Do we know anything about rapamycin’s dose and effect relationship?
For example, it is known that statins exert most of their positive effects at a low dosage (e.g., 5 mg), and when the dosage increases, the positive effects go up marginally, but the risk of side effects increases significantly.
Do we have any rough sense of the lowest effective dose of rapamycin that could still have positive effects (even if it’s only 50–80% of the maximum possible benefit) while minimizing the risk of side effects?
I’m really curious what this curve might look like (x axis: effect; y axis: side effects).
Dosage is the $64,000. None have been established for Rapamycin used off- label for longevity. One problem is that apart from mice, Rapa is used as part of a cocktail of drugs given to transplant patients. Here the only concern is organ rejection. Obviously you can’t ethically give such people placebos as controls. Even among the medical experts we see online there is no consistent dosing. Peter Attia takes 8 mg per week and is frank that he gets regular mouth ulcers from it. Others take somewhere between 6 and 12 mgs a week, though a couple of them cycle one month off every three months. Someone posted a video on here recently in which a bearded expert gave very precise numbers which I have not seen before, but I don’t know his sources. He said quite authoritatively that >5mg every two weeks begins to inhibit MTORC2, which he said has more harmful effects than inhibiting MTORc1. I have no idea where he got this information, which sounds highly speculative to me, frankly. But I suspect he’s right that inhibiting MTORc1 and 2 too much might have negative side effects. Finding that balance is the Holy Grail.
We have the mouse dose response relationship but we don’t know it for humans…
Here are the dose translations from the other rapamycin studies - mice metabolize rapamycin much faster. I would say we really don’t know the details of how the ITP and other trials showing the longevity impacts of rapamycin on mice lifespans translate to humans… the tests just haven’t been done (and may never, given that rapamycin is a generic medication so unless a government or nonprofit steps up to do the clinical trials, there is no financial incentive for a company to do the clinical trials).
My belief is that the best we can do is test different dosing levels and timing approaches on our own bodies, track blood test and functional results closely - and modulate in a way that we think will optimize results.
I think daily dosing in mice is roughly equivalent to about once every 4 days or so in human terms given the speed that mice metabolize rapamycin is about 4 times faster.
There was a human study that looked for MTOR2 inhibition. It wasn’t present at 20 mg weekly or less. It was present at 40 mg weekly in 50% of patients. @McAlister posted the paper here.
So your bearded expert seems to be making a WAG. Unless he’s talking about 5 mg daily. That’d definitely inhibit MTOR2.
Now if only we knew if mTORC2 inhibition was the source of the negative side effects. Dr Kaeberlein has expressed reservations about this assumption.
I agree that each person should explore rapa as they see upside greater than downside. Start with the same dosing that “everyone” else uses. Then go from there slowly. Try not to do too many things at once or you’ll lose the signal.
And I would be cautious about assuming that future unfelt / uncertain but hoped for benefits would be greater (and “worth it”) than present felt/seen negative side effects.
My rapa protocol gets me to a sweetspot for me of almost zero negative effects except for tiredness for 36 hours, and a known set of benefits:
lower joint pain
zero allergies
almost no illnesses (and the rare cold is super mild)
plus a shot at other recoveries of function lost to aging that I don’t know about (added to the potential for negative side effects that I don’t know about).
