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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Lately I’ve been taking the equivalent of 12 mg every other week.
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AnUser
#62
Any reservations for using everolimus instead? Why do you take it less frequently than every week but with higher dosing?
Thanks. I’m happy to see I’m not out on a limb with my own dosing (essentially the same as yours).
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I think everolimus would be fine. As for why I take it less frequently. I think the evidence indicates that that will maximize the benefits while minimizing the side effects.
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adriank
#65
Hope so, I am not going to try everomilus until there is more data.
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Yesterday I took comprehensive blood tests and other tests because it is now two years since I decided to start taking a low dose of rapamycin once a week. Now afterwards was it the right decision for me? I would say yes. Firstly because it has totally stopped my chronic bleeding gum that I have struggled with almost throughout my life and different dentists, hygienists and others have not been able to help. But when I started taking rapamycin then after a while the bleeding just stopped. So I’m very happy that I found a solution for this because chronic bleeding gum increases the risk of different age-related diseases.
Secondly I think this decision to start taking rapamycin has forced me to deepen my knowledge around how to self-experiment in a better way, to build up a professional network that I can use but also deepen my understanding around my own biology and how I work. I think all this will be very valuable for me when the big breakthroughs in the longevity field hopefully come because the data and safety around these future interventions will most likely not be perfect. So I guess I will need to take higher risks later in life to increase my odds of not dying and the thing I’m doing now is to prepare myself for that.
Thirdly it is also important for me to deepen my understanding around mTOR inhibitors to see if it may be a promising intervention to use when Rapamycin Longevity Lab develops advanced combinational therapies. My current view is that it’s a mistake to not use mTOR inhibitor as a base ingredient in combinational therapies for longevity. But we need of course much more than just a mTOR inhibitor such as rapamycin to radically extend lifespan.
But now it’s time for me to stop taking rapamycin for three months. The reason for that is that I want to see if some biomarkers improve or worsen and also see if cycling rapamycin may be good. I will take different tests before and after. I have also added tests from TruDiagnostics and GlycanAge because I’m curious to see if something can be detected by them. When the three months has past I will start taking rapamycin again and it will be very interesting to see if some changes can be detected. The last thing I will do this year is to add a glucose regulator to my protocol. Probably Acarbose but it could also be Canagliflozin or some other one.
In around one month I will get my results back from the tests I have done. Let’s see if they also indicate if it was a right decision for me to take rapamycin or not. A bigger summary on that in the future!
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AnUser
#67
How are your apoB or LDL-C levels doing, if you want to share? Done anything to change those for prevention of ASCVD, as your levels were somewhat high for APOB in the past, or not for now?
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Below is the biomarkers that I have gathered throughout the two years. It will be very interesting to see the next data gathering. Jan 2023 was pre data before I started taking rapamycin.
I don’t take any medication for lowering LDL or ApoB but I did some changes in my first meal intake during last year which may have had some effects. You can read more about what I did in this post.
https://x.com/KristerKauppi/status/1761315679582466488
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Do you do aerobic and/or strength bearing exercise? VO2 max? You might find a boost or decline in capacity during your 3 month Rapamycin embargo.
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AnUser
#70
You might want to lower that further, I’ve written a good review here on the topic here: Apolipoprotein B (ApoB)
Basically having an apoB of 100 mg/dl rather than 70 mg/dl doubles your lifetime risk of CVD events like strokes or heart attacks, based on data from genetic studies. It’s in that post with a source.
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I have not done a VO2 max test but in the gym I have experienced progress but I got one shoulder injuiry last year around March which forced me to rehab for many months but now I’m coming back step by step.
Thanks for highlighting this! I have talked with my physician about starting low dose of Rosuvastatin but I wanted first see what effects I could achieve with only diet changes. So that will come but again thanks for pointing this out. I really appreciate it!
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