Thank you, Krister, I will listen to the video. Meawhile I would like to signal one thing that may confuse the issue here. You appear - correct me if I’m wrong - to conflate rapamycin with a catabolic state, or as inducing catabolic processes. But I don’t believe that is an accurate picture. Rapamycin can be a catabolic and an anabolic agent depending on context. The anabolic aspect is how rapamycin can allow muscle tissue growth and sarcopenia amelioration.
Regarding whether rapamycin would’ve been helpful in sick end stage of life subjects, is obviously a complicated question. Are we talking about initiating rapamycin at that point, or stopping ongoing dosage. In any case, I don’t believe the answer is obvious at all. I think it is entirely dependent on the specific morbidity. If the patient is struggling with a bacterial infection in an immune compromised condition, yes, rapamycin should be discontinued… although there is the complicated question of dosage where a higher dose suppresses some aspects of immunity, whereas a lower dose might enhance immunity - so perhaps the answer is adjust the dose (even down to zero!). Late stage dementia - unclear. It seems like there is a lot of suggestion that rapamycin might be strongly neuroprotective and AD-preventive (MK keeps asking for a trial of rapa in AD prevention!), but possibly once AD is established, rapamycin might be destructive(?).
And that graphic you sketched out at the end of your post - I strongly disagree with conceptually. The last panel starts with “accellerated aging” —> “increased risk for catabolic driven disease” —> “too much catabolism (breakdown)”. And the implication is that rapamycin in this context is a negative because it is “catabolic”. And here is where I fundamentally and profoundly disagree. Rapamycin is what is slowing down the accelleration of aging.
So my proposed graphic would be: “senescent immune system” —> “inflammaging mediated breakdown of tissue” —> “frailty”.
Many studies have shown that rapamycin rejuvenates the immune system in old people (including the Mannick study), and attenuates inflammaging. Inflammaging is a major modality of aging (which all geroprotective agents to date specifically address, according to MK!). Rapamycin slows down aging through attenuating systemic dry inflammation. Rapamycin is a break on the accelleration of the aging process.
Now you are proposing to remove the break to slow down the accelleration. This to me is totally illogical. It’s as if a car is hurtling down a steep street in San Francisco, and your remedy is to remove the break (rapamycin) to slow down the accelleration! It is exactly backwards. Which is why I said you need rapamycin more at old age. So now you say, “ok, let’s not remove the break, until the very end stage just before the crash, and then we remove it and go out in a blaze of glory!” I am completely flabbergasted by this suggestion. At no point do I see a reason to remove the break, what would be the point?? OK, I guess if you are on your deathbed, I see no reason to push rapamycin down your throat with a stick five minutes before your last breath - so there we can find grounds for agreement. Otherwise, no, absolutely not - I see your graph as confusing the cure for the disease.
But hey, it’s great to explore the issues, because they are very important - and I am very happy we can fruitfully exchange views and disagree, all in the pursuit of a common goal, health and longevity. Btw. I think your mTOR search initiative is terrific, and you are making a solid contribution to the field!
