Looking at the mouse studies, a human would need to take 8mg/kg/day or so of Rapa to have an aging effect. Current 6mg/week dosages are at homeopathic levels. Hopefully, no one will take rapa at those high levels, as it would massively suppress your immune system.
Rapa at current levels might have some benefit as an anti-inflammatory, by very mildly suppressing mtor 2 / the immune system. It probably isn’t doing much for your mitochondria.
To get an anti-aging benefit we need something that only suppresses mtor 1 and not 2. Whatever that compound is it’s not Rapamycn.
That is factually untrue. I personally take higher doses, but at a much lower frequency than most longevity rapamycin users. However, 6mg will have an effect and still be “in the system” at the end of a weekly cycle.
Personally, I’m waiting on What Mannick’s company has to offer: Pipeline . I’ve seen several interviews where she claims better safety and efficacy. For example, TOR101 only inhibits mtorc1, even up to 30mg/kg in mice. It will be expensive!
Sure, it looks interesting, but its going to be 5 to 10 years before its FDA approved and available commercially, if it ever makes it through the phase 3 trials.
This is far from true. Because of the much longer plasma half-life of rapamycin and over 7 times slower metabolism of humans compared to mice, daily intake in mice is actually pretty close to a weekly intake for humans. In addition, you need to apply metabolic scaling to estimate the human equivalent doses.
This isn’t an accurate statement, so I’m guessing you meant that they share certain subunits.
One can regulate the other as they’re part of the same cellular network, but they are assembled independently and one is not necessary for the other’s formation.
I think what Joseph is trying to say is that there is a poorly defined feedback mechanism whereby if you inhibit mTORC1 at a high level, consistently over a longer period of time, you eventually see mTORC2 inhibition. I’ve yet to see any researchers define this process in any detail, and the exact dosing level needed, and the days of dosing required, are not well defined and likely vary by person.
So, it’s a general concept right now. If you inhibit mTORC1 long enough at a high enough level, you will eventually get mTORC2 inhibition with rapamycin. Beyond that I don’t think we know a ton, in this area. (IMHO).
I partially agree with you but the through levels aren’t just a function of the frequency of dosing but of the dose. If humans were to take massive doses like the mice in the rodent studies, then they would have significant through levels even if they take it just once a week. The mice given rapamycin daily are getting a dose of rapamycin every 1.6 half-lives (with their 15 hour plasma half-life). For a human with a 60 hour half life,1.6 half-lives would be 96 hours or 4 days. So if we go by half-lives, a dose given to a mouse daily is equivalent to a dose given every 4 days for a human. If we compare metabolic rates a dose given daily to a mouse would be somewhat similar to once weekly for a human given that humans have roughly 7-times slower metabolic rates. Given this, a daily dose for a mouse would be close to a dose given 1-2 times weekly for a human, depending on whether we use the half-life or metabolic rate to translate the doses. Since most people are taking it weekly, one could argue that the mice are getting it a bit more frequently but the difference isn’t huge. That said, the mice are certainly getting more constant exposures because they don’t generally reach close to zero through levels between doses, but that’s largely because they are given such large doses relative to what humans are getting. If an adult human were to take 10 mg twice weekly or 20 mg weekly they too would have through levels fairly close to that of the mice.
You’re missing the core point. The mice and marmosets on life-extending doses never see plasma levels lower than the levels seen in transplant patients under daily dosing. People taking once-weekly doses get lower than that at least as fast, if not faster, than 24 hours after their weekly dose because they fully run out terminal half-life and spend much of the week at far lower levels instead of taking a new dose and reaching a steady-state trough level.
You make a valid point. Most of the lifespan studies use doses that are so high that they won’t reach a low through between the doses. There is still some evidence that such a high frequency that doesn’t allow for a low through level between doses isn’t necessary to get at least some of the lifespan benefits. A lower frequency will probably give a lot of benefits also. Note that rapamycin given to old mice every 5 days (at a dose of 2 mg/kg intraperitoneally) also appears to increase lifespan, although more studies are needed testing such lower frequency. Intermittent Administration of Rapamycin Extends the Life Span of Female C57BL/6J Mice - PubMed Importantly, that is a regimen that result in a low through level between doses. Their level is just under 5 ng/mL on day 3 after rapamycin dosing as seen by Figure 1 in PMID: 26463117. That should be enough to reach a low through on day 4-5.
Exactly. That’s my understanding too from the studies I’ve read that discuss how rapamycin inhibits mTORC2. That’s also why I think the search for some better mTOR inhibitor than rapamycin is largely futile, given that rapamycin is already a very “clean” mTORC1 inhibitor.
