mTOR is an oncogene.
“It is also well known that mTOR is an oncogene and has been clinically applied as a target molecule for cancer therapy [19,20].”
Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy
“Recent studies in cancer biology indicate that mTORC2 activity is essential for the transformation and vitality of a number of cancer cell types”
Mice only die of cancer which in THEIR model, Rapamycin is delaying cancer AND, the higher the dose, the longer the lifespan improvement.
Longevity, aging and Rapamycin
The debate rages on re mTOR1/mTOR2/longevity/geroprotection. Will this be resolved anytime soon for those of us past mid life? When will a “superior” mTOR inhibitor be FDA approved and clinically “safe” and at what cost? That is a LONG runway.
In humans, the seminal Rapamycin/cancer/GFJ study, one of the lead oncologists (Dr. Mark Ratain):
“We did not have a sufficient sample size to look at predictors of adverse events, although increased glucose and triglycerides are indicators that the drug is working.”
Phase 1 Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients
“We chose to examine a phosphorylation site on the direct mTOR substrate, Thr389 on p70S6K, as a pharmacodynamic marker of sirolimus activity in the sirolimus alone study. We observed inhibition of phospho-p70S6K 48 hours after administration of sirolimus at all dose levels (Figure 1, p = 0.006). Interestingly, even at the 10 mg weekly dose, phospho-p70S6K activity was suppressed 1 week after the initial dose. The highest dose levels in both studies exceeded our minimal target AUC goal of 3810 ng-hr/ml. In the sirolimus alone study, the single weekly dose of 60 mg was associated with significant diarrhea and gastrointestinal upset. The recommended phase 2 doses from this study are 90 mg, 16 mg, and 35 mg when administered alone, with ketoconazole, and with grapefruit juice, respectively”. Based on the relatively long half-life of sirolimus, our studies hypothesized that sirolimus could be administered on a weekly schedule which would, in turn, simplify administration and provide a period of immune cell recovery and reduce immunosuppressive effects. Intermittent dosing schedules in animal models have demonstrated antitumor activity equivalent to continuous administration, but without prolonged immunosuppression. Weekly administration appears feasible and acceptable to patients"
The above study was of course, existing cancer stabilization/regression, not prevention. But we can see WEEKLY dosing is typically FAR higher than most of us are experimenting with. (The lowest weekly dosing in the Sirolimus alone arm of the GFJ study was 10mg)
But in humans, some of the side effects of long term dosing schedules can be serious and detrimental to longevity:
Rapamycin has been around for a long time, in hundreds of studies. I would venture to classify it as a relatively “safe” drug if used with full knowledge. Once dosing stops, side effects appear to reverse.
We don’t have the “human/Rapamycin” magic therapeutic dosing regiment, but my (n=1) gut feel is that we need to be venturing into some form of “mild” mTOR2 inhibition to get cancer (other?) mediated longevity benefits. (with currently available Rapamycin, not to say a completely different protocol if/when other mTOR1/mTOR2 inhibitors with clinical data become available)
Concluding, the preponderance of evidence seems to suggest that for prevention (at least for cancer), we need to be upping dosing (10mg/week min), religiously monitoring n=1 blood markers/side effects.
