Peptide Briefs

MOTS-c

Evidence grade: C — reviewed October 2026

Controlled human trials of MOTS-c: 0 completed. Controlled human trials of a MOTS-c analog: 1 (CB4211, Phase 1a/1b; the 1b portion was 20 participants for 28 days). Registered and recruiting: 1 (native MOTS-c, Phase 2a, no results). Pilot or open-label human studies: several observational studies measuring the body’s own MOTS-c; no study has administered native MOTS-c to humans. Animal studies: many (mouse models of diet-induced obesity, insulin resistance, exercise capacity and muscle).

Also known as: mitochondrial open reading frame of the 12S rRNA type-c; MOTS-c; the analog is CB4211 (CohBar)

Sequence: 16-amino-acid peptide encoded inside the mitochondrial genome (MT-RNR1), not the nuclear genome. Published sequence: Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg.

One-line rationale: A mitochondrial-derived peptide with a large, consistent animal literature on metabolism and exercise, human data that is almost entirely observational, and one small controlled trial that tested a modified analog rather than MOTS-c itself. It grades C because the human evidence is pilots, correlations and a 28-day analog study; it is not D because that evidence exists, is published, and a registered Phase 2a is now recruiting.

What it is

MOTS-c was described in 2015 by Changhan Lee and colleagues at USC as a peptide translated from a short open reading frame in mitochondrial DNA. In cells and mice it activates AMPK, the energy-sensing enzyme that metformin and exercise also act on, and shifts metabolism toward glucose use and fat oxidation. Circulating MOTS-c falls with age in humans and rises sharply with exercise.

That biology is why it gets described as an “exercise mimetic” and a longevity compound. Both descriptions come from animal and cell data.

Human evidence

Observational. Several studies have measured MOTS-c in blood or muscle and correlated it with insulin sensitivity, age, or training. In a 2021 Nature Communications study of ten sedentary healthy young men, skeletal-muscle MOTS-c rose 11.9-fold after a bout of stationary cycling and was still elevated four hours later; circulating levels rose about 1.6-fold during exercise and returned to baseline by four hours. These studies measure the body’s own peptide; none of them gave MOTS-c to anyone.

CB4211 (the analog). CohBar’s CB4211 is a modified MOTS-c-based peptide with improved pharmacokinetics; it is not the native 16-amino-acid peptide. The program ran a Phase 1a single- and multiple-ascending-dose study in healthy adults (safety only; the multiple-dose part was 7 days of daily subcutaneous dosing in healthy non-obese volunteers) and a Phase 1b in 20 adults with obesity and at least 10% liver fat: 11 received 25 mg daily subcutaneously and 9 placebo, for four weeks. Topline results in August 2021 reported lower glucose, reduced liver-injury markers, and a modest weight-loss trend. The results were released by the company, not published in a journal, and the program was discontinued when CohBar merged into TuHURA Biosciences in 2023.

Phase 2a, native MOTS-c (2026). NCT07505745, sponsored by Hudson Biotech, is a randomized, double-blind, placebo-controlled Phase 2a of once-daily subcutaneous MOTS-c for 12 weeks in adults with prediabetes and overweight or obesity, planned at 120 participants, at Peking University Shenzhen Hospital. It is the first controlled efficacy trial of MOTS-c itself. The registry lists it as recruiting, started February 2026, with primary completion estimated for February 2027 and no results. Two cautions: the record has not been updated since April 2026, and the listed start date precedes the registration date, so treat the timeline as approximate. It is not registered as a U.S. FDA-regulated drug study.

Regulatory. MOTS-c is not approved anywhere. It was on the FDA Pharmacy Compounding Advisory Committee docket in July 2026, which concerns whether compounding pharmacies may use it; it is not a review of efficacy. FDA’s briefing document for that meeting states that the nomination included no clinical studies or human exposure data for MOTS-c by any route of administration, and that FDA identified none.

Animal evidence

Consistent and extensive: in mice, MOTS-c treatment improved insulin sensitivity, reduced weight gain on a high-fat diet, increased exercise capacity in young and old animals, and protected against muscle loss in several models. These are the studies most often quoted as if they were human findings.

Safety signals

No human safety database exists for native MOTS-c. CB4211 was reported as well tolerated at the doses tested over 28 days; that is the sum of the controlled human safety data, and it is for a different molecule. Nothing is known about long-term use, dosing in humans, or interactions. Research-use-only MOTS-c sold by vendors has not been tested in any of the studies above.

Why C, not D or B

D on the Grade Key is anecdote or a single preliminary report. MOTS-c has a published animal literature, published observational human work, and a controlled analog study, so it clears D. B requires at least one controlled human trial of the compound itself; the CB4211 study is of an analog and was never published, no study has administered native MOTS-c to humans, and the Phase 2a has no results. If NCT07505745 reports and publishes, the grade will be revisited.

See also

Tirzepatide (grade A; what a completed program looks like). Epitalon (grade C; another compound where the longevity claims run ahead of the human data). Grade Key.

Sources

  1. Lee C, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443-454.
  2. Reynolds JC, et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021;12:470.
  3. CohBar Inc. Topline results, CB4211 Phase 1a/1b study in NASH and obesity. Company release, August 2021. ClinicalTrials.gov NCT03998514.
  4. ClinicalTrials.gov NCT07505745. A Phase 2a study of MOTS-c in adults with prediabetes and overweight or obesity (Hudson Biotech). Registered 2026; recruiting.
  5. Alzheimer’s Drug Discovery Foundation, Cognitive Vitality Reports. MOTS-c. (Independent evidence summary; notes that MOTS-c has not been clinically tested in humans as a therapeutic.)
  6. FDA Pharmacy Compounding Advisory Committee, meeting of July 23, 2026: FDA briefing document on MOTS-c (states no clinical studies or human exposure data were identified for the native peptide).
  7. Kim KH, et al. Mitochondrially derived peptides as novel regulators of metabolism. J Physiol. 2017;595(21):6613-6621. (Review.)