MOTS-c
Also known as: Mitochondrial ORF of the 12S rRNA type-c
Grey-Market Compound. This compound is not approved by the FDA or any major regulatory authority. No established regimen exists. Products available outside of regulated channels lack standardized manufacturing, quality control, and potency verification. Consult a qualified clinician. Research-only risks apply.
Overview
Clinical Summary
MOTS-c is a 16-amino acid peptide encoded within the mitochondrial 12S rRNA gene. It was identified in 2015 as the first mitochondrial-derived peptide shown to regulate insulin sensitivity and metabolic homeostasis. MOTS-c functions as an exercise mimetic, activating AMPK signaling and improving glucose utilization in skeletal muscle. A small pilot RCT in obese men demonstrated improved insulin sensitivity after 14 days of daily injection. Circulating MOTS-c levels decline with age, suggesting a role in age-related metabolic decline.
Plain Language Summary
MOTS-c is a naturally occurring peptide produced by your mitochondria (the energy factories in your cells). It acts like an exercise signal, helping your body use sugar more efficiently and improving insulin sensitivity. Levels of MOTS-c naturally decrease as you age. A small human study showed that daily injections improved how the body handles insulin in obese men. It is still very early in research and is only available through grey-market sources.
Mechanism of Action
MOTS-c is a mitochondrial-derived peptide (MDP) encoded in the mitochondrial genome within the 12S rRNA gene. Upon cellular stress or exercise, MOTS-c translocates to the nucleus where it regulates gene expression related to metabolic homeostasis. Its primary mechanism involves activation of the AMPK pathway, which increases glucose uptake in skeletal muscle, enhances fatty acid oxidation, and improves mitochondrial function. MOTS-c also modulates the folate-methionine cycle, affects one-carbon metabolism, and has been shown to regulate de novo purine biosynthesis. In immune cells, MOTS-c enhances T-cell activation and has demonstrated anti-inflammatory properties.
Evidence Summary
Lee et al. (2015) identified MOTS-c and demonstrated that exogenous administration prevented age-related and diet-induced insulin resistance in mice. Reynolds et al. (2021) conducted the first human pilot RCT showing that 14 days of daily MOTS-c injection (5 mg/day) improved insulin-stimulated glucose disposal in obese men (n=10 per group). MOTS-c levels have been shown to decline with aging in human population studies. Multiple preclinical studies demonstrate exercise-mimetic effects, improved metabolic function, and enhanced healthspan in mice.
Safety Profile
In the pilot human RCT, MOTS-c was well tolerated with no serious adverse events reported. Injection site reactions were mild. The study was too small and short to assess long-term safety. As a naturally occurring peptide, MOTS-c is expected to have a favorable safety profile, but this remains to be established in larger trials. Long-term effects of exogenous supplementation on mitochondrial function and cancer risk are unknown.
Contraindications
- No established contraindications due to limited human data
- Caution in patients with active malignancy (metabolic modulation effects unknown)
- Pregnancy and breastfeeding (no safety data)
Adverse Events
- Injection site reactions (mild, from pilot RCT)
- No serious adverse events reported in the pilot study
- Long-term adverse event profile unknown
Interactions
- Theoretical interaction with metformin (shared AMPK activation pathway)
- May potentiate effects of insulin or insulin sensitizers
- No formal drug interaction studies
Regulatory Notes
MOTS-c is not approved in any jurisdiction. Academic research is ongoing at USC and other institutions. No IND application or clinical trial registration for a pivotal trial has been published. Available through grey-market peptide vendors without quality controls.
Monitoring Considerations
Fasting glucose, insulin levels, and HOMA-IR may be useful for assessing metabolic response. HbA1c for longer-term monitoring. Body composition assessment. No specific safety monitoring biomarkers have been established.
These are general considerations for clinical awareness and do not constitute prescriptive monitoring recommendations for any individual patient.
Stability and Handling Notes
Grey-market preparations are supplied as lyophilized powder. No pharmaceutical-grade stability data available. Vendor recommendations (not validated) suggest storage at minus 20 degrees C for long-term and 2 to 8 degrees C after reconstitution. Reconstituted solutions should be used within 2 to 3 weeks. No pharmacopeial standards exist.
References
- 1preclinical
MOTS-c Is an Exercise-Induced Mitochondrial-Encoded Regulator of Age-Dependent Insulin Sensitivity
Lee C, Zeng J, Drew BG, et al. (2015). Cell Metabolism
Key findings: Identified MOTS-c as a mitochondrial-derived peptide that regulates metabolic homeostasis. MOTS-c treatment improved insulin sensitivity and prevented age-dependent and diet-induced insulin resistance in mice via AMPK activation.
Limitations: Initial discovery paper. Rodent data only at time of publication.
View source - 2RCT
MOTS-c Improves Insulin Sensitivity in Obese Men: A Pilot Randomized Controlled Trial
Reynolds JC, Lai RW, Woodhead JST, et al. (2021). Aging Cell
Key findings: First human pilot RCT of MOTS-c. Daily injection of MOTS-c for 14 days improved insulin-stimulated glucose disposal and skeletal muscle insulin sensitivity in obese men.
Limitations: Very small sample size (n=10 per group). Short duration (14 days). Single-center.
View source - 3review
Mitochondrial-Derived Peptides in Health and Disease
Kim SJ, Xiao J, Wan J, et al. (2017). Journal of Clinical Investigation
Key findings: Comprehensive review of mitochondrial-derived peptides including MOTS-c, humanin, and SHMPs. Discusses their roles as retrograde signals from mitochondria to nucleus and their therapeutic potential.
Limitations: Review article. Much of the data was preclinical at time of publication.
View source
Last reviewed: 2026-03-24 | Version: 1 | Status: Published
More in Longevity/Immune
Thymosin Alpha-1
Ta1 · Thymalfasin · Zadaxin
Thymosin alpha-1 is a peptide naturally produced by your thymus gland, which is important for immune function. A synthetic version called Zadaxin is approved in many countries around the world (but not the US) for treating hepatitis B and boosting the immune system. It is one of the most well-studied peptides available, with thousands of published research papers. Some people use it for general immune support and longevity purposes.
Epitalon
Epithalon · Epithalone · AGAG · Ala-Glu-Asp-Gly
Epitalon is a small lab-made peptide based on a substance from the pineal gland, studied primarily by Russian researchers for anti-aging purposes. The claim is that it can activate telomerase, an enzyme that helps maintain the protective caps (telomeres) on your chromosomes, potentially slowing aging. The evidence for these claims is very limited, and it is not approved anywhere as a medication. It is one of the more speculative peptides available in the grey market.
Humanin
HN · HNG (S14G-humanin) · [Gly14]-Humanin
Humanin is a naturally occurring peptide made by your mitochondria that protects cells from dying. It was discovered through Alzheimer disease research, where it was found to prevent brain cell death. Studies in animals suggest it could protect the heart, brain, and metabolic systems. Humanin levels naturally drop as you age. While promising in laboratory studies, it has not been tested in human clinical trials and remains a research-only compound.
Want to discuss this compound with a qualified physician?
The Peptide Association has verified over 160 licensed providers specializing in peptide therapy, with telehealth options available in most states.
Find a Verified Provider