LukeMV
#42
Is there a replay of the zoom call?
Also to note, these are self-reported periods which can have some variation. I participated in the bioavailability trial. I normally had taken the weekly dose on Saturday night, but moved it to Sunday night so that I could have a blood draw on Monday morning about 9-10 hours later. The level of accuracy of timing between the dose and the blood draw could not be expected to be the same as if both were in a clinically controlled environment. This has a high probability of impacting variability both individually and between individuals.
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PEARL trial results webinar:
I havenāt watched it yet, so have no spoilers or spanners yet.
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The apparent sex/gender effect is interesting. Two non-mutually-exclusive hypotheses:
-Women have lower body mass and a higher % body fat, (e.g. In this study,, men aged 50-60 weighed 88.2 kg and were 31.3% body fat, vs. 70.2 kg and 40% BF in women). So the same 10 mg dose would lead to substantially higher overall and lean tissue exposure for the women.
-Perhaps females benefit more from rapa, as in the mouse studies (though this itself seems to be at least in part due to blood levels)
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LukeMV
#46
Wow, he confirms that because they found out during the trial that the compounded Rapamycin was underpowered, the doses used were more like 1.5mg and 3mg per week. That is a disaster. I guess itās good they found some benefits of the 3mg dose at least.
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helenas
#47
Kaeberlin mentioned the appearance of sex-dependence effect washes out on closer inspection of all the data, but I havenāt delved into the specifics to know what heās referring to.
At this point, I think they need to do tests with enteric coated Rapamycin at higher doses. Low doses are getting us nowhere.
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Its hard to jump through the regulatory and procedural hoops on this. On this occasion they were caught out with the difficulties of placebo. Because they wanted people not to know if they were taking rapamycin they ended up with a pretty useless trial.
For someone do to the experiment I have just done with an effective dose of 50mg of enteric rapamycin (because of the grapefruit) would be a massive regulatory problem.
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Itād probably be better to try doses like 9 mg or 20 mg equivalent. I agree that 50 mg might have some pushback.
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I had already used 6mg x multiplier.
It is important to remember that I use it infrequently. I have moved from every 21 days now to probably 42 days, but maybe longer.
The bad side effects occur when it remains effective for too long a period. My current view is to see what happens with 16mg x multiplier every 42 days for a while.
Remember I do weekly blood tests so I know if anything has shifted in my blood biomarkers really quickly.
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helenas
#52
Not sure if this vid already posted, apologies if so. Video from week or two prior to the trial results:
LukeMV
#53
You donāt think there is any value in letting the drug build in your system with more frequent dosing of every 7-14 days? Curious what you think.
The problem is that the drug has beneficial and harmful effects. Hence you need a cycling process so that you get the beneficial effects (a spring clean on the mitochondria) without too much of the harmful effects (inhibition of cell division).
Still time will tell.
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There are two ways rapamycin can cause problems: immune issues if mTORC1 is suppressed chronically and other issues if mTORC2 gets suppressed. An argument for a higher peak being beneficial might be along the lines of achieving desirable mTORC1 suppression by penetrating more tissues with the compound. On the other hand, AUC might be considered a potential problem to the extent that binding mTORC1 too much leads to the indirect suppression of mTORC2. The problem with the āmultiplierā stuff is that knocking down CYP3A4 almost certainly expands AUC, and it would be plausible that expanding the AUC by prolonging circulation is more likely to disrupt mTORC2.
The question with higher dose less frequently versus lower dose more frequently is an optimization question. I suspect 1mg per day is worse than 7mg once per week. And 365mg once per year is also probably worse than 7mg once per week. The comparison between 7mg weekly and 14mg biweekly and 21mg once every three weeks is where it seems more interesting.
Because of the available data, we can model different dosing regimens and look at serum curves of rapamycin and even simulate tissue concentration curves. What Iād like to see is models of senescent cell concentrations and curves showing those under different dosing regimens.
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This is a good starting analysis.
To me the objective of rapamycin (from a longevity perspective) is improving mitochondrial quality. For that you need the maximum of mitophagy that does not cause atoptosis or problems at a higher level.
Hence it may be possible that 365 once per year is a good option, but if I am going to approach that I wish to do so gradually as I expect any side effects to appear gradually.
Do we have any sense of the underlying process that degrades mitochondrial quality and the rate at which it operates relative to the impact of a given dose of rapamycin in reversing it?
Whether itās mitochondrial quality or some other Variable X, it seems like we have only a black box: we know that as time passes a living organism āagesā at some rate, that āagingā either causes or is itself a progression of Variable X, and that rapamycin reverses the progression of Variable X.
Things we ought to figure out:
(1) what is Variable X?
(2) what is the typical rate of progression / accumulation / depletion of Variable X w.r.t. time?
(3) how does the peak serum concentration and AUC of rapamycin relate to the impact on Variable X?
It seems like the @John_Hemming conjecture can be characterized as:
(1) Variable X is degradation of mitochondrial quality [mitochondrial DNA heteroplasmy].
(2) Degraded mitochondria increase as a percentage of total mitochondria over time at some unknown rate.
(3) The peak serum concentration of rapamycin is correlated with an increase in mitophagy that leads to a reduction in the fraction of mitochondria that are degraded.
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Gokhan
#59
Kudos to the agelessRx team & others for this major effort. There are very interesting findings from this study, most notably about bioavailability, safety, side effects. However, when it comes to life extension endpoints, I find the results unconvincing. After reviewing the paper, it seems that none of these endpoints were clearly achieved. The lack of consistency across sexes and dosages is notable. I find it difficult to place much weight on a result that is only observed in women, at a specific 10mg dose, and only in terms of osteoarthritis scores. This approach is sometimes referred to as p-hacking, where multiple hypotheses are tested until something appears significant.
That said, I appreciate the sponsors and everyone involved for providing these valuable data points. According to the study, the rapamycin groups reported more improvements in chronic ailments compared to the placebo group:
- Chronic issue improvement: Placebo (n=14), 5 mg (n=24), 10 mg (n=28)
- Chronic issue worsening: Placebo (n=12), 5 mg (n=4), 10 mg (n=6)
I plan to continue taking my low-dose biweekly Rapamycin, as it has improved my well-being, consistent with the studyās findings.
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This would , of course, depend on who is doing the compounding. Enteric coated is essential in preserving the potency of Rapamycin and compounded is not enteric coated. Bio availability as noted by another poster ALWAYS varies dramatically between patients and even in the same patients under different circumstances. We live in this deluded idea that most people produce the same levels with the same drugs but that just is not true.
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From memory, itās possible to put powders into caps at home then paint them with a layer of shellac to get them through the stomach and deeper into the digestive system.
Iām not sure how well that would work for rapamycin, but in the right circumstances, its certainly something I would consider for myself.
