissues/diseases, such as cancer, it will likely be beneficial to inhibit both mTORC1 and mTORC2 where others, such as the aging process in general, might benefit from mTORC1-selective inhibition to avoid the negative metabolic side effects associated with prolonged treatment of the drug (Stallone et al ., 2009; Houde et al ., 2010). Current literature supports that the inhibition of mTORC1 contributes to the longevity effects of rapamycin and the inhibition of mTORC2, specifically in the liver, causes the negative effects of rapamycin on glucose homeostasis. However, more experiments are required to understand how the inhibition of these 2 complexes on a tissue-by-tissue basis affects the longevity of the organism as a whole.

Source

I’m just reviewing more on the whole issue of mTORC2 inhibition as its an important area I’m still learning about. Here are some notes from a podcast with one of the Novartis authors of the 2014 Mannick paper:

Peter Attia asked Lloyd Klickstein:

How much exposure to rapamycin before you start to see this dual-prong of inhibition of TORC1 and TORC2?

His response was:

In humans, after a week to a month, you can start to see consequences of TORC2 inhibition with a rapalog alone and it’s reflected in hyperglycemia and hypertriglyceridemia. This happens in “normal” people as well—i.e., non-diabetic, non-immunocompromised

In one experiment. Patients with polycystic kidney disease that were otherwise healthy, took the rapalog (RAD001) and a substantial fraction saw these biochemical changes in their blood

  • The dose was 5 to 10 mg a day (equivalent to 2-8 mg of rapamycin)
  • BUT… not everyone has these effects and that it unclear why that’s the case

Again - in this example the doses are very high - 5mg to 10mg PER DAY - for weeks or month+.

Additionally - there is significant controversy over the interpretation of the “hyperglycemia and hypertriglyceridemia” mentioned above. Many researchers - Matt Kaeberlein and Mikhail Blaggosklony, included - who believe that these are benign effects that are part of the lifespan extension effect.

E.g. Fasting and rapamycin: diabetes versus benevolent glucose intolerance

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Also, in the same interview, Lloyd Klickstein said, about the study with the rapalog everolimus:

    • Each of the doses did a different thing to TORC1 inhibition…
      • The .5 mg dose partially inhibited in a sustained fashion.
      • The 5 mg once a week fully inhibited TORC1 for a couple days out of the week
      • The 20 mgs would fully inhibit TORC1 over the dosing interval (i.e., nonstop inhibition of MTORC1 until your next dose)
  • Did any of these have TORC2 inhibition?

    • Nobody had to discontinue the drug for that reason

how many people actually had adverse effects which was surprisingly constant

  • Placebo group=12
  • .5 mg daily=22
  • 5 mg weekly=20
  • 20 mg weekly=27

Mouth ulceration (canker sores) were the most common side effect of rapamycin/rapalogs

  • 11.5% of the 0.5 mg daily
  • 4%, of the 5 mg weekly
  • 17% of the 20 mg weekly
    • That tells a very interesting story about the kinetics of this drug.
    • Lloyd Klickstein: We don’t know why this can cause ulcers

The side effects they saw in this study at the different doses were as follows (n = 218):

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In support of rapa every 2 weeks is this video with Dr Green ; Rapamycin: Practical Dosage & Benefits | Dr Alan Green Episode 4 - YouTube

Green mentions 2 weeks to allow rapa 62 hr half life to decrease blood level then re-dose.

Green mentioned on top of the desire to suppress mtor, he used the words: benefit of rapa is also due to a differential between blood level now vs post dose. I add the words; spiking, pulsing. VS continuously keep mtor supressed. Just attempting to bring Dr Green comments here. Best to all.

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Wondering if there is any research or anecdotal information about rapamycin and resistance exercise. It seems pretty clear that while rapamycin supplementation reduces muscle wasting (sarcopenia) in aging mice, it also blocks protein synthesis. Since I do both cardio and resistance training, I wonder if one should schedule resistance training at 1. the end of the week after taking sirolimus or 2. during the washout vacation period? See

https://www.gssiweb.org/sports-science-exchange/article/sse-123-nutrition-and-the-molecular-response-to-strength-training

Interesting question regarding the differentiated issue of cardio and resistance training. I also do both - biking for an hour 3 or 4 times a week, and strength training 2 or 3 times a week for 45 minutes or so. I don’t change my schedule based on my rapamycin intake - but I do expect different results.

From what I’ve read, in the first few days after rapamycin intake you likely have much higher mTOR inhibition - so muscle growth after workout will likely be minimized. But - I think it was discussed by Peter Attia and Matt Kaeberlein in their recent podcast, or perhaps another one - generally the theory is just keep exercising on your regular schedule, and you’ll get some benefit. When mTOR is highly inhibited your workout will help to maintain your muscle and help prevent muscle wasting (due to lack of mTOR) - and then when the mTOR inhibition has receded - i.e. later in the week, you’ll get more gains.

On the broader issue of strength training / muscle building and rapamycin use - did you see this previous conversation?

I initially worried about rapamycin inhibiting muscle growth. However, something I read recently (frustrated that I didn’t record source) said that taking rapamycin periodically will enhance muscle growth because the periods of autophagy will enable the anabolic phase to work better.

There is a whole discussion on the muscle / rapamycin / mTOR issue here:

You may have seen this:

Full PDF below:

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Has anyone written about best time of day to take rapamycin? i.e. does it matter if taken in the morning or at night?

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Yes, generally better in the morning as rapamycin can be stimulating for some people.

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thank you. after doing research and thinking about rapamycin for 2 years, i just took my first dose this morning. i went straight to 5mg of rapamune, figuring that this is probably the minimum effective dose, and can go to 6mg next week. i have done 3 day fasts several times, so i figured that i have some experience with inhibiting mtor the natural way. other then a small headache the first hour (very likely a placebo type of effect), i feel totally normal. i also put on a glucose monitor for the next two weeks to see if anything changes from my norm.

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Thanks for the update. Please let us know results - positive or negative with the glucose monitor and any other side effects.

I just checked my ketones, as rapa seems to be somewhat of a fasting memetic, and is supposed to increase utilization of fatty acids. i was at 0.7mmol which is fairly low and may just be a result of not really eating much carbs today. (on a 3 day fast, i can hit on day 3 4-6mmol)

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Oh wow, I jsut had some carbs (not a lot), about 11 hours after taking 5mg, and my glucose response was MUCH higher (around 40 points higher then where it should be after what I ate) the normal. Based on this I will be extra careful with carbs when at peak dosage, and maybe add back metformin or take acarbose when eating a carby meal.

I would highly recommend that people take a look at their post prandial glucose levels after dosing rapa

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