If the half life of Rapamycin of 2.5 days results in 15% remains in your blood at the end of the week, over the course of weeks, does this percent increase or remain at the same level?
Secondly, a lot of opinions here think a shorter half life is better, but wouldn’t higher blood levels over the week provide additional benefit?
The half life of rapamycin varies quite a bit between individuals (sex/race/age/fitness levels etc.) from the studies I’ve seen… so don’t take any estimate (e.g. 15% after two days) as a given. I suspect you may have seen this threads, but if not please check them out:
The general reason some people here get concerned about the longer half life is that the mTORC2 inhibition tends to happen when taking higher doses or rapamycin over longer periods of time, through feedback mechanisms (between mTORC1 and mTORC2) when mTORC1 is inhibited. So, on the one hand you are right - higher blood levels may provide some increased benefit, but there are two countervailing arguments;
that in an ideal world what we are trying to do with rapamycin is counter the problem that as we get older mTOR tends to get turned on all the time, so to turn it down much of the time, but at the same time we need periodically higher levels of mTOR for growth and repair in our body, so its a balance.
Secondly, as you increase the levels of mTORC2 inhibition its thought that the risk of side effects (and severity of side effects) go higher - so if you are, as a hypothetical example, ending the week with 15% remaining blood sirolimus levels (vs. peak) after the first week, then that will continue to rise each week because on week two you’re adding your dose to a new baseline of mTORC inhibition… so over time, you may see an increase in side effects.
This is what concerns people about longer half lives of drugs, and why some people like the idea of using Everolimus. See this thread also: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?
The shorter half-life allows you to take a higher dose (i.e. more mTORC1 inhibition) but with a lower risk of mTORC2 inhibition.
If you haven’t already - I also recommend the podcast that @Krister_Kauppi did with Brian Kennedy, who talks about how rapamycin can be helpful in correcting disregulated mTOR signaling as people get older, but you don’t want to turn it off all the time:
Thank you for the Youtube threads.
If the 15% remaining at the end of the week compounds over time, weekly regiments needs to be paused intermittently. I’ve seen that some folks use a 2 week cycle.