[educational]16-aa mitochondrial-derived peptide (12S rRNA region of mtDNA), produced under metabolic stress; ‘exercise in a vial.’ Mechanism: modulates the folate cycle / purine biosynthesis → AMPK → SIRT1 + PGC-1α (mito biogenesis, glucose uptake, fat oxidation) and inhibits NF-κB (↓inflammation) → mitohormesis. Plasma MOTS-C falls with age. — MOTS-C deep dive
Mechanisms
Evidence
[educational] Only human data is the CB4211 analog phase-1 (NAFLD: −25% liver enzymes, −6% fasting glucose). Mice: obese −20% body weight/−25% blood sugar; endurance +30–50% (favors slow-twitch/endurance fibers, not strength); muscle preservation (15%→5% in immobilization); lower endogenous MOTS-C in Alzheimer’s & CAD patients. — MOTS-C deep dive
[literature]First registered human RCT of MOTS-c (2026): NCT07505745 — Phase 2a, double-blind, subQ MOTS-c vs placebo in prediabetes + overweight/obesity; primary endpoint = OGTT-derived insulin sensitivity (Matsuda Index) at 12 wk (safety to Wk 16). Recruiting, no results — upgrades MOTS-c human evidence from the CB4211 analog to a trial of the peptide itself. — SOURCE-motsc-prediabetes-phase2a-nct07505745
Anecdotes
[anecdote-bb] A-tier for performance; the SLU-PP-332 + methylene blue + MOTS-c mitochondrial stack reported to improve energy, training capacity, and off-season fat resistance. — Anabolic Roundtable ~01:42–01:48
[educational] Ranked #5 longevity peptide — AMPK activation (‘exercise in a vial’: mito function, insulin sensitivity, fat-burning); aging-mouse data preserved muscle/bone and showed a +7% lifespan trend (NS, low power). Edges SS-31 by ‘training’ the mitochondria at any age. — Longevity Top-5
Physician protocols
[protocol] SubQ; no PK data → conservative. HED ~23 mg/week but dosed less frequently: 5 mg (→7.5) 3×/week, 30 min pre-aerobic-exercise and/or morning, 4 weeks on / 4 off (hormesis). — MOTS-C deep dive
Practical notes
[warning]Folate depletion → ↑homocysteine risk (folate-cycle modulation): check homocysteine/folate before & after; take methylated B vitamins on OFF days only. Also theoretical mitochondrial overstress (too catabolic vs mTOR; electron leak) — support with Mg glycinate/CoQ10/ALA. FDA category-2 (not compoundable); WADA-banned. — MOTS-C deep dive
[regulatory]US status changing (2026): the “FDA category-2 / not compoundable” note above is now superseded — MOTS-c was removed from Category 2 (Feb 2026) and is on the FDA PCAC 503A agenda for July 23 2026 (use evaluated: obesity & osteoporosis). Advisory/non-binding, outcome unknown; still not FDA-approved, still WADA-banned. — SOURCE-fda-pcac-503a-peptide-review-2026