The six / MOTS-c
MOTS-c
Also: Mitochondrial open reading frame of the 12S rRNA type-c
A peptide encoded by the mitochondria rather than the nucleus, discovered in 2015, with striking mouse data and a human record that is observational only.
Class
Mitochondrial-derived peptide, 16 amino acids
Encoded in
The 12S rRNA gene of mitochondrial DNA
Origin
Discovered 2015, Lee, Cohen and colleagues, University of Southern California
Policy form
MOTS-c acetate
Permitted routes
Subcutaneous or intramuscular injection only
Human evidence
Low: observational only; no controlled trial of administered MOTS-c
What people ask for it for
Metabolic health, insulin sensitivity, energy and 'exercise in a vial'. It is the peptide people who already train ask about.
What the policy allows
MOTS-c acetate. Subcutaneous or intramuscular injection only.
Strength of the evidence
LowGood science behind the molecule, published in strong journals by an academic group with no product to sell. The mouse results are real and the human results are about the body's own MOTS-c, not injected MOTS-c.
Where it comes from
Mitochondria carry their own small genome, long thought to encode only the machinery of energy production. In 2015 Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California reported a 16-amino-acid peptide hidden inside the mitochondrial 12S ribosomal RNA gene, which they named MOTS-c. It was the second mitochondrial-derived peptide found after humanin.
The discovery paper, in Cell Metabolism, showed that the peptide circulates in blood, acts on skeletal muscle and prevented diet-induced obesity and insulin resistance in mice. A 2021 Nature Communications paper from the same group showed that exercise raises MOTS-c in human muscle and that giving it to old mice improved their physical performance.
The biotech CohBar took an analogue, CB4211, into an early human trial for fatty liver and obesity around 2021; the programme did not continue. MOTS-c itself reached the grey market through the longevity and athletic communities, and anti-doping laboratories now test for it.
How it is thought to work
From cell and animal models unless stated
MOTS-c activates AMPK, the enzyme that senses low cellular energy and switches the cell towards burning fuel. In models it does this by interfering with the folate-methionine cycle, which raises AICAR, a natural AMPK activator.
In skeletal muscle it increases GLUT4 and glucose uptake and promotes fatty-acid oxidation, which is the basis of the insulin-sensitivity and 'exercise mimetic' descriptions.
Under metabolic stress it moves into the cell nucleus and regulates genes involved in the antioxidant response, an unusual behaviour for a mitochondrial product.
What the research shows
Study by study, labelled by what it was. The third column is the citation; the full references are at the foot of the page.
In cells and animals
Mice on a high-fat diet
Prevented obesity and insulin resistance; improved glucose handling.
Lee et al., Cell Metabolism 2015; PubMed 25738453
Aged mice, late-life dosing
Improved running capacity and physical performance; the peptide was identified as an exercise-induced regulator of age-related decline.
Reynolds et al., Nature Communications 2021; PMC7817689
Rats, exercise training
Improved myocardial performance during training.
PMC8505603
Autoimmune diabetes model
Protected pancreatic islets from immune destruction.
PMC10083145
In people
Skeletal muscle MOTS-c after acute exercise
Rose roughly twelve-fold, an observation about endogenous MOTS-c.
Reynolds et al., 2021
Circulating MOTS-c across ages and metabolic states
Declines with age and is inversely related to metabolic dysfunction in observational studies.
Frontiers in Endocrinology review, 2023
Administered MOTS-c, any controlled trial
None published. The only human dosing was of an analogue, CB4211, in an early-phase trial that did not continue.
FDA briefing, 2026
Safety, and what is not known
- There are no peer-reviewed human safety data for MOTS-c, and FDA identified no human exposure data for MOTS-c drug products. Long-term safety is unknown.
- The policy's Appendix B notes that the available safety evidence runs in one direction, meaning the animal work reported benefit without harm, and that most documented use is single-ingredient.
- An AMPK activator that changes how muscle handles glucose is not a trivial thing to give a person on diabetes medication. The clinician's history-taking matters more here than for most of the six.
- It is on the WADA list and anti-doping laboratories test for it. If you are tested, know before, not after.
What the HHS policy says about MOTS-c
MOTS-c acetate
Subcutaneous or intramuscular injection only.
- Appendix B records updated characterisation data, that most documented use is single-ingredient, and that the safety evidence is one-directional.
- One peptide per product; MOTS-c may not be blended with a GLP-1 or anything else.
All ten conditions of the policy →
Sport
Prohibited at all times as a metabolic modulator (AMPK activators, S4.4) on the 2026 Prohibited List, and detectable.
Regulatory status
-
Never
FDA approval. No application for approval of this substance has been filed in the US, and no trial exists that could support one.
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September 2023
Placed in Category 2 of FDA's interim 503A bulk substances list, the category for substances where FDA identified significant safety risks. Reputable pharmacies stopped compounding it.
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April 2026
Removed from the active Category 2 table after the Federal Register notice announcing advisory committee review.
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July 2026
Pharmacy Compounding Advisory Committee recommended it for the 503A bulks list on July 23, by 7 votes to 5 with two abstentions.
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October 28, 2026
Covered by the HHS enforcement discretion policy. Compoundable by state-licensed pharmacies and physicians that meet all ten of the policy's conditions, for an individual patient on a valid prescription. Still not on the 503A bulks list and still not approved.
Getting MOTS-c through Healthy Peptides
You complete a health intake. An independent clinician at Beluga Health reviews it and decides whether MOTS-c is appropriate for you, and by which permitted route. If prescribed, a state-licensed pharmacy that meets every condition of the HHS policy compounds the single-ingredient product and ships it to you. Healthy Peptides sells you the program; Local Healthcare bills you as its agent.
What we will and will not tell you
- WillWhat the research on MOTS-c actually shows, graded honestly, and the routes a pharmacy may prepare.
- WillWho made it, who prescribed it, who billed you, and how to report a problem.
- Will notCall MOTS-c approved, proven, safe or natural, or promise a result.
- Will notPublish a dose or protocol. That is between you, the clinician and the pharmacy label.
Questions about MOTS-c
What is MOTS-c?
A 16-amino-acid peptide encoded in mitochondrial DNA, discovered in 2015 at USC. The body makes it, exercise raises it, and in mice giving extra prevents obesity and improves physical performance. Injected MOTS-c has never been tested in a controlled human trial.
Is it an exercise mimetic?
In mice it reproduces some of the metabolic effects of exercise, through AMPK. In people the only evidence is that exercise raises the body's own MOTS-c. Nothing shows that injecting it does what training does, and the policy does not change that.
What human data exist?
Observational only: levels rise with exercise and fall with age and metabolic disease. The one human dosing study was of an analogue, CB4211, in an early-phase trial that did not progress. No published trial has given MOTS-c itself to people.
Is it safe?
Unknown. No human safety data exist. The animal work reported no harm. Because it acts on glucose handling, a clinician will want to know about any diabetes medication before considering it.
Is it banned in sport?
Yes, at all times, as an AMPK activator under WADA S4.4, and it is detectable.
MOTS-c is not FDA-approved and no clinical trial has established that it is safe or effective for any use. The research described on this page is reported as what it is, cell, animal or small human studies, and is not a benefit you should expect. Programs are provided only where an independent, licensed clinician determines they are clinically appropriate after reviewing your health history, and not everyone qualifies. Compounded MOTS-c is prepared by a state-licensed pharmacy under a patient-specific prescription and the conditions of the HHS enforcement discretion policy of October 28, 2026, which is not an approval and may be withdrawn. Availability varies by state. This page is general information, not medical advice. Last reviewed October 29, 2026.
Sources
- Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism 2015
- Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications 2021
- MOTS-c: a novel mitochondrial-derived peptide regulating muscle and fat metabolism (review). 2016
- The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. 2019
- Superpower peptide guide: MOTS-c
- HHS: Enforcement Discretion Policy Regarding 503A Compounding Using Certain Peptide Bulk Drug Substances, with Appendices A and B (October 28, 2026)
- AJMC: FDA panel backs 6 peptides for compounding (July 2026)
- FDA: Bulk drug substances used in compounding under section 503A
- WADA: 2026 Prohibited List