karelena wrote:I have read some newer articles with "low dose rapamycin," as low as 0.5 mg/kg in mice
I'd like to see that 0.5 mg/kg study; please link or cite. In PMID 24341993
, 0.75 mg/kd per day
of rapa had no effect on lifespan in male mice, and only a modest effect in females (who get higher blood levels at the same dose, though the difference was small at this lower end of the dosing scale, and who aren't as affected by the diabetic side-effects as males).
karelena wrote:I have read some newer articles with ... intermittent dosing (3 times a week, then a week off or once a week)
Intermittent dosing has only been used in small (underpowered) pilot studies, or in obese and/or cancer-prone mutant mice: there's far more evidence in favor of daily dosing — and this already assumes that it works in humans as it does in mice.
karelena wrote: Also, a typical human dose for transplant patients is 1-2 mg/day, much lower than the human equivalent of 8mg/kg (human dose equivalent would be 0.66 mg/kg or 47 mg/day for a 70 kg human!) I'm going to look and see if anyone has measured the mouse blood levels as we do in humans (target level for transplant patients is 6-20 ng/ml);
Happily, we actually do know something about blood levels, as Brian has already noted; unfortunately, they don't support the utility or safety of low-dose, intermittent dosing. On this, see his previouspost, and:https://www.longecity.org/forum/topic/8 ... t&p=823679https://www.longecity.org/forum/topic/8 ... t&p=823716https://www.longecity.org/forum/topic/8 ... t&p=823757
(Longecity post URLs sometimes process screwily: if you don't get 3 posts about rapa dosing by me, drop me a note).
In the Mannick et al vaccine trial (PMID 29997249)
, they got twice as many total side-effects at 20 mg once/week than at 5 mg once/week, including four times as many cases of mouth ulcers, but no better immune priming. There was no benefit at all at 0.5 mg daily.
Note that this study used everolimus/RAD001, not rapa proper. We don't know exactly how to translate from everolimus to rapa, but the usual clinical dose in transplant patients is 5 to 10 mg everolimus/day and 2-8 mg of rapamycin.
And that's just one outcome (vaccine response) — and not a lifespan benefit, and not prevention of AD. And despite all the knowledge they gained through three clinical trials, their own short-acting mTOR inhibitor (BEZ235/RTB101) failed in Phase III
, which says a lot about how hard it is to game this all out.
Now: the main reason I came here to post
. No one seems to have posted PMID 32173556
(though it was listed in a ToC posted by user Fiver in April), and it has strong bearing on ApoEε4 carriers — and might raise some concern for those with only one allele. In mouse models
, they find that ε3s get few if any of the benefits of rapa that ε4/ε4s do, and actually impairs
their brain glucose metabolism, though they did get some cognitive benefit and lower anxiety:
We found that in the [mice that express human APOE4 gene and overexpress Aβ (the E4FAD mice)], rapamycin normalized bodyweight, restored [cerebral blood flow] (especially in female), BBB activity for Aβ transport [that is, efflux of Aβ out of the brain], neurotransmitter levels, neuronal integrity and free fatty acid level, and reduced Aβ retention, which were not observe in the E3FAD-Rapa mice. In contrast, E3FAD-Rapa mice had lower [cerebrovascular reactivity] responses, lower anxiety and reduced glycolysis in the brain, which were not seen in the E4FAD-Rapa mice. Further, rapamycin appeared to normalize lipid-associated metabolism in the E4FAD mice, while slowed overall glucose-associated metabolism in the E3FAD mice. Finally, rapamycin enhanced overall water content, water diffusion in white matter, and spatial memory in both E3FAD and E4FAD mice, but did not impact the somatosensory responses under hindpaw stimulation.
It's unfortunate they didn't include an ε3/ε4 group, but this certainly makes rapa a bigger gamble for one-allele carriers (and arguably contraindicated for ε3/ε3).