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MOTS-c

67
evidence score
peptide
Research Only
281 studies
mitochondrial open reading frame of the 12S rRNA-cMOTS c peptide

MOTS-c is a 16-amino-acid peptide encoded in the mitochondrial genome (12S rRNA region), making it the first mitochondria-derived peptide identified. It acts as a metabolic regulator, improving insulin sensitivity, activating AMPK, and mimicking exercise adaptations. Circulating levels decline with age and in metabolic disease. Animal data shows reversal of diet-induced obesity, improved glucose tolerance, and extended lifespan. Currently in early Phase I human trials. Compelling candidate for metabolic disease, longevity, and performance.

Evidence

Moderate evidence

Safety

Unknown safety profile

Clinical Status

Preclinical

Last Sync

Feb 19, 2026

Last Reviewed

Not reviewed yet

Physician Notes

Critical: depletes folate at 2-3 weeks of use. Start leucovorin + methylcobalamin from day one. Do not wait for symptoms. Use on workout days.

FDA Status:Category 2. Pending reclassification to Category 1 (RFK announcement Feb 27, 2026). Not yet formally available.

Monitoring

  • Folate levels (can deplete)
  • Homocysteine
  • Fasting glucose
  • Supplement leucovorin + methylcobalamin from day 1

Contraindications

  • Folate deficiency (correct first)
  • MTHFR mutations (relative, supplement aggressively)
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Dosing

Typical
10 mg
5 mgRange15 mg
FrequencyDaily or 5x/week subcutaneous (research dosing from animal studies)

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Pharmacology

Half-lifeUnknown in humans; hours estimated
OnsetDays to weeks in animal models
DurationOngoing dosing required for sustained effects
Routes
subcutaneous
intravenous

Evidence Score

67
Level B — Moderate
281 studies indexed · 1 meta-analysis
Scoring Factors
Volume(24%)~49/100
Quality(24%)~44/100
Sample Size(12%)~86/100
Consistency(14%)~86/100
Replication(8%)~86/100
Recency(18%)~86/100

Scores estimated from study counts. Exact breakdown computed after research sync.

Evidence Levels
AScore ≥75 with at least 1 meta-analysis and 3+ RCTs
BScore ≥50 with at least 1 RCT or meta-analysis
CScore ≥25 — observational or animal evidence only
DScore <25 — very limited or preclinical data

Plain-English Snapshot

MOTS-c is currently categorized as a peptide compound.

Evidence is moderate (67/100): promising signal from 281 indexed studies, but context and population still matter.

Safety scoring is incomplete. Start conservatively and monitor carefully.

Core mechanism

Mitochondria-to-nucleus retrograde signaling via AMPK and AICAR; improves insulin sensitivity, metabolic flexibility, and exercise capacity

Practical Context

Strongest current signals

  • Level C: Mitochondria‑derived peptides: Promising microproteins in cardiovascular diseases (Review).
  • Level D: 0.5 mg/kg is identified as the optimal cardioprotective dose within the tested range, producing coordinated anti-apoptotic, antioxidant, and anti-inflammatory effects.
  • Level D: MOTS‑c protects against placental injury via Nrf2 activation in hypoxia‑induced intrauterine growth restriction mice.

Compound Profile