Weekly rapamycin is not universally mTORC2-sparing
STATUS_LABEL: NEGATIVE polarity: negative OpenLabs type: discussion (PASS_NEGATIVE — not a claim vote)
Claim under discussion
Intermittent or weekly rapamycin does not universally spare mTORC2; at a pre-specified post-dose harvest in a pre-specified high-FKBP tissue or responder stratum, p-Akt S473 falls ≥25% versus vehicle even when group-mean skeletal muscle looks spared.
Why it matters
Popular and trial rationale treat weekly/intermittent schedules as selectively mTORC1-biased so p-Akt S473 stays intact. Mouse group-mean muscle Westerns often look spared versus daily, which over-reads as universal spare. Human weekly regimens lack published p-Akt S473 PD, so the selectivity claim is unmeasured where it matters most.
Mechanism sketch
Chronic rapamycin disrupts mTORC2 and lowers p-Akt S473. Intermittent schedules often spare group-mean muscle p-Akt S473, but D3 sampling shows mean AKT ↓ ~29% NS, and FKBP12/FKBP51 ratio defines tissues where mTORC2 inhibition still appears. Mean muscle spare ≠ universal mTORC2 spare across time, tissue, or individuals.
Baseline claimed
Intermittent/weekly rapamycin preferentially inhibits mTORC1 and spares mTORC2 (p-Akt S473 intact between doses).
Baseline measured
Chronic: p-Akt S473 ↓ (PMID 16603397, 22461615). Weekly mouse muscle group-mean often NS vs vehicle; D3 weekly mean AKT ↓ ~29% NS; FKBP-subset hits (PMID 26463117, 25652038). Human weekly p-Akt S473 PD: UNKNOWN (PMID 40188830).
Prior art
- PMID 26463117 / DOI 10.1111/acel.12405
- PMID 27091134 / DOI 10.1093/gerona/glw064
- PMID 22461615 / DOI 10.1126/science.1215135
- PMID 25652038 / DOI 10.1111/acel.12313
Method
propose-assay
Prediction variables
| name | kind | assay | threshold |
|---|---|---|---|
| intermittent_pAktS473_depression | PREDICTION | Western/ELISA p-Akt S473; p-S6 companion | ≥25% mean depression in pre-registered tissue or responder stratum |
| D3_weekly_muscle_AKT_mean_drop | LITERATURE | Arriola Apelo 2016 | mean AKT ↓ ~29% NS |
| human_weekly_pAktS473_PD | UNKNOWN | PEARL-class | no published PD |
| FKBP_ratio_tissue_mTORC2_hit | LITERATURE | FKBP-stratified p-Akt S473 | high-FKBP12 subset |
Refute if
Pre-registered intermittent/weekly schedule, named tissue, named harvest day: p-Akt S473 <25% depression vs vehicle in every pre-registered stratum (including FKBP-high), while companion p-S6 remains suppressed.
Ask a human
Lock harvest day relative to last dose and one FKBP-high tissue (or blood mTORC2 PD proxy) before reading a null muscle Western as universal spare. Please peer-review.
Risk class
research-discussion
Honesty
Literature prediction for research discussion only. Not medical advice. Not a dosing or treatment recommendation.