mTOR (the protein) forms two separate complexes that do different jobs. mTORC1 regulates protein synthesis, autophagy, and growth in response to nutrients and growth factors — and it's the one rapamycin blocks. mTORC2 phosphorylates Akt/PKB and affects cell survival and glucose metabolism — and critically, it is not directly blocked by rapamycin (it doesn't use the same Raptor-dependent mechanism). Long-term rapamycin dosing eventually suppresses mTORC2 too, indirectly — the likely source of the insulin-resistance side effect seen with daily dosing.
| Tier | What it means | Studies |
|---|---|---|
| B | Direct human evidence | 13 |
| C | Animal in vivo | 17 |
| D | Mechanistic / in vitro / review | 43 |
mTORC1 — 75 studies total. "mTOR Complex 1; regulates protein synthesis, autophagy, and growth in response to nutrients and growth factors."
| Tier | What it means | Studies |
|---|---|---|
| B | Direct human evidence | 1 |
| C | Animal in vivo | 2 |
| D | Mechanistic / in vitro / review | 11 |
mTORC2 — 14 studies total. "mTOR Complex 2; phosphorylates Akt/PKB, affects cell survival and glucose metabolism." mTORC2 THO2009 D — rapamycin does NOT fully block mTORC1 either — using Torin1 (which jams the active site directly), this study showed rapamycin leaves important mTORC1 jobs running, notably 4E-BP1 phosphorylation.
mTORC1 is rapamycin's direct target, so its studies are where you'll find the growth/autophagy/protein-synthesis effects; mTORC2 is where the metabolic side effects trace back to, and it only shows up because chronic rapamycin dosing eventually reaches it indirectly — not because rapamycin was designed to hit it. This is the basis of one of the Atlas's flagged open questions: whether a dosing strategy that hits mTORC1 (for the benefit) while sparing mTORC2 (avoiding the metabolic cost) is achievable, and if so, whether it's a matter of drug selectivity, dose, or timing. See the full open question.
