Regarding #2, even though rapamycin inhibits the mTORC1 enzyme complex it actually increases the activity of the upstream Akt regulator enzyme. (The above mouse study also notes this as well.) This is pretty remarkable because most other substances that might inhibit mTORC1 will usually inhibit Akt too (e.g., metformin). So this might be a key aspect to the beneficial effect of rapamycin, assuming it is actually helping.
Wanted to bump this again, in my best estimation I think Akt is the major key to the
immediate symptom relief that people are describing both with Rapamycin and mTor activators. It's important to distinguish this from the longer-term effects [and even from post-exercise effects].
This isn't exactly news, it's mostly Alpha Lipoic Acid (AMPK activator) that gives this link. Myself and others have had temporary excellent experiences with it, provided blood sugar if maintained as above, and it clearly can't be because of its role as cofactor, and there are too many other antioxidants to use if it was only that.
The ALA may work just because it increases Akt, here are the studies I accumulated:
https://link.springer.com/article/10.1007/s10863-012-9460-1
https://www.ncbi.nlm.nih.gov/pubmed/11602326
https://www.ncbi.nlm.nih.gov/pubmed/17274632
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4331247/
https://www.ncbi.nlm.nih.gov/pubmed/17360480
https://www.ncbi.nlm.nih.gov/pubmed/17274632
https://www.ncbi.nlm.nih.gov/pubmed/18931933
and it inhibits mTorC1 at the same time through AMPK.
In fact inhibiting mTorC1 should
provide more energy temporarily to most people's bodies. The only way this would be different in CFS/ME is if mTorC1 itself alone is in fact the most important key to unlocking PDK, so badly that it would counteract its energy-consuming nature - this is what I (and I assume others) had been assuming originally, but it's highly counterintuitive.
mTorC2 however works the opposite way, it increases Akt.
Regardless I think it's the same for Rapamycin. Rapamycin inhibits mTorC2 with chronic use but the dramatic effect is tissue-specific, and furthermore a bunch of studies show that in skeleton/adipose/other tissues, deleting mTorC2 doesn't significantly ruin Akt, because the body has compensatory mechanisms [google this part].
The best of my understanding and the above comes from this single article:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031984/
It could use more graphs but the results and discussion are well related.
The bastardized version is, "Akt is the energy producer from substrates; mTorC1 is major energy consumer". They intermingle with FoxO1-3, mTorC2 and AMPK.
I noticed on the forum - this needs a poll or something - people using the mTor activators were taking them
before exercise. This is fine for amino acids since they have dual roles and effects, but most mTorC1 activators don't make much physiological sense to take during activity. Normally you'd want to
lower mTorC1 during activity, and increase it only during recovery and the rest of the day, and you'd want mTorC1 dominating in the long-term period for CFS/ME.
Again the only thing that would violate this would be a CFS/ME specific mechanism whereby mTorC1 itself - and not Akt - helps unlock PDK. But even in this case it may still make sense to follow normal physiology if your first goal were to lower
post-exercise effects.
Akt can in fact activate PDH [and/through lower PDK - sorry this was a typo] by repressing FoxOs and other factors, and it's very logical that it should increase PDH in general. The part that needs clarification is whether mTorC1 itself has any exclusive effect on it that Akt does not.
But in the meantime I think increased Akt is major enough to explain the symptom relief from Rapamycin.
This is speaking largely about normal skeletal tissue, but Akt has tons of other effects such as modulating effects from LPS and immunity.