Let’s be fair. It is a fact, that there is no study showing rapamycin mediated life extension in humans - nor will there ever be, same as CR or any life extension in humans, it’s not practically possible. All we can ever have are biomarkers and proxy health indicators. And while there are some hints with CR (CALERIE study), there is zilch with rapamycin (excepting the near null result of the PEARL trial). Even the Mannick study was (a) everolimus, not sirolimus, (b) short term and very narrow in scope.
It remains fully possible that rapamycin is a net negative for lifespan and healthspan in humans.
Obviously, as a rapa user, I’m gambling that it’s a net positive. However, I do keep in mind something Matt Kaeberlein said - he indicated that it’s possible for rapamycin to both slow down aging and cut lifespan short. He said this in the context of possible negative side effects, such as lowered resistance to bacterial infection - lab animals live in conditions where they are protected from certain risks, which protection does not exist in freely living humans. So your biological age has slowed down, but unfortunately you died early of a bacterial infection. Or, if lipid disregulation is dire, perhaps a MACE situation. And so on. Dire side effects in humans might allow rapamycin to both slow down aging and cut life/healthspan short.
Keeping this firmly in mind, I am vigilant about all possible risk factors associated with rapamycin, in order to couteract them if possible. In other words, I believe that for free living humans, it’s important (perhaps even critical) to augment the treatment with adjunctive therapies. First and foremost - vaccinate the full panoply of available vaccines for pathogens you might commonly encounter (pneumonia and other respiratory germs, td etc.). Second, you should combine this with glucose control - especially if elevated by rapamycin: whatever works best for your particular situation, acarbose, glp-1RA, sglt2i, pioglitazone, metformin etc. Third, you need to add lipid controlling therapies, especially if your lipids are elevated by rapamycin, whatever works best for you: statin, BA, EZ, PCSK9i etc. And so on down the line for other possible enhancements or modifications of rapamycin effects. There are even hints of this being a viable and enhancing approach in the ITP trials combining rapamycin with other agents.
Chris Masterjohn is a - sorry - master, of mechanistic reasoning and speculation. That’s fine. But it’s rather surprising, that he doesn’t do what should be a natural consequence of such reasoning: if there are side effects, see if there are not ways of ameliorating or eliminating them. He points to glucose and lipid disregulation - but does not do what any physician would do: if there is a life saving medication with unfortunate side effects, you keep the medication but add adjunctive therapies to help with the side effects. But that comes down to the underlying assumption - if you gamble/speculate that rapamycin is a net good, then you add those other therapies. If you assume that rapamycin is a negative, then indeed it makes little sense to ameliorate side effects, you stop it altogther as it’s a negative to begin with. All it tells us, is that Chris Masterjohn deems rapamycin a negative “the worst longevity idea yet”. Which is fine - we all get to play the odds as we see fit. But the evidence against rapamycin that he provides, such as it is, I personally find unconvincing. I’m playing the other side of this gamble - in combination with a few other drugs. However, I try to be driven by the data - if something comes out one day showing rapamycin to be a net negative, or the balance of evidence turns against it, I’ll change my stance accordingly - just the facts, ma’am. I remain eternally vigilant. YMMV.
