#1

The Enigma of Rapamycin Dosage

REVIEW| MARCH 06 2016

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#2

Although we achieve the lower end of this range with periodic low dosing, whether it gets to the cancer tissues is less clear.

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#3

from the paper:
PA [phosphatidic acid] binds mTOR in a manner that is competitive with and antagonistic to rapamycin […] rapamycin cannot bind to mTOR unless PA dissociates from the FRB domain of mTOR. A PA-based model for the differential sensitivity of mTORC1 and mTORC2 to rapamycin may trigger new routes of cancer therapy

Or anti-aging therapy, with higher mTORC1 inhibition without much mTORC2 inhibition.

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#4

The paper’s main conclusions:

The three problematic areas are the different doses of rapamycin required to: (i) achieve the same effect in different cell lines; (ii) suppress the phosphorylation of different mTORC1 substrates; and (iii) suppress mTORC1 and mTORC2. All three effects can be attributed, at least in part, to the interaction between mTOR and PA.

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#5

I wanted to bump this thread because the paper raises some really interesting points as you say.

one possible strategy for dealing with unknowns (e.g. phosphatidic acid levels) and the fact that different concentrations of rapamycin maybe required to impact different cells and systems is to vary the dosing. This is something most people on here to do anyway but I thought it might be useful to propose some ideas.

Given the data showing that the benefits of rapamycin can be achieved (in mice) through only short-term use in late middle age, I think we can hypothesize that even short-term adoption of each of these strategies could have a beneficial impact.

High dose / long break. I’ve gone as high as 22mg with a 3 week break. Rationale was to ensure blood brain barrier crossing but give enough time for full clearout between dosing.

Multiday / medium break There is some evidence that autophagy is heightened on day4+ of mtor inhibition/fasting. At the moment I’m trying 6mg taken over two days (3mg per day) to extend the period of mtor inhibition to hopefully 4days +. I’m then giving myself a 10-day break to ensure clear out

Standard dosing 6mg with a 1 week break for 3 months followed by a 2 month break

curious what varying strategies other people use!

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#6

I vary both dosage (4-8mg/2weeks) and the amount of grapefruit I eat 3 hours before (8-11 oz). I hope this will reduce mTORC2 inhibition for the lower doses and perhaps get into more niches of the tissues at the higher doses. I take a 1 month break once or twice a year.

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