If your concerned about rebound and want to keep your dose low and consistent, is there any proof that it brings your immune system to an unhealthy low? Did I read that pretty much all the studies in other animals are in daily dosing with proven results? A lot of us don’t want to play around with the dosing and what we are taking during the dosing, we just want a set and forget approach
Are there tests on humans at daily dosing ? This was the one test I could find A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects - PubMed .
All the organ transplantation / immune suppression studies and applications are daily dosing. We have a member here, @LaraPo who is a kidney transplant recipient and she uses Rapamycin to keep her immune system a little lower (I think she takes 1mg/day most days) to help prevent rejection of the kidney. She is also very careful about potential infections… avoiding crowds, etc.
So the biggest downside is immune suppression as a risk (unless you only do a few days a week, or pause every week or two for a while). Also - I think its likely you’ll inhibit mTORC2 with increased risk of lipid and blood glucose disregulation, which are thought to be caused by ongoing, persistent regular dosing of rapamycin.
The daily dosing in animals don’t really translate well to humans for two reasons; mice have a much faster 1/2 life for rapamycin (I think something like 15 hours), vs. 60 hours for humans, so in a sense one day for a mouse (from a rapamycin dosing perspective) is like 4 days for a human.
Also - all the animal studies have the animals in pathogen-free environments (very clean, antiseptic environments) so the risk of infection is low. Most people don’t live in this type of environment, so even if the animals are immune-compromised, they are still like the “boy in the bubble” and not exposed to germs, so don’t have to worry about infections.
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LaraPo
#3
There’s no proof that low and consistent dosing, with occasional breaks, brings your immune system to unhealthy low. I’m on a more or less consistent dose of 0.5mg at this time. Before it was 1 mg. I take it 4 days a week and break for 3 days. My monthly bloodwork doesn’t show that my immune system is over suppressed. In fact all biomarkers on my CBC with differential and renal panel are very healthy.
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I would not take daily dosing at age 77 with a natural degeneration of my immune system due to ageing. Maybe for young or treating specific diseases. The only disease I have is ageing. In Mannick, elderly took .5 mg daily, but did not get as good a response to the flu vaccine vs 5 or 20 mg weekly.
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I’m still looking for rationale for once a week dosing vs daily for longevity, as mouth sores can be a problem with the former. thanks
jakexb
#6
From the recent Peter Attia / Matt Kaeberlein / David Sabbatini podcast episode, they said that the practice of one a week dosing comes from the Joan Mannick study with Everolimus and showing enhanced immune function with weekly dosing. Apparently daily dosing worked as well. But there is theorizing that daily dosing can suppress Mtorc2 while intermittent only suppresses Mtorc1, which is what we care about for longevity. It’s not proven to be the best regimen and our current dosing is also just a guess based on the limited human information available.
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so are there concrete immune suppression studies for the organ transplantation necessity for rapamycin? or is it a hypothesis since rapamycin works for the organ transplant that it lowers the immune system?
Rapamycin was originally approved by the FDA for immune suppression and use by organ transplant patients, so yes, lots of studies on this prior to approval by the FDA.
You can see all the documents FDA documents submitted as part of its approval, they are here if you want to look at the actual research that was done:
With a specific focus on the pharmacology aspects, such as in this document here:
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Arhu
#9
Try it. I tried 2mg every other day but I got stomatitis after a few weeks from that in spite of being able to tolerate 16mg+gfj without side effects
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I’m wondering what you meant by “after a few weeks”. Do you recall how many weeks? I’m toying with trying Rapamycin 2mg every other day, but just for a course of one month. I was inspired by the recent study that show growth in volume of the hippocampus in APOE-4 carriers. Those subjects took 1mg per day. I happen to have a bunch of 2mg pills, so I was thinking to try every other.
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Are we sure this is accurate? I’m thinking - not. Per Matt Kaeberlein, in one of his podcasts, rapamycin studies on mice are performed in SPF certified labs. This means that the mice and their environment are certified to be free of only a specific list of pathogens, not all pathogens, so not like the bubble boy situation. As Matt put it, other than those specific pathogens, the labs are full of thousands of other bacteria and viruses.
Does this mean that SPF labs are highly unnatural environments compared to that of common human living condition? You’d think that, but it’s not completely clear. What if the SPF lab is free of the deadly mouse pathogens “x, y, and z”, but our human has been vaccinated against deadly human pathogens “x1, y1, and z1”? Would we then say that the SPF lab environment is comparable to a vaccinated human environment insofar as safety of dosing with rapamycin? I don’t know.
Bottom line, the “mice in a pathogen free lab” cannot be compared to a human environment full of pathogens claim is not so clearly valid. YMMV.
I am probably on the extreme other side of this debate as I go for a large dose, but really infrequently.
I take the view that chronic inhibition of mTOR is bad in a number of ways, we know about immune and glucose/lipids, but there is also creation of new stem cells. High levels of inhibition can cause other side effects such as edemas.
Also when mitophagy occurs I would like it to run at a higher level at any one time rather than a lower level. That will selectively clear a bigger proportion of the cells with a lower MMP including not just the lowest, but more up the line. That means that when fission occurs with the remaining mitochondria the average will be higher.
Hence I would aim for the maximum safe level of mTOR inhibition, but infrequently.
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Again: the trough levels of the mice (as well as marmosets) on daily dosing disprove this notion.
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Matt K. did mention in a video that in one of this studies inhibition of mtorc2 was actually part of why mitochondrial problems got better in mice. Perhaps low dose daily in humans but below transplant doses (so using 1mg/day) may help some? without completely shutting down 2c. This can further be adjusted by taking it with fat or not, so far most human studies using 1mg/day I have seen seem to be using it on a fasted state and not with a meal
