If you look at this list with what many of the longevity leaders are taking. No one is taking such high doses on a weekly basis.
https://x.com/KristerKauppi/status/1782713047506637189
But it’s interesting that you tested that high doses and thanks for sharing your experiences about it. This reminds me of my interview with Joan Mannick where she mentioned how big the mTOR inhibition effect was around different doses. 5mg/weekly = 40% mTOR inhibition and 20mg/biweekly = 80%. Your dose is 12mg/weekly. I guess you are inhibiting mTOR more than 80% with that dosing every week which is probably too much. In her study the side effects were also higher on that type of dose and the immune improvement was not as good as with 40% mTOR inhibition. Here is a time clip from that interview.
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adriank
#42
@Krister_Kauppi have you ever done a blood test to check your rapamycin level? If you did, how long after you take did you do your blood test. Thx.
Example I did my blood test 2hrs after and I got 2.1ng/mL and at 24hrs it is about 9.1ng/mL. At 12 hours I got 39.1ng/L. I should add that I also take GFJ with my rapamycin.
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I have not yet checked my blood levels but I have plans on doing that. It has not been easy to do that in Sweden. There is a person in Holland who is developing a home kit for testing blood levels and when that is launched I will make quite many tests.
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adriank
#44
I must admit without getting a blood test, I would be uncomfortable to take rapamycin. Then again, I got the worse rapamycin brand possible … lol.
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What brand did you get and how did you get it? I take Rapamune from Pfizer.
adriank
#46
I got Siroboon … so I take 20mg every week with GFJ. My next lot is Biocon… and I will start with 8mg a week and see what the blood test yield.
Even if these numbers were close to true, they are still meaningless without context. There is no mentioning of the time at which this inhibition supposedly was seen. Was it 2 hours after dosing, or 12 hours or 72 hours or what? mTOR is of course not inhibited by a constant amount when rapamycin is taken weekly. It’s most likely going to be inhibited significantly in the first 12 hours with a strong decline in the inhibition thereafter and likely no inhibition after several days.
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The obvious issue is of course your body weight, so 5mg for someone who is 50kg, will not be the same as 5mg for someone who is 100kg.
Also I am not sure what measuring rapamycin blood levels tells us. What matters is tissue absorption and penetration. What are the tissue levels? Each tissue is different wrt. time and degree of penetration. This also depends on age and individual clearance capacity. The Blood Brain Barrier becomes more leaky in older age, so a large molecule like rapa might penetrate the BBB easier when you’re older. At what dose does rapa penetrate the BBB? None of this do we know from a blood levels test. Now, if there is some kind of reliable translation, maybe there is some value, but I don’t know of any.
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@Olafurpall My guess is that it’s not a short period and more some kind of average levels. But contact Joan Mannick and I think she will answer. Please let me know what she answers. Very curious to know.
@CronosTempi The dose was decided based together with a expert team from Novartis and most likely also based on lots of non public data. But I fully agree that body weight is one potential parameter to take in consideration. Here is a quite interesting data collection I did last year. Around 0.1mg/kg in average seems to be one very simplified calculation of target dose. But of course reality is more complicated than this.
https://x.com/KristerKauppi/status/1663482129022431232
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@CronosTempi Although I agree that tissue levels are ultimately what is important, we don’t have data on tissue levels. We do have data on blood levels so that’s the most useful data as of now.
@Krister_Kauppi Do you have her email? I don’t find it doing a quick google search and Tornado therapeutics only gives a general contact form.
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Yes. The figure suggests that rapamycin is taken up strongly by the liver, kidney, spleen, lung heart and bladder in rats, but taken up to a smaller extent (but still fairly strongly) by the muscles and brain. This can probably serve as an estimate for humans, but as they state in the full text article, the patitioning between different organs has not been determined in humans.
“The extensive tissue distribution of rapamycin has been confirmed by studies performed in rats where tissue to blood partition coefficients (Kp) were reported to be more than 40 [35]. However, these partitioning determinations have not been performed in humans and the relationship between the concentration of rapamycin in tissues and the effictive and toxic effects of rapamycin is currently unknown.”
Note that
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I think you’re right! I don’t think I need to email her, because I think I found the answer. At 29:32 in your interview, you give PMID: 25540236 as the reference. That study says this in the full text:
“Modeling and simulation based on mTOR-mediated phosphorylation of its downstream target S6 kinase (S6K) predicted that the 20 mg weekly dosing regimen inhibited mTOR-mediated S6K phosphorylation almost completely, the 5 mg weekly dosing regimen inhibited S6K phosphorylation by more than 50%, and the 0.5 mg daily dosing regimen inhibited S6K phosphorylation by about 38%
over the dosing interval (12).”
Reference 12 above is this study: Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data - PubMed
That one shows the inhibition of S6K (a proxy for mTOR inhibition) in cancer cells and peripheral blood mononuclear cells of humans at different doses of everolimus and at different time points. This is seen in Fig 3 in the full text. Note that they say this about Fig 3:
“The model-simulated inhibition of S6K1 activity was summarized in a comprehensive manner, howing the mean percent inhibition over time,which was calculated as area under the inhibition curve divided by the dosing interval.”
This quote makes it clear they are calculating the area under the inhibition curve divied by the dosing interval. That’s basically the average inhibition over the dosing interval.
If you look at the figure above. Look at C and D. The area under the curve for the light blue line (5 mg weekly) is about 75% in C and 40% in D. The average of that is around 50-55%. So that’s the inhibition you’re getting on average over 7 days when taking 5 mg of everolimus once weekly. While the chart doesn’t go further than 7 days, you can see by the slope of the curves that 20 mg taken every other week would lead to greater average inhibition than that, maybe somewhere about 80%. So it all makes sense now.
I would love to see similar data on rapamycin ingestion by humans. I don’t recall if there was any good data on how much oral everolimus is equivalent to 1 mg of oral rapamycin in humans. Did anyone have good data on that?
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Great finding and thanks for sharing this! If I remember it correctly I found some of the data in company presentations and annual reports but even better to get it from a study. So big thanks for sharing this!
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@Olafurpall Thanks for this analysis. Everolimus is far more powerful than I expected. The idea of “turning down” mTOR is apparently false with everolimus. It almost shuts the door. Plus it has a long lasting large effect. If I knew rapamycin had this same effect and time course I would take less and less often.
What dosing of rapamycin do you use?
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Interesting, when you say that Everolimus is more powerful mTOR inhibitor than Rapamycin what do you base this on? Personal experience? If so, what doses are you comparing with between Rapamycin and Everolimus?
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I’m just reacting to @Olafurpall analysis of the data presented.
“The average of that is around 50-55%. So that’s the inhibition you’re getting on average over 7 days when taking 5 mg of everolimus once weekly. “
I would have guessed (literal guess) that Rapa had a 75% inhibition over the first few hours, and perhaps a 50% inhibition average over the first 24 hours, and almost nothing after a few days, assuming a 5mg dose. So my reaction was of surprise.
I am taking ~12mg of Rapa every two weeks with a one week break every 5 weeks. I only feel a slower recovery from hard workouts done in the 24 hours before dosing. Everolimus must be much more powerful….at least I hope so since I don’t want such a big mtor shutdown for so long. I only want a hit and run effect.
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But if that mTOR inhibition effect will result in greater longevity effect both healthspan and lifespan then you will not be against that high inhibition or? My guess is that you view that high type of mTOR inhibition is more detrimental instead of benefical. It’s interesting view but if I have understanded it right then the human doses are quite low compared to many animal studies done. Like the latest one done on common marmosets which used a really high dose and the preliminary result showed both healthspan and lifespan effects (around 15% median lifespan extension).
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@Krister_Kauppi its definitely a topic with lots of unknowns. No one gets to ask a marmoset or rat or mouse how they feel on bigger (and maybe more continuous) dosing. I think mTOR is important for my health and lifestyle, so I don’t want it turned down all the time. I just want to turn it down for short periods (1 day?) every couple weeks or so to help mTOR to work properly…to make sure I’m getting sufficient autophagy.
This is what I have come to believe after 1.5 years of exploring this topic. I am still surprised by new information regularly. But I have to do the best I can with what information I have now. I try not to hurt myself.
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Last year I started sketching on this picture and different ways to navigate between anabolic and catabolic processes so that we don’t push things too much in either direction.
https://x.com/KristerKauppi/status/1633420545642360834
I will soon update this image again with new interesting measurements to keep an eye on. If will never be that easy to just look at one measurement and draw a conclusion that a person is too anabolic or too catabolic but I think this “framework” may help out in one or the other way.
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