One useful aspect of this forum is that people try different dosing regimes and report on them.
Thinkining mechanistically Rapamycin’s function is to encourage the destruction of inefficient mitochondria (we say recycling, the mitochondria are destroyed together with their DNA).
It strikes me, therefore, that it is the proportion of inefficient mitochondria that are destroyed that primarily drive the outcome as cells generally select mitochondria up to a value of MMP for mitophagy (this will be partially stochastic anyway).
This would be driven by the level of mTOR inhibition. Hence although we know that for some people when dosing goes too high (or too frequent and too high) there are negative side effects (probably mainly from preventing cell division, but also from metabolic problems driving glucose too high).
A question worth considering is whether people found particular improvements rapidly after increasing dosing or not. There would I would think be some gradual improvements from continuing the protocol at a given dose.
However, does anyone have any experiences of changes that came rapidly after increasing the dosing?
John, I asked you before, so I’m sorry for repeating my question, but are you not concerned about a potential rebound effect with such high dosing?
You previously referred to insulin resistance shortly/the days after high dosing. Indeed that is an issue, but it was not what I referring to. Blagosklonny for example suggested that if (very) high doses of Rapa are taken intermittently, mTOR may get over-activated in between those doses.
I’m using an AI to cite some potential reasons, albeit I’m not sure about the quality of the answer:
"Based on the search results, there are several potential reasons for mTOR overactivation during drug-free periods when using intermittent high-dose rapamycin therapy:
Competitive binding: Rapamycin competes with phosphatidic acid ¶ for binding to mTOR. When rapamycin levels decrease, PA may have increased access to mTOR, potentially leading to overactivation1.
Differential sensitivity: mTORC1 and mTORC2 have different sensitivities to rapamycin. As drug levels decrease, mTORC2 may become active before mTORC1, potentially causing an imbalance in mTOR signaling1.
Rebound effect: The sudden absence of mTOR inhibition after a high dose may cause a compensatory overactivation of the pathway1.
Metabolic adaptation: Chronic rapamycin treatment can cause metabolic changes, including insulin resistance in some models. When the drug is removed, these adaptations may contribute to mTOR overactivation24.
Cellular nutrient sensing: mTOR integrates signals from nutrients, oxygen, and energy levels. The absence of rapamycin may allow for increased sensitivity to these activating signals6.
It’s important to note that while these mechanisms are plausible, the exact reasons for potential mTOR overactivation during drug-free periods are not fully understood and may vary depending on the specific context and individual factors.
Selvarani, R., Mohammed, S., & Richardson, A. (2024). Targeting ageing with rapamycin and its derivatives in humans: a systematic review. The Lancet Healthy Longevity, 5(2), e152-e162. Redirecting
Zhao, J., Zhai, B., Gygi, S. P., & Goldberg, A. L. (2015). mTOR inhibition activates overall protein degradation by the ubiquitin proteasome system as well as by autophagy. Proceedings of the National Academy of Sciences, 112(52), 15790-15797. https://doi.org/10.1073/pnas.1521919112"
So far I have taken 3 high doses 1x16 and 2x22mg both with accelerators (that perhaps gives 3.5 times the bioavailability).
In the end I have to be primarily concerned about how things affect me personally rather than anyone else’s theoretical view.
I do weekly blood tests. That means I can track my blood markers back weekly to May 2022 (and 4 weekly a couple of times before.)
I think we have to assume that the main function of rapamycin is through mTOR.
I have one lab which provides a wide range of markers including insulin. What happened when I took a large dose was initially that insulin was normal, then my systems adjusted to have higher insulin, then the glucose underswung. What I found at the end of a fasting period some time after a high dose (probably 10 weeks) was that my insulin was below the normal range.
I think the mechanism here is hepatic insulin resistance from inhibiting mTOR in the liver.
Hence on the basis of my own biomarkers I am not concerned that there is any long lasting activation or inhibition of mTOR. I think things come back to normal (save that the mitochondria are more efficient).
Thanks for the answer. Your comprehensive blood work and the changes you are observing, are very interesting. I hope you will keep us updated about your blood results - and thanks for your generosity in sharing those results.
Around June 2023, I increased my Rapamycin dose, 6mg every week (morning with buttered coffee), to 20mg every 2 weeks (again in the AM with buttered coffee). Approximately 3 months later I experienced a pretty rapid weight loss of some 12-15 lbs over maybe 3 weeks. Dr. Green and Agetron have reported similar experiences.
Since that time I’ve put on the weight again, but have done so while slightly dropping my percentage of body fat relative to the lowest weight.
I’m going to be exploring this with detailed bloodwork (including tracking blood-rapamycin levels) in the near future. I’ve just been traveling too much to do this lately. I will report on this as I do it.