This is speculation, perhaps right, perhaps wrong. But a couple of points. In rapamycin experiments on mice/rats (other animal models), the treatment continues until death. Yet this shows max LSE (lifespan extension). Are you suggesting that stopping the treatment at some point (old age?) would allow these animals to live even longer? That’s possible, but there is a counter argument. Namely, that even a short rapamycin treatment gives the mice almost the same benefit as lifelong (until death) exposure. But, note, crucially, not longer. I therefore find it unpersuasive that if the treatment was longer, but stopped in old age, it would suddenly make them live longer than if the treatment continued. Furthermore, you mention the mechanism that might make this shift advisable centers around mTOR. Well, CR is a potent mTOR inhibitor, and in CR experiments the animals that live the longest are on CR the longest and most severe, i.e. have their mTOR inhibited most strongly. Strike against that hypothesis.
I also disagree based on the mechanistic speculation (since we’re both speculating here!). I don’t think frailty is caused by mTOR inhibition. In fact, there are grounds to think the opposite. Rapamycin - and CR - preserve muscle function at any age (see: PEARL trial), and specifically in old age, even as an intervention against sarcopenia. Also, rapamycin is an immune modulator. Inflammaging is responsible for muscle tissue deterioration, and inflammaging leads to frailty. Rapamycin attenuates inflammaging - this is one of the primary mechanisms of operation by this drug and what is responsible in large part for its benefits. Inflammaging increases with age, and so the need for rapamycin increases with age - removing it will shorten the life of an old organism, not prolong it.
One needs to see the proper model of how frailty develops. It doesn’t develop because the body stops building muscle/bone/tissue in response to a failing signal from mTOR, and we need to increase the signal. Instead what happens is that there is less response to the signal. The mTOR is working fine and needs no boost, instead the signal is not responded to - likely in part due to systemic inflammation. We need to treat the systemic inflammation with rapamycin, CR, etc., and now the signal can get through. Also, please note - again, the PEARL trial (and other studies), just because rapamycin inhibits mTOR doesn’t mean you can’t build muscle - in the PEARL trial women on rapamycin built more muscle (and anecdotal reports from some members here seem to have the same effect). And there is no reason to think the same isn’t true for other tissues and in old people. In fact we have evidence for that - the Mannick trial… in old people rapamycin rejuvenated a whole system - the immune system (which is associated with longevity!).
Bottom line - my hypothesis is the opposite from your hypothesis. I think rapamycin is especially important in old age. I believe the evidence is overwhelmingly in favor of my hypothesis and against your hypothesis. But of course, a hypothesis must be tested, and it should be easy enough to do in mice: have two cohorts, one lifelong rapamycin and one where it is withdrawn in old age. I place my bet fully (croupier, please put ALL my chips here!) on lifelong rapamycin - maybe even increase the dose in old age😁!
