Dose dependence of mTOR supression

Is there any good evidence for how much mTOR is supressed by each dose of Rapamycin from 1mg to 10mg?

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That is an interesting question, but its also a complex one; the mTOR inhibition likely varies by cell type, tissue, and organ, and by person (personal biology). I don’t think we have the answer right now - perhaps someone else has seen a paper that addresses this but I can’t recall any.

Part of the issue is that while rapamycin has been around a long time, and in clinical use in organ transplant patients for over 20 years, that application and their goals are very different from the ones in longevity applications. Their goal is very simple, a limited amount of immune suppression (just enough so that the organ is not rejected by the body, but still high enough to provide protection from other foreign invaders. They target a specific continuous blood level of sirolimus on an ongoing, daily basis to achieve that - I seem to recall 5ng/ML to 15 ng/ML, but I may be wrong.

In summary, I think this is still an area that needs a lot of research.

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Hi RapAdmin

Thank you very much indeed for your informative reply.

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Is there at least some anecdotal evidence that 6mg is better than 1mg?

Can 1mg of Rapamycin supress mTOR?

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I recommend you watch some of the videos with the researchers focused on rapamycin in our Rapamycin FAQ (link at the top of the page when on desktop computers).

There is a lot of data that suggests that “higher” doses of rapamycin results in greater longevity, so that is the general evidence that there is a dose/response relationship. Many researchers believe that the longevity increase is due to the mTOR inhibition, but there are also theories that it may be due to microbiome changes, or senomorphic changes, or inflamation reduction. So the “cause / effect” relationship of mTORC1 inhibition and longevity is not established fact I don’t think; though it may be close. That is the operating assumption right now I believe for most mTOR researchers.

Most of people currently using rapamycin seem to be (in mouse equivalent dosing) in the low levels tested (note: mice were dosed rapamycin in their food, daily, so that is another difference - vs. us using rapamycin dosed once weekly or so). As you can see, there is a dose/longevity effect for higher dosing of rapamycin and longer lifespan. Many researchers think that is likely due to increased mTOR inhibition, but I wouldn’t say all researchers in this area agree with that theory.

Here are the National Institutes on Aging Results from their rapamycin studies (these are the best rapamycin studies):

Sirolimus
Dose
mg/kg/day
Dose
Blood/Sirolimus
Level
Male Median LS Increase Female Median LS Increase
4.7ppm ∼2.24 3 to 4 ng/mL 3% 16%
14ppm ~6.67 9-16 ng/mL 13% 21%
42ppm ~20 23-80 ng/mL 23% 26%

Here are results from all the higher dose studies I could find:

Sirolimus
Dose
Mouse
mg/kg/day
Dose
Mouse:
Blood/Sirolimus
Level
Human
mg/kg/day
Dose
Dose for 60kg Human Daily Dose adjusted for longer half-life (/4)
4.7ppm ∼2.24 3 to 4 ng/mL 0.182 mg/kg 10.92 mg 2.73 mg
14ppm ~6.67 9-16 ng/mL 0.542 mg/kg 32.54 mg 8.135 mg
42ppm ~20 23-80 ng/mL 1.626 mg/kg 97.56 mg 24.39 mg
126ppm ~60 4.878 mg/kg 292.68 mg 73.17 mg
378ppm ~180 45 to 1800 ng/mL 14.634 mg/kg 878.04 mg 218 mg

Based on the FDA animal to human dosing conversion guide here.

Note: ½ life for sirolimus in mice is approx. 15 hours, vs. approx. 62 hours in humans. So, mice metabolize sirolimus approximately 4 times faster than humans.

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Hi RapAdmin

Thank you very much indeed for your very informative reply.

I am hugely appreciative of all the work you have done and continue to do on this forum.

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A good thread on the possible mechanisms of action for rapamycin’s effect of increasing lifespan:

Here: How Rapamycin Extends Lifespan (mechanism and implications) Discussion

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