A peptide encoded in mitochondrial DNA, discovered in 2015, that does something real in mice and has been given to humans exactly once, as a modified analogue, in a trial whose formulation the sponsor then abandoned.
Summary
MOTS-c is a 16-amino-acid peptide encoded by a short open reading frame inside the mitochondrial 12S ribosomal RNA gene. In mice it activates AMPK in skeletal muscle and prevented age- and diet-induced insulin resistance and obesity.1
Exercise raises MOTS-c in human muscle and blood, and in mice intermittent injection improved physical performance at every age and extended healthspan when started late in life.2
A common East Asian mitochondrial variant that changes one residue of MOTS-c is associated with higher type 2 diabetes prevalence in sedentary men, and the variant peptide is less active. That is the strongest human evidence that the peptide matters.3
No trial of MOTS-c itself has reported. An analogue, CB4211, completed a Phase 1a/1b study in 88 people in 2021 with encouraging biomarkers; the company later stated the formulation was not suitable for further development and could not improve it.45
A Phase 2 trial of MOTS-c in 120 adults with prediabetes began recruiting in February 2026.6
In human blood in vitro, MOTS-c is broken down within minutes, and the FDA stated it is "unclear whether exogenous administration" by subcutaneous injection "can generate pharmacologically active concentrations."7
On 23 July 2026 the FDA's advisory committee voted 7 to 5, with two abstentions, to recommend it for compounding for obesity and osteoporosis, against the FDA's recommendation. The FDA has not acted.8
Listed as prohibited on the Global Drug Reference Online database used by anti-doping organisations.7
The Most Common Error About This Compound
Calling it an "exercise mimetic" as if that were a measured effect in people. The phrase comes from the mouse work, where it is earned.2 In humans, what has been measured is that exercise raises the body's own MOTS-c. Nobody has shown that injecting it does what exercise does, and the one human trial of anything related used a different molecule and stopped.
Identity
What Is MOTS-c?
Mitochondria have their own small genome, long thought to encode only 13 proteins of the respiratory chain plus RNAs. In 2015 a group at the University of Southern California reported a short open reading frame within the 12S rRNA gene that encodes a 16-residue peptide, which they named MOTS-c. It is found in tissues and in plasma, its level falls with age, and under metabolic stress it moves to the nucleus and regulates nuclear gene expression.19
Its primary target appears to be skeletal muscle, where it inhibits the folate cycle and de novo purine synthesis, which activates AMPK, the cell's energy sensor.1 AMPK activation is what exercise, metformin and caloric restriction have in common, which is the source of the exercise-mimetic language.
Evidence Base
What Do the Mouse Studies Show?
Two landmark papers, both from the group that discovered the peptide.
The 2015 paper reported that MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity.1 The 2021 paper in Nature Communications reported that MOTS-c enhanced physical performance in young, middle-aged and old mice, regulated nuclear genes related to metabolism and proteostasis, and, when started three times a week at 23.5 months, the equivalent of old age, increased physical capacity and healthspan.2
The 2021 paper also contains the human observation on which most marketing rests: exercise induced endogenous MOTS-c in skeletal muscle and in circulation in human volunteers.2 That is a measurement of what the body makes, not of what an injection does.
The Genetic Evidence
This is the most persuasive human data, and it involves no injection at all.
A mitochondrial DNA variant common in East Asian populations, m.1382A>C, changes lysine 14 of MOTS-c to glutamine. A meta-analysis of three cohorts totalling 27,527 people found that men, but not women, carrying the variant had a higher prevalence of type 2 diabetes, and in one cohort the effect was confined to men in the lowest tertile of physical activity. In mice, the normal peptide reduced weight and improved glucose tolerance on a high-fat diet; the K14Q variant did not.3
That is evidence that the endogenous peptide has a metabolic role in humans, that the role interacts with exercise, and that it may be sex-specific. It says nothing about whether the synthetic peptide, injected, does anything.
What Human Trials Exist?
| Study | What was given | Population | Result |
|---|---|---|---|
| NCT03998514, CohBar, 2018 to 202110 | CB4211, a modified analogue of MOTS-c, subcutaneous, ascending doses | 88 healthy and fatty-liver-disease adults | Well tolerated; sponsor reported significant reductions in ALT, AST and glucose and a trend to lower weight after four weeks; never published4 |
| NCT07505745, Hudson Biotech, from February 20266 | MOTS-c, subcutaneous, 12 weeks | 120 adults with prediabetes and overweight or obesity | Recruiting; primary endpoint insulin sensitivity; completion estimated 2028 |
The CB4211 story deserves its own paragraph, because it is the closest this compound has come to being a drug. CohBar, founded by the peptide's discoverer, took a modified analogue through a randomised, double-blind, placebo-controlled Phase 1a/1b study and announced positive topline results in August 2021.4 By May 2023 the company told the SEC that it "does not believe that the formulation of CB4211 used in the Phase 1b stage of the trial is suitable for further development" and that "efforts to develop an improved formulation have not been successful to date."5 The data were never published in a journal.
A company with the discoverer as founder, a positive Phase 1b and a patent could not make a formulation it was willing to take forward. That is a fact about the difficulty of delivering this peptide, and it bears directly on a powder in a vial.
What Did the FDA Find?
Reviewing the compound for its advisory committee in July 2026, the FDA "did not identify data, such as publicly available clinical studies, evaluating the administration of MOTS-c-related" substances "to humans," and concluded there was "a lack of evidence to evaluate the effectiveness" for any of the nominated uses: insulin resistance, obesity, osteoporosis, vascular calcification, muscle and fat metabolism, and longevity.7 The CB4211 study concerned a different molecule and does not appear in that finding.
The Delivery Problem
Does Injected MOTS-c Survive?
This is the question that separates MOTS-c from most peptides in the library, and the FDA raised it directly. In vitro, incubation of MOTS-c with human whole blood at body temperature for 15 to 60 minutes "results in rapid proteolytic hydrolysis" into shorter peptides, and the agency stated it is "unclear whether exogenous administration of MOTS-c to humans via the nominated SC route can generate pharmacologically active concentrations of the peptide over time."7
The mouse studies worked, so the peptide reaches its target in mice at the doses used. CohBar's analogue was modified precisely to address stability, and still ran into formulation problems.5 Whether unmodified MOTS-c injected subcutaneously into a person lasts long enough to do anything is the question the 2026 Phase 2 trial will be the first to answer.
Safety
What Is Known?
From the analogue: CB4211 was well tolerated with no serious adverse events across 88 people.4 From MOTS-c itself: nothing. The FDA found no pharmacokinetic study, no nonclinical toxicity study, no human exposure data and no adverse event reports, and cautioned that the absence of reports "does not imply that the substance is safe."7
Structurally, MOTS-c is a peptide every human cell makes, which is a reason to expect low intrinsic toxicity. A 16-residue injectable of unverified purity is a separate question, and the FDA's specific concern was immunogenicity from aggregation and impurities.7
What Is Unknown
Dose, frequency, duration, whether it works at all in people, and whether the sex-specific effect seen in the genetic data means it does different things in men and women.3 A 2023 review states plainly that "no effective method of applying MOTS-c in the clinic has been developed."9
Sport and Drug Testing
Is MOTS-c Prohibited?
The FDA's review notes that MOTS-c "is a prohibited substance on The Global Drug Reference Online database," the reference anti-doping organisations use.7 It is not named on the WADA list itself; as an unapproved substance with performance-related claims it falls under section S0. A tested athlete should treat it as prohibited.
Regulatory Status
Is It Approved Anywhere?
No. MOTS-c has no marketing authorisation, no monograph and is not a component of any approved drug.7
What Happened in July 2026?
In September 2023 the FDA placed MOTS-c in Category 2 of its interim compounding policy, stating it "has not identified any human exposure data on drug products containing MOTs-C administered via any route." As of April 2026 it appears among substances nominated but withdrawn.11
On 23 July 2026 the Pharmacy Compounding Advisory Committee considered MOTS-c free base and acetate for the 503A bulks list. The nomination, since withdrawn, proposed subcutaneous injection at 5 mg and 10 mg. The FDA proposed against inclusion: neither form was well characterised, the extent of compounding use was unknown, and there was no human data on safety or effectiveness.7 The committee voted 7 to 5, with two abstentions, to recommend inclusion for obesity and osteoporosis.8
The recommendation is advisory. As of this page's verification date the FDA has not added MOTS-c to the bulks list, and no pharmacy in the United States has a lawful basis on which to compound it.
Related ONPEPS Coverage
MOTS-c sourcing and quality: a peptide that blood destroys in minutes
MOTS-c cost and access: paying for a Phase 2 that has not reported
Semaglutide: what an approved metabolic peptide's evidence looks like
AOD-9604: the last metabolic peptide whose human trials were run, and what they found
FDA peptide news July 2026: the votes, the dissent and what happens next
What Would Change This Page
The Hudson Biotech Phase 2, due to complete in 2028, would be the first controlled human measurement of MOTS-c itself and would answer the delivery question either way.6 Publication of the CB4211 data would let the 2021 topline be examined. The FDA's decision on the July 2026 recommendation would change the access position for a compounded injectable.
References
Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454. Open access. pubmed.ncbi.nlm.nih.gov/25738459
Reynolds JC, Lai RW, Woodhead JST, Joly JH, Mitchell CJ, Cameron-Smith D, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12(1):470. Open access. pubmed.ncbi.nlm.nih.gov/33473109
Zempo H, Kim SJ, Fuku N, Nishida Y, Higaki Y, Wan J, et al. A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). 2021;13(2):1692-1717. Open access. pubmed.ncbi.nlm.nih.gov/33468709
CohBar, Inc. CohBar announces positive topline results from the Phase 1a/1b study of CB4211 under development for NASH and obesity. Press release, 10 August 2021. Company topline announcement; not peer reviewed. globenewswire.com
CohBar, Inc. Form 10-Q for the quarter ended March 31, 2023, filed 11 May 2023. States the Phase 1b formulation of CB4211 is not suitable for further development. sec.gov
ClinicalTrials.gov. NCT07505745. MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity. Sponsor Hudson Biotech. Phase 2, 120 participants estimated, recruiting from February 2026. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT07505745
US Food and Drug Administration. MOTS-c-related bulk drug substances (MOTS-c (free base) and MOTS-c acetate): FDA presentation to the Pharmacy Compounding Advisory Committee, 23 July 2026. Docket FDA-2025-N-6895. fda.gov
ONPEPS. FDA peptide news July 2026: the only source you need. Records the 7 to 5 vote with two abstentions on MOTS-c. onpeps.com
Zheng Y, Wei Z, Wang T. MOTS-c: a promising mitochondrial-derived peptide for therapeutic exploitation. Front Endocrinol (Lausanne). 2023;14:1120533. Open access. pubmed.ncbi.nlm.nih.gov/36761202
ClinicalTrials.gov. NCT03998514. A Phase 1a/1b Study of CB4211 in Healthy Non-obese Subjects and Subjects With Nonalcoholic Fatty Liver Disease. Sponsor CohBar, Inc. 88 participants, completed April 2021, no results posted. Record retrieved 16 September 2026. clinicaltrials.gov/study/NCT03998514
US Food and Drug Administration. Category 2 of the Bulk Substances Nominated Under Sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act. Entry for MOTs-C. Content current as of 22 April 2026. fda.gov
Not Medical Advice
MOTS-c is not approved for human use in any jurisdiction, no human dose has been established, and no controlled trial of the peptide itself has reported. Consult a qualified healthcare provider before acting on anything here.
Evidence counts on the library index retrieved 23 July 2026. Literature and regulatory sources verified 16 September 2026. The FDA had not acted on the July 2026 advisory recommendation as of that date. Re-verify against docket FDA-2025-N-6895 before relying on any regulatory statement here.