Yes, I agree. Matt’s study was very influential but it was the revelations at the webinar that are confusing like Alan dosing on two consecutive days and Blagosklonny on daily dosing ( though apparently for other health issues).
I am 80 and a little older than Dr. Green; yet he only prescribed 6 mg wkly for me. For the past 7 & 1/2 months this dosage has done absolutely nothing for me, except I am a little weaker in the gym and have at least as many aches and pains as ever. Unlike much younger folks I canNOT wait for more years of research to perhaps determine the ideal dosage protocol. For me right now I know it has to be substantially higher than 6 mg. Sometimes a patient may make doctor-like decisions based on the best information available. This may be one of those times. According to Dr. Green, a mouse, except for the brain, is physiologically 99% the same as a human.
With mice, some things in common, others not so much.
Interestingly enough he also has a Law degree.
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.
Very confusing and we’re not much closer to solving the dosing dilemma than when I started 5 years ago.
We can check biomarkers but then what? Do we stop rapamycin? Cut down the dose? Treat the biomarkers?
Does the average layperson even know the cutoffs for the biomarkers and how to treat them?
Dosing may also be very individual .
IF mTOR proxy biomarkers are trending/improving (liver/kidney, phenoage) markers even with mildly elevated glucose/lipids (sign of mTOR2) and not crossing into anemia*/*lymphopenia, I say stay or up dosing. By mildly, if you’re hbA1c is < 5.5, let it rise a few points. If LDL-C and TG rise a bit (say 10-15%), but your TG/HDL, APOB, small dense LDL don’t rise much, stay or up dosing and don’t treat.
Let’s wing it, and call it “benevolent” in honour of Dr B.
*My definition of anemia is different than say conventional doctor anemia. Mine: Iron deficiency anemia: serum ferritin less than 12 µgr/dl, transferin saturation percentage less than 15, and Hb less than 14 mg/dl.
My doc dosen’t want my Ferritin below 80, yet I’ve been way below 80 for years. My Ferritin was 14 3 months ago.
*“Lymphopenia or lymphocytopenia is defined as an absolute lymphocyte count of less than 1.5 × 109/L in adults.” My last blood panel, I was at 3.7, lab lower cut off is 3.2, so I have room to spare.
How’s that for navigating the n=1 waters?
Full disclosure, I am not a health care professional, this is not medical advice.
For 6 mg of sirolimus, you are only getting about 30% of it. Maybe if you take 6mg with a grapefruit juice, your body may be able to absorb more sirolimus.
Mac, are you saying that rapamycin can lead to lower ferritin levels and other lower iron markers?
Those seem very reasonable to me.
Knowing that it’s a side effect of rapamycin, I’d be willing to accept a HbA1c < 6
Not advocating either way Sirolimus alone or with GFJ, putting cost aside. I was doing GFJ for a while, but to provide better reproducibility, I am on Sirolimus alone (powder) recent month in new exploration.
Interesting through, although small sample size, in the GFJ cancer study, the largest cancer stabilization (% of cohort) happened in the Sirolimus alone arm.
Yes your n=1 cellular absorption and mTOR suppression, there are an infinite combination of variables, but pushing into mTOR2, however one gets there, is my central thesis.
Rapamycin can lead to anemia as side effect of prolonged exposure AND mTOR2 suppression. 2nd or 3rd leading toxicity side effect of weekly HIGH dosing in the GFJ/cancer study.
My n=1 very low iron is a self induced parallel longevity hack, not by Rapamycin. I donate 450 ml blood every 7 weeks, been doing that for years, relatively low iron intake diet.
I want to hover just above my definition of anemia. Given my very short runway, I may, however, cross into true anemia if I venture into mTOR2 suppression.
Lots of runway! Modern self hacking Wright brothers?
The blood donations are smart. I recall a study from years ago that it very significantly reduced cancer incidence.
Very true! Just hoping that we don’t crash.
So 20mg a week with GFJ is effectively the equivalent 60mg in terms of bioavailability. Is that correct?
Without doing blood testing to know for sure, but yes, based on the study, AUC was 350% with GFJ.
But some nuance in the cancer/study GFJ intervention.
“For the Sirolimus plus grapefruit juice study, Sirolimus was administered alone in week 1 and with grapefruit juice starting in week 2, one day prior to sirolimus. Grapefruit juice (supplied by Florida Department of Citrus), 240 cc, was administered once daily without interruption. This dosing was based on research demonstrating that the half-life of intestinal enzyme inhibition of grapefruit juice is 12 hours(21) thus providing time for modulation prior to Sirolimus dosing.”
Some people on this forum take GFJ 1-2 hours prior to dosing. I had been taking one GF night before, and one morning of (2 hrs before) dose.
makes since Mac. Regarding Iron, do you look only at your Ferritin numbers or do you look at other measures? And what is the low end that you are shooting for for Ferritin and other indices? Thanks
Full iron panel, not just Ferritin. Ferritin is a POOR measure of cellular iron stores.
I am homozygous H63D, so I am prone to store iron. Sure enough, my first ever Ferritin was 340 (mild elevation, not say full on clinical hemochromatosis, Ferritin > 1000). I have crushed it now, regularly below 20.
I am trying to stay just above low cutoff saturation and above Hb minimum per my “anemia” definition above.
I have sneaking suspicion that the “labs” are not measuring my true cellular iron stores given my genes… I will continue to push this envelope until how I feel, my exercise blunting, or labs go haywire.
Thanks for the suggestion; but I am also on a statin and the cardiologist said do NOT drink GFJ. Anybody know if something else, like orange juice, would help absorption? Alternatively I could take a larger dose.