MOTS-C

Origin and structure

MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California described it in March 2015, after finding a short reading frame of 51 base pairs inside the mitochondrial gene for 12S ribosomal RNA (MT-RNR1). It codes for a peptide of 16 amino acids, Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg, with the formula C101H152N28O22S2 and a molar mass of 2174.6 g/mol. The peptide occurs in skeletal muscle, heart and brain, and circulates in the blood of humans and rodents.

MOTS-c belongs to a small family of mitochondrial-derived peptides. The first, humanin, has 24 amino acids, is encoded in the 16S rRNA gene and was found in 2001 as a factor that protected nerve cells against amyloid-beta; six small humanin-like peptides (SHLP1 to 6) followed. Much of the MOTS-c research comes from one network around Lee and Cohen. Cohen is one of the founders of the company CohBar, and the group's 2022 review discloses that the intellectual property on humanin, MOTS-c and the SHLPs, on which Cohen is named as an inventor, was licensed to CohBar.

How it is thought to work

In the 2015 study the main target of MOTS-c appeared to be skeletal muscle. In cultured cells it slowed the folate cycle and the purine production linked to it, which led to a build-up of AICAR in its phosphorylated form (also called ZMP), a natural intermediate that switches on AMPK, the enzyme that senses an energy shortage in the cell. AMPK in turn stimulates fatty-acid oxidation and glucose use. In the same cells, switching AMPK off only partly blunted the effect of MOTS-c on glucose use, so the authors concluded that AMPK explains part of its action, not all of it. A 2018 study from Lee's laboratory added that under metabolic stress, such as a shortage of glucose, MOTS-c moves from the mitochondria into the cell nucleus and regulates stress-response genes, working together with the transcription factor NRF2.

All of this comes from cell cultures and mice. FDA reviewers noted in 2026 that the molecular target of MOTS-c is still unknown, that no animal study has measured how the effect changes with the dose, and that there are no pharmacokinetic studies in animals or people. In human blood in a test tube, MOTS-c was rapidly cut into shorter fragments, so it is unclear whether injected MOTS-c reaches active levels in the body.

Is MOTS-c approved?

No. No medicine containing MOTS-c is authorised in the EU, the Netherlands or the US. The FDA's 2026 review found no authorised product listed by the EMA, no monograph in the European or US pharmacopoeia and no approved drug that contains it. In the Netherlands it is not a registered medicine, so it may not be sold or promoted for use in people; our shop sells it as research material only.

In the United States the question has been whether pharmacies may compound it. On 29 September 2023 the FDA placed MOTS-c in Category 2 of its interim policy for bulk substances nominated for compounding, the group for substances that may pose significant safety risks, citing possible immune reactions, peptide impurities and the absence of any human exposure data. The nomination, from a US pharmacy network, was later withdrawn, and the FDA then evaluated MOTS-c on its own initiative. Its staff review, dated 11 May 2026, proposed not adding the free base or the acetate salt to the list of substances pharmacies may use: neither was well characterised, and the FDA found no human safety or effectiveness data for any of the nominated uses, which ranged from insulin resistance and obesity to osteoporosis and longevity.

On 23 July 2026 the FDA's Pharmacy Compounding Advisory Committee nevertheless voted in favour of adding MOTS-c, as it did that day for BPC-157, KPV and TB-500. The vote is advice only: adding a substance to the list takes an FDA rulemaking, and none had been published when this page was checked in October 2026. On 14 October 2026 the FDA sent an 'Interim Access Policy for Compounding Using Certain Peptides' to the White House regulatory office (OIRA) for review; its text, and the peptides it covers, have not been published. Even a favourable decision would only allow pharmacy compounding; it would not make MOTS-c an approved drug.

In sport it is prohibited at all times. The WADA Prohibited List names MOTS-c in class S4.4.1, activators of the enzyme AMPK, next to AICAR, and the 2027 list keeps it there. In the Netherlands the Dopingautoriteit applies the same list.

What the research shows

Almost all of the evidence comes from cells and rodents, or from measurements of the body's own MOTS-c in people. No study has tested whether MOTS-c given as a treatment does anything in humans. The main findings:

• Obesity and insulin resistance (mice, 2015): mice on a high-fat diet given daily MOTS-c injections for eight weeks gained less weight and stayed more sensitive to insulin than untreated mice, and one week of treatment restored insulin sensitivity in the muscle of older mice.
• Physical capacity (mice, 2021): MOTS-c improved treadmill performance in young, middle-aged and old mice, in groups of 5 to 19 animals. Old mice treated three times a week from 23.5 months of age had better grip strength and walking ability late in life; their median lifespan was 6.4% longer, but the difference across the whole survival curve was not statistically significant.
• Other animal models: studies from other groups report less bone loss in mice, less vascular calcification in rats and less weight gain in mice after removal of the ovaries. FDA reviewers pointed out in 2026 that none of these studies tested a range of doses.
• Exercise in people (2021): in 10 sedentary young men, MOTS-c in thigh muscle rose 11.9-fold after an interval session on an exercise bike, and blood levels rose about 1.5-fold before returning to baseline within four hours. This shows that exercise raises the body's own MOTS-c, not what injected MOTS-c does.
• Age: in people, MOTS-c levels in the blood are lower at older ages, while levels in muscle are higher.
• Genetics (2021): an Asian-specific variant, m.1382A>C, changes the 14th amino acid of MOTS-c (K14Q). In three cohorts totalling 27,527 people, men who carried it had type 2 diabetes more often and women did not; in a Japanese cohort the excess was confined to the least physically active men. In mice, the K14Q form lacked the metabolic effect of normal MOTS-c. In people this is an association, not proof that MOTS-c protects against diabetes.

CB4211: the only human trial, of an analogue

CohBar developed CB4211, which it described as an improved analogue of MOTS-c, as a treatment for fatty liver disease (NASH) and obesity. It was tested in a randomised, double-blind, placebo-controlled phase 1a/1b trial (NCT03998514) at four US clinics, with results announced in August 2021:

The results were released by the company and have never appeared in a peer-reviewed journal. In its annual report of March 2023 CohBar wrote that the formulation used in phase 1b was not suitable for further development and that attempts to improve it had not succeeded. No later CB4211 trial has been registered, and because CB4211 is a different molecule, its results cannot be carried over to MOTS-c itself.

• Phase 1a: 65 healthy adults received single doses or seven daily doses of CB4211 at ascending levels, or placebo. The first formulation was deposited under the skin and left persistent, painless lumps, so the study was paused to change the formulation.
• Phase 1b: 23 adults with obesity and fatty liver were randomised to CB4211 or placebo for four weeks; 20 were assessed (11 versus 9). ALT, a liver enzyme, fell by 21% on CB4211 and rose by 4% on placebo; AST fell by 28% against 11%, and blood glucose by 6% against no change. Liver fat fell by about 5 percentage points in both groups, which the company linked to the controlled diet all participants received in the clinic, and body weight showed only a trend.
• Safety: no serious adverse events; the only side effects in more than 10% of participants on CB4211 were transient, mostly mild to moderate injection-site reactions, which the company's slides put at 79% of people on CB4211 against 33% on placebo.

Frequently asked questions

Has MOTS-c been tested in humans?

Not as a treatment. No study that gave MOTS-c to people has been published, and the FDA found no human exposure data in 2026. Human research covers the body's own MOTS-c, for example its rise in muscle after exercise, and one company trial of the analogue CB4211 in healthy volunteers and people with obesity and fatty liver.

Is MOTS-c 'exercise in a vial'?

That claim rests on mice. MOTS-c improved running capacity in mice, and exercise raises the body's own MOTS-c in people, but no study has tested whether injected MOTS-c improves fitness, endurance or body composition in humans.

Did the FDA approve MOTS-c in 2026?

No. In July 2026 an FDA advisory committee voted to recommend that US pharmacies be allowed to compound MOTS-c, against the advice of FDA staff, who had found no human data. The vote is advice only; the FDA had not decided by October 2026, and even a favourable decision would not make MOTS-c an approved drug.

Is MOTS-c legal in the Netherlands?

MOTS-c is not a registered medicine in the Netherlands, so it may not be sold, advertised or supplied for use in people. Buying and selling it as research material is a different status, which our guide on research-use-only products in the Netherlands explains.

Is MOTS-c banned in sport?

Yes, at all times, in and out of competition. WADA names MOTS-c in class S4.4.1 of the Prohibited List, activators of the enzyme AMPK, and keeps it there in the 2027 list. The Dopingautoriteit applies the same list in the Netherlands.

What is the difference between MOTS-c and humanin?

Both are peptides encoded in mitochondrial DNA. Humanin has 24 amino acids, comes from the 16S rRNA gene and was first studied as a protector of nerve cells against amyloid-beta; MOTS-c has 16 amino acids, comes from the 12S rRNA gene and is studied mainly for metabolism and exercise. In people, MOTS-c in the blood is lower at older ages; for humanin the studies disagree, and in the largest, of 693 people aged 21 to 113, levels rose with age.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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