Doses and schedules of rapamycin for longevity: does aging exist or only age-related diseases?
Mikhail Blagosklonny
This is a brief version of “groundbreaking paper” that I have no time to finish.
Rapamycin for life-limiting disease/condition
Current doses and schedules of rapamycin for longevity are based on the wrong objective: to minimize side effects.
Side effects of rapamycin are not remarkable and less dangerous than the side effects of many other drugs [1]. Since 1999, millions of patients with serious illnesses tolerated rapamycin well. Continuous (everyday) even high doses were studied successfully in patients [2]. A failed suicide attempt (103 tablets or 103 mg) caused no effects except elevated blood lipids [3]. In some studies, side effects were higher in the placebo group than in the rapamycin-treated group [4].
The most popular schedule of rapamycin for longevity is 5-7 mg once a week. The schedule is well tolerated, according to yet unpublished results. It is based on the assumption that the intermittent schedule has fewer side effects than everyday doses. But this never was compared. For example, 1 mg rapamycin every day was also well tolerated in a clinical trial in healthy elderly [5]. So, both schedules have negligible side effects. But are they equally effective for life extension? We do not know.
If daily schedule is well tolerated by heathy individuals why are we all focused on pulsed schedule? I know that immunosuppression might be the problem but as much as understand there might also be benefits in longevity trough better cancer, autoimmune prevention etc. From literature I understand that suppressing TORC2 reduces T cells that are responsible for bacterial infections so suppressing all the time might potentially cause more bacterial infections and thus higher use of antibiotics… but would also extend the longevity benefits? I am just thinking aloud. Since study using:
[> “Rapamycin + Rifampicin gives 30 - 50% lifespan extension”
there might be something in that… just thinking, not suggesting anything. Has anyone tried rapamycin with daily dosing for longevity? Any thoughts on this?
AIUI his paper only says ideal dosing will vary by individual. Personally, because autophagy is cyclical thing, I see a cyclical approach as being logical.
Ignoring people who want their immune system to be restrained I don’t therefore see a logic for daily dosage, but that might be possible.
The mice in ITP is given daily doses, I don’t see a case stronger than that. It seems to be a can of worms, side effects of daily vs. weekly dosing. If the AUC is equivalent are the side effects similar?
From a simple efficacy perspective, you are right. But the issue is that lab mice live in pathogen free environments so the issue of immune supression is much less of an issue (or as it seems a non-issue, as the mice in the trials are not dying from infections). So we even though for longevity purposes
the mouse studies seems to suggest higher, and daily is better it doesn’t translate to humans living in the real world very well.
Can’t you just stop taking rapamycin if you get an infection or think you’ve been infected and get over it as you stop suppressing mTOR?
Symtoms of infections: fever, cold, etc. Oura ring can measure body temperature deviations well.
The other side effects are more worrying to me, but if my chronological age was higher I’d probably think differently.
It depends on your age, health, and the type of infection. Though very rare (this is the only example I know of), bad things can happen… in one study a 27 year old woman with tuberous sclerosis was taking high doses (10mg/day) of everolimus, got an e-coli infection and was dead in a few days. See this post for details: What is the Rapamycin Dose / Dosage for Anti-Aging or Longevity? - #256 by RapAdmin
We need more data on the level of immune system suppression in healthy individuals using rapamycin at different doses, and the impact in the real world. It could be as you say, something you could easily deal with by stopping dosing, and taking antibiotics, etc. - but we don’t really know right now I think.
Do we know when the patient got the e coli infection? Regardless the rapamycin seems to have supressed her immune system so the infection spread to her blood and caused sepsis. The infection wasn’t supressed. There isn’t any reporting of her having fever or something.
As an older person who takes the highest possible dose without too many unpleasant side effects as per Blagosklonny, I cannot tolerate taking it too often. The pulse dosing has already been thoroughly discussed.
Because: (Quoting from Melih on another thread):
"The reason humans use weekly dosing vs mice daily is because mice have about 7x the metabolism we have. (Someone correct me if I’m wrong)
Basically the 5 half lifes of rapamycin get excreted before it’s the next day and the mice will be ready for the next dose. Humans have to wait a whole week or two for it to be out of their system."
Another excerpt from his paper:
“In theory, high intermittent dose of rapamycin (for example, 30 mg every 3 weeks) may produce a high peak level to ensure that even rapamycin-resistant cells will be targeted. (Probably, everolimus is better for this purpose because of short half-life). A high peak concentration may affect neurons, protected by the blood brain barrier, and stem cells in their niches. A high single dose of rapamycin was shown to maintain lower body weight by shifting the set point long-term in rats [25]."
(Coincidentally 35 mg triweekly has been my dosage for a while, with no intolerable side effects)
"I suggest that optimal dose/schedules are individual, depending on age, gender and spectrum of pre-diseases in each particular person.”
Its not an AUC issue because it is cyclic. The body goes through phases of autophagy/mitophagy and other phases of growth/being fed. If there are no phases it is not clear what is happening.
I wouldn’t necessarily agree as both really are markers that rapamycin is working. Both might be controlled by CR and exercise. Especially lipoproteins IMO reading about rapamycin should get back to normal when you maintain reasonably low BF and when “enough” adiposity was converted by rapamycin induced lipolysis… and this is slow process and it might take some time depending on individual. Same with glucose levels, rapamycin reduces secretion of insulin so glucose levels in blood get higher and are not converted to fat… I believe that while you are taking rapamycin you should have some CR diet and enough exercise and possibly eat low glycemic CH… I might be completly wrong and in a year or so will change my mind but at this point I am still optimistic.
I would be curious to find out if that lady who tried to commit suicide by taking 103 mg of Rapa experienced any beneficial health benefits? If so, that could be cause enough right there…
