Switch mTORC1 off and not effect mTORC2?

Has anyone done work on the question.

What would be the ng/mL required in blood to switch mTORC1 off and not effect mTORC2?

Looking for the black cat in the darken room.

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I don’t think its exactly a blood level issue to inhibit mTORC1 but not mTORC2, its more complex and not exactly understood from what I’ve heard. Somewhere between a week and a month of continuous (daily) dosing of rapamycin starts to cause mTORC2 inhibition…

Here is the best we have I think - from the Lloyd Klickstein interview with Peter Attia:

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

  • 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

In summary :

  • Inhibition of TORC1 seems favorable (after the development stage)
  • Inhibition of TORC2 is generally not a good thing

⇒ David Sabatini’s has studied what happens when several components of the TORC1 complex are knocked out:

  • Inhibition of TORC1 extends lifespan and health span in rodents
  • But if you do that to TORC2, it accelerates death

Oh - I should also mention, that one of the ways to back into this calculation (of the blood sirolimus level that does impact mTORC2 (or not) is to look at the target blood levels of rapamycin used in transplant patients.

I’ve seen research that suggests it may be the mTORC2 inhibition that is key in the immune system suppression, that is desirable in organ transplant patients (to avoid organ rejection), but which we in the anti-aging community are trying to avoid. In this paper (immune regulatory functions of mTOR inhibition) it states:

Targeting Rictor has also established that mTORC2regulates the actin cytoskeleton through the small GTPase RHO and protein kinase C (PKC)14. TSC1–TSC2 has been shown to regulate cell adhesion and migration26, but it is not clear whether TSC1–TSC2 signals to and regulates mTORC2 directly. Regulation of cell movement and adhesion is an important feature of effective immune responses, so it is possible that mTORC2 might also be shown to modulate immune reactivity when specific inhibitors become available.

So, my thinking is that you can sort of identify the point where you get mTORC1 inhibition (but not mTORC2 inhibition) by looking at the doses used in organ transplantation patients as a guide.

I’ve not done extensive research on this, but this paper on doses for kidney transplant patients suggests:

The usual maintenance dose of Sirolimus in these patients is 2 to 5 mg/d and its optimal maintenance trough level is 5 to 10 ng/mL. The required Sirolimus doses may differ markedly from patient to patient. It is because of high inter and intrapatient variability in its pharmacokinetics.

And in renal transplants - this Medscape discussion seems to suggest:

The study by Oberbauer and associates[1] suggests, for sirolimus plus steroid-treated patients, sirolimus target concentrations of 20-30 ng/mL for months 3-12 after transplantation and 15-25 ng/mL thereafter.

and another opinion:

Our sirolimus targets are similar to tacrolimus targets: 10-15 ng/mL in the early phase, 8-12 ng/mL in the intermediate phase (3-12 months), and 6-10 ng/mL thereafter (in the absence of rejection or specific drug toxicity

So - obviously, lower than these daily dose ranges are going to result in lesser immune system suppression.

Interestingly, today at the American Aging Association annual meeting / conference, researchers were reporting on their clinical trial of rapamycin for cognitive impairment. They seem to be taking a dosing strategy similar to what you are discussing - high enough (on a daily basis) to inhibit mTORC1, but not so high as to inhibit mTORC2. See twitter discussion below:

“RAPA will be administered orally 1mg daily”

From the “REACH RCT with 40 participants” clinical trial, post above

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Exactly - they seem to be doing what you are talking about… they have the same goal, highest dose without mTORC2 problems…

But I’ve seen no evidence that the daily lower dose is better in terms of results than the higher dose once per week.

Thinking…2mg on Sunday’s, then 1 mg everyday till Saturday, repeat weekly.

8mg total per week

This is a question for the AMA with Matt Kaeberlein - would 8mg spread out as you’ve suggested be expected to be better (for longevity, or side effect risk) than a single dose of 8mg one day a week?

I suspect he’ll say we don’t know, and don’t have any research to support one way or another.

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If I recall correctly, in the Lloyd Klickstein interview with Peter Attia, it was mentioned that it’s the trough levels of rapamycin which were being kept above a certain level in transplant patients, in order to maintain their immunosuppression (i.e. TORC2 inhibition). So, presumably, we want to allow our trough levels to reach below the lab assay level of detection before dosing rapa again. This is one of the reasons why I have chosen to dose sirolimus every 14 days rather than weekly, given that its half-life is roughly double that of everolimus.

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Yes, that is correct. But the new study using rapamycin for alzheimers mentioned above is using 1mg a day so they must have some data that it is safe.