Question on starting strategy-Rapamycin

[DeStrider]

I dose every week at 4 mg + GFJ.

[Olafurpall]

@mccoy

Joan Mannick discussed (podcast with Krister Kauppi) that the activation of mTORC2 (which we want to avoid) comes when lipids and glycemia start trending upward. She also said that a 40% to 80% activation in mTORC1 is all right, whereas higher activations did not yield effects in her study on flu vaccination.
Bryan Kennedy (podcast with Krister Kauppi) says that when mouth sores start to occur, that’s also a warning (a canary in the coal mine) that we are taking too high a dose.
So, an obvious strategy would be to check closely these 3 parameters (or similar like skin rashes and so on) and when they manifest to readjust downward the dosage until we can find a minimum effective dosage (MED) which will not bring about unwanted and possibly detrimental side effects.

I agree that it’s good to keep these parameters (glucose, lipids and mouth sores) in mind when figuring out a good dose to take. Just keep in mind that these are only a rough proxy for mTORC2 activation. I’m pretty sure people can have too much mTORC2 activation without necessarily having any of these side effects and they can have almost no mTORC2 activation while having some of these side effects. Whether you get mouth sores probably depends even more on how sensitive your mucus membranes are to rapamycin and mTORC2 inhibition and to other things involved in mouth sore regulation. There are people that get mouth sores from a single 1 mg dose, and I strongly doubt they are getting anything close to effective doses in lots of tissues in the body. There are also people that can tolerate very large doses without ever getting the mouth sores, doses that are probably increasing mTORC2 too much. The same can be said about glucose and blood lipids. Whether a person experiences changes in them in response to rapamycin may just depend on sensitivity of the liver in particular to rapamycin or on various other things.

Optimally I would combine side effect monitoring with blood levels of rapamycin to determine a good dose. Both are useful.

[mccoy]

@Olafurpall

Optimally I would combine side effect monitoring with blood levels of rapamycin to determine a good dose. Both are useful.

I agree, my personal issue is that I wouldn’t be able to monitor blood concentrations of rapamycin, being compelled as it were to sail in the dark. I would have to take advantage of previous knowledge on dosages and individual responses as desctibed.

[adssx]

@CronosTempi

Start (s)low, but not too low (see the posts where an mtorc researcher claimed a too low dose actually activates mtorc1), and escalate from there, slowly, while carefully monitoring and measuring effects against a baseline.

Here’s the source: Top 5 - Which Currently Available Longevity Interventions Do You Think Are the Best - #201 by Jonas

So your reasoning and strategy make a lot of sense: we know that about 3 mg/week is safe and identical to placebo in men (PEARL trial); therefore, it’s a good starting dose.

@CronosTempi

Also, I believe dosages must be optimised for individuals. Mice in a given cohort don’t have, seems to me, as drastic individual body size differences as humans, and so you could use a single dose amount for all. But f.ex. dogs differ dramatically in size, so giving the same dose to a mastiff and a pug would be absurd. Hence, for dogs (and cats) they standardize per body weight (which the don’t bother for mice), I believe it was something like 0.15 per kg. I believe the same must happen for humans. I find it absurd when studies just use one dose for all - and perhaps that might account for some of the sex differences in human reaction to rapa. In humans, size matters

Good point. In the PEARL study, they note:

Participants received placebo, 5mg or 10mg compounded rapamycin (equivalent to 1.43mg or 2.86mg of generic formulations) weekly.

Supplementary Table S2 gives the average weight for each group:

• “10mg” (so 2.86mg of generic sirolimus):
  • Female: 65.81 kg => 0.04 mg/kg (of generic sirolimus)
  • Male: 84.06 kg => 0.03 mg/kg
• “5mg” (so 1.43mg of generic sirolimus):
  • Female: 62.65 kg => 0.02 mg/kg
  • Male: 84.17 kg => 0.02 mg/kg