mixedAnecdotalMay 2, 2026
Metabolic peptide curiosity
MOTS-c gets discussed less as a single compound and more as part of the broader metabolic and longevity-peptide review cluster.
Reddit / r/medicinemedium confidencereddit
Source MOTS-c
Mitochondrial ORF of the 12S rRNA type-c
Anti-AgingNot ApprovedPhase IIResearchSubQ
Popular for:Exercise mimetic, metabolic health, insulin sensitivity
4
Registered Trials
5
Trial Publications
231
PubMed References
Phase II
Evidence Level
Overview
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino-acid peptide encoded in the mitochondrial genome. The short version: people usually care about it for exercise mimetic, metabolic health, insulin sensitivity, but the strength of the evidence depends heavily on indication and study type.
MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA Type-c) is a 16-amino-acid peptide encoded in the mitochondrial genome. Discovered in 2015 by Dr. Changhan David Lee at USC, it is the first mitochondrial-derived peptide shown to regulate metabolism at the cellular level. It functions as an exercise mimetic, improving insulin sensitivity, fat metabolism, and exercise capacity.
**Originally developed for: **Research into mitochondrial signaling and aging. MOTS-c was identified during a study of mitochondrial-derived peptides and their role in metabolic regulation. Its potential as an exercise mimetic and anti-aging agent emerged from subsequent research.
Research Snapshot
What the evidence says
Phase IIMOTS-c currently shows 4 registered trials from ClinicalTrials.gov, 5 PubMed trial publications (4 RCT-tagged), and 231 PubMed references matching the stored source query. Treat PubMed references as literature surface area, not a count of clinical trials.
Known vs uncertain
Known signals
- 4 registered trials are tracked from ClinicalTrials.gov intervention records.
- 5 PubMed clinical-trial publications are indexed.
- 4 PubMed randomized controlled trial publications are indexed.
- 231 PubMed references are tracked separately from trial counts and can include animal, in-vitro, review, mechanism, or clinical records.
Open questions
- Evidence strength may vary by indication, route, formulation, and population.
- Public anecdotes can highlight interest or concern but do not establish clinical efficacy.
- Regulatory status and compounding access can change independently from the research literature.
Mechanism of Action
MOTS-c activates the AMPK pathway (the master metabolic sensor), which promotes glucose uptake, fatty acid oxidation, and mitochondrial biogenesis.
Key Research Benefits
Primary Benefits:
Exercise mimetic — Activates AMPK and mimics the metabolic benefits of exercise (Lee et al., 2015, Cell Metabolism)
Improved insulin sensitivity — Prevents age-related and diet-induced insulin resistance in mice
Fat metabolism — Promotes fatty acid oxidation, reduces fat mass in animal models
Metabolic homeostasis — Regulates glucose uptake and energy expenditure
Secondary/Emerging Benefits:
Anti-aging — Endogenous MOTS-c levels decline with age; supplementation may reverse age-related metabolic decline
Cardiovascular protection — May improve endothelial function and reduce cardiovascular risk markers
Anti-inflammatory — Reduces systemic inflammation markers
Osteoporosis prevention — Animal studies show improved bone density
Clinical Evidence Summary
Research Pipeline
Preclinical
Animal
Phase I
Phase II
Phase III
Approved
4
Registered Trials
5
Trial Publications
4
RCT Publications
231
PubMed References
ClinicalTrials.govPubMed ESearchExact-name queryChecked May 3, 2026
Registered trials are ClinicalTrials.gov intervention records. Trial publications are PubMed records tagged as clinical trials or randomized controlled trials. PubMed references are broader source-query matches and can include animal studies, in-vitro work, reviews, mechanism papers, and trial publications.
4
Registered trials
5
Trial publications
4
RCT publications
231
PubMed references
49
Reviews
0
Meta-analyses
Registered trials source
Jun 1, 2026
MOTS-c
Uses the exact compound name as a ClinicalTrials.gov intervention query.
View source- Lee et al. (2015, Cell Metabolism) — Discovery paper. Demonstrated MOTS-c as a mitochondrial-encoded peptide that regulates insulin sensitivity and metabolic homeostasis via AMPK activation.
- Lee et al. (2019, JACS) — Showed MOTS-c translocates to the nucleus under metabolic stress to regulate adaptive gene expression.
- Reynolds et al. (2021) — MOTS-c levels in human plasma are associated with physical function in aging populations.
- CohBar Phase 1b trial (CB4211) — MOTS-c analog tested at 25 mg/day SubQ in obese patients with fatty liver. Showed improvements in body weight and liver fat.
> Clinical trial status: CB4211 (MOTS-c analog by CohBar) completed Phase 1b. Native MOTS-c has not entered human clinical trials. Research is primarily preclinical (animal models).
Key PubMed References
231 PubMed references · showing top 25 by relevance
View all on PubMedMitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart.
Human Study
Pham T, Taberner A, Hickey A, et al. · Frontiers in physiology · 2025
PMID: 40661667Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes.
Human Study
Kong BS, Lee H, L'Yi S, et al. · Experimental & molecular medicine · 2025
PMID: 40855115Endurance training enhances skeletal muscle mitochondrial respiration by promoting MOTS-c secretion.
Animal Study
Feng Y, Rao Z, Tian X, et al. · Free radical biology & medicine · 2025
PMID: 39706498The mitochondrial genome-encoded peptide MOTS-c interacts with Bcl-2 to alleviate nonalcoholic steatohepatitis progression.
Review
Lu H, Fan L, Zhang W, et al. · Cell reports · 2024
PMID: 38206815Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane.
Human Study
Jia H, Zhou LC, Chen YF, et al. · Theranostics · 2024
PMID: 39267782Anecdotes & Sentiment
Public discussion, not clinical evidence
This section summarizes what people are talking about in public sources. It can be useful for spotting questions, hype cycles, and recurring concerns, but it is separate from the evidence sections above.
Side Effects & Safety
**Common Side Effects:** - Injection site redness or mild irritation - Mild GI discomfort (nausea, stomach upset) - Transient flushing - Generally well-tolerated in the CB4211 Phase 1b trial **Rare but Serious Risks:** - Hypoglycemia risk — MOTS-c improves insulin sensitivity; those on diabetes medications should monitor blood sugar closely - Very limited long-term safety data in humans > Contraindications: Caution in diabetics on insulin or sulfonylureas (hypoglycemia risk).
Common Side Effects:
Injection site redness or mild irritation
Mild GI discomfort (nausea, stomach upset)
Transient flushing
Generally well-tolerated in the CB4211 Phase 1b trial
Rare but Serious Risks:
Hypoglycemia risk — MOTS-c improves insulin sensitivity; those on diabetes medications should monitor blood sugar closely
Very limited long-term safety data in humans
> Contraindications: Caution in diabetics on insulin or sulfonylureas (hypoglycemia risk). Not recommended during pregnancy/breastfeeding. Limited interaction data — use caution with other metabolic-altering compounds.
Known Interactions
No curated interaction entry is live for MOTS-c yet.
Until the interaction table is fully populated, use the interaction checker and related peptides below to explore adjacent compounds and likely research pairings.
Comparison Pages
Frequently Asked Questions
Research Disclaimer
This page is for research and educational purposes only. The information presented is based on published scientific literature and does not constitute medical advice, diagnosis, or treatment recommendations. Regulatory status can vary by compound, formulation, indication, and jurisdiction. Check official labeling, registry records, and qualified professional guidance before making any health-related decision. The studies referenced are linked to their original PubMed sources for verification.