Some considerations - if rapamycin works in a pretty much all classes of animals that it’s been tried, it would be very bad luck if it suddenly stopped working in humans. It’s possible - there’s the theory that humans have already optimized all the longevity pathways and as a species we live considerably longer than we have a right to looking at size longevity correlations. Therefore there is nothing left to optimize pharmacologically. All you have left is re-engineering the genome so that you have a new design of our species. A little pessimistic, it seems to me.
Anyhow, how would we know if rapamycin is doing anything for humans? Perhaps we can take inspiration from CR research. The same argument has existed as to whether CR works in humans. CR works in most species tried (there are some exceptions in rotifers and the monkey studies were equivocal, but the monkey studies were fatally flawed). But the same “optimized for longevity” argument was made for humans, plus the idea of how CR emerged as an evolutionary adaptation doesn’t apply to humans the way it applies to mice (starving mice on CR can survive longer to last another harvest season, but harvest seasons are not relevant to humans on a decades long perspective).
However there’s been a great deal of interest in CR in humans, and dedicated health nutters have even tried (moi - 8 years) it. But scientists were interested in exploring the question of CR in humans. Obviously you’re not going to run human lifelong trials, so they settled on the next best thing - biomarkers. CR’d mammals have a distinct biomarker profile. What if we put humans on CR and saw if they too got that biomarker profile - if yes, then there’s hope that perhaps CR could work in humans. Enter the CALERIE trial. The result? Well, most biomarkers were similar to mammals on CR, but not all - there were some distinct differences. What to make of it? Seems that CR certainly appears to extend healthspan, as all the biomarker changes were toward a healthier clinical biomarker profile, but obviously that’s far from proof that CR works in humans to prolong lifespan (even if it does seem to prolong healthspan) - perhaps the verdict could be “cautious optimism”.
Taking a page from CALERIE, we need to do something like that in humans. Is there a common biomaker profile in mammals on rapamycin? What does a biomarker profile of people on rapamycin look like? How does it compare to animals? We have shockingly little data. The PEARL trial was fatally flawed.
Ultimately, with nothing to go by, perhaps we can draw a parallel to CR. The CR biomarker profile overlapped a great deal with simply “healthy organism” profile. Lipids, glucose etc. numbers were very good. So in some ways, you could say that maybe rapamycin should be judged according to a similar standard. The rapamycin biomarker profile should also overlap to a large degree with healthy clinical biomarkers. That might tell us something about healthspan, but of course, again, it won’t tell us about lifespan, and most importantly it won’t tell us about the rate of aging - and that also for the very good reason that we don’t have good rate of aging biomarkers nailed down.
Be that as it may, we are far at sea. We don’t even have basic data. It seems we should at least try for that which is feasible and/or practical - establish a rapamycin biomarker profile of “life prolonging” in mammals where it’s been clearly shown, and then run a rapamycin trial in humans and see what kind of biomarker profile we get. So… waiting!
