Let me add that personally, I plan to continue weekly rapa for about 3-4 weeks after my surgery, depending on how fully my M3M wound sites heal. But once I consistently hit side effects at what I presume will be the roughly same dose range, I’m going to do a washout and retest to really nail down Cmax and Ctrough, in my case.
I repeat I simply do not know what is optimal dosing if we assume rapa is beneficial in humans and all animal studies translate. It might not and even if they do, many don’t realize the subtleties involved with mice studies that literally drove Dr. Miller to develop their own protocol for reproducibility. And even then, there are a few minor subtleties to account for that the ITP doesn’t ie gut bacteria differences.
But I have some clues.
I was going with phase 1b style dose escalation (I use modified Fibonacci schema originally due to lack of precise data, but not starting at LD10) simply because blood levels are highly individual and we already know ultra-high doses aren’t lethal and probably still beneficial. My main goal is to figure out pharmacokinetics and side effects for my individual situation. We already have human data that intersubject variability in rapa levels is 45% and intrasubject variability is 38%.
As for dosing frequency, we don’t even know what’s the best in mice. Maybe you are right about your dosing schedule but I have no empirical evidence in animal studies to go off it being beneficial and there is empirical evidence against it. I’ve sort of alluded to it before, but let me explain further.
My approach is I’m running the odds favoring a high Cmax approach with the least side effects as far as I can tell - pretty similar to Dr. B’s stated approach with some minor differences, but I got to this independently from literature review and then after taking different views in consideration with more literature review. I may have some modifications in the future.
Here’s what the evidence is so far for mice is at high Cmax when you look at intraperitoneal 8 mg/kg daily albeit not much comparable to NIA ITP mice, we have evidence of ultra-high dose having a beneficial effect.
This means a 6 mg per week dose could be 5-10x off for maximum benefit for lifespan and maybe 60 mg per week is optimum for maximum lifespan for all I know, considering the NIA ITP showed 3x higher dose showed a greater increase in lifespan. We don’t know optimal Cmax and Cmin trough, but presumably, if I go high up ie 12-65 mg, I would start spacing out frequency aggressively to keep Cmin trough lower to reduce the risk of a potentially too high trough (ie impaired wound healing and other critical functions that cannot be done with higher rapamycin troughs because rapa abolishes signaling - see: Effect of Rapamycin on Wound Healing: An Experimental Study - ScienceDirect), not just because of the subjective experience of Dr. Green’s patients. It obviously changes less AUC - but I’m thinking more on the lines of reward vs risk for my own risk tolerance based on empirical data.
As for why I still favor a high pulse dose with high Cmax, Let me point out one of the many reasons why crossing the BBB is possibly important that isn’t seen in some of the lower Cmax in animals:
I would also point out we know impaired wound healing and stem cells in kidney transplant patients from continuous dosing hence I would rather keep Cmin low with enough buffer. We also know that so-called “bad” IGF-1 and “pro-aging” BCAAs like leucine are important for muscle satellite cells (stem cells), but we probably can’t do that with a high Cmin rapamycin level: Insulin-like growth factor-1 (IGF-1) and leucine activate pig myogenic satellite cells through mammalian target of rapamycin (mTOR) pathway - PubMed
I also would point out that testing biomarkers and monitoring symptoms are nice to haves, but they are not adequate for my risk tolerance. At some point, I might consider giving biomarkers using skin biopsy a try just to be sure. I think this is going to be important because if I was ever at high risk for cancer - I’d probably take more potential risk with higher levels of mTORC2i.
I also will point out that if one actually read the NIA ITP results carefully - instead of just the abstract and median lifespans on the graphs - the mice with the highest dose (so far) had the highest elevated serum glucose and highest median lifespan!
All these “mTORC2i = bad” folks will have to reconcile this apparent empirical “benevolent pseudo-diabetes” phenomenon with their assumptions based on diseased populations. I am not saying mTORC2i must be “good” btw - I am thinking severe mTORC2i should be avoided based on the uncertainty involved, but mild mTORC2i does not seem extremely harmful in the short run, perhaps possibly beneficial, and seems to normalize downwards after some time. It appears to me that hyperglycemia is reversible, unlike diabetes, so it’s a different process. This is based on my assumption of my low average baseline fasting insulin and CGM glucose low average baseline to begin with.
I’ll also mention minimal infection vulnerability is important and I think some here get too cavalier about it. But that’s for another discussion.
