MOTS-c Research Overview: Mouse Data, Human Trials, Status

MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA rather than the nuclear genome. The evidence for its effects comes almost entirely from mice and cultured cells. As of 2026-11-08 we found no published human treatment trial of MOTS-c itself and no approval in any jurisdiction we checked.

Key points

• MOTS-c was described in 2015 by a University of Southern California group. Its main mouse results come from that group; two authors disclosed ties to CohBar, which developed an analogue [1][3].
• The only completed human trial we found tested CohBar’s analogue CB4211, not MOTS-c: 20 obese adults with fatty liver, four weeks, company-reported. Liver enzymes fell; liver fat did not differ from placebo. The program later stalled [10][12].
• A Phase 2 trial of MOTS-c itself is recruiting in China (120 planned, started 2026-02-02). No results are posted [15].
• FDA reviewers found no human exposure data in May 2026, yet an advisory committee voted 7 to 5 (2 abstentions) on 2026-07-23 to recommend MOTS-c for the US compounding list. No final FDA action has been reported [16][18][20].
• The “very cope” placement in a viral post is partly supported: benefit is unshown in people, but that is not a failed test.

What MOTS-c is and how it was found

Lee and colleagues reported in Cell Metabolism in March 2015 that a 51-base-pair open reading frame inside the mitochondrial 12S rRNA gene yields a 16-amino-acid peptide, which they named MOTS-c. Humanin was then the only other reported peptide from a short open reading frame in mitochondrial DNA, hence the label “mitochondrial-derived peptide” [1]. They detected MOTS-c in mouse and rat tissues and in human and rodent blood by ELISA, and fasting lowered it in mouse muscle and plasma [1]. One author (Cohen) is a CohBar stockholder and consultant; another (Lee) a consultant [1].

What the mouse studies found

Study	Model	Size	Result
Lee 2015, high-fat diet [1]	Male CD-1 mice, 8 weeks old, 60% fat diet, daily injections for 8 weeks	10 per group	Less weight gain at identical calorie intake and less fatty liver; no weight effect on normal diet. FDA’s summary: about 20% lower body weight [16]
Lee 2015, insulin clamp [1]	Male C57BL/6 mice, high-fat diet, 7 days	6-8 per group	Glucose infusion rate needed to hold blood sugar rose about 30%, driven by muscle glucose disposal rather than liver output
Lee 2015, ageing [1]	Male C57BL/6, 12 versus 3 months	6 per group	Seven days restored insulin-stimulated glucose uptake in old-mouse muscle to young levels
Reynolds 2021, young [3]	Male CD-1 and C57BL/6J, 12 weeks	5-8 per group	Longer treadmill running after 10 days; grip strength and memory maze unchanged
Reynolds 2021, old [3]	C57BL/6N, 22 months	18-19 per group	Ran about twice as long and 2.16 times as far; 17% reached the top speed stage versus none of controls
Reynolds 2021, lifespan [3]	Intermittent treatment from about 24 months	18-19 per group	Median lifespan +6.4%, maximum +7.0%; the authors call it a trend (P = 0.23) needing larger cohorts

Both papers were funded by public and foundation grants and disclosed CohBar consulting and shareholdings for Cohen and Lee [1][3]. FDA noted in 2026 that rodent work did not assess dose-response and that the peptide’s molecular target is unknown [16].

What the human data show

None of these is a treatment trial of MOTS-c.

• Exercise. In 10 sedentary young men (mean age 24.5), muscle MOTS-c rose 11.9-fold and plasma 1.5 to 1.6-fold after cycling; plasma returned to baseline within four hours [3]. A randomized study of 30 participants (10 per group, Cohen a co-author) saw only a non-significant upward trend in plasma MOTS-c after endurance exercise [4].
• Obesity. Plasma MOTS-c was similar in 10 lean and 10 obese adults (0.48 versus 0.52 ng/mL) [5]. In 40 obese and 57 control Chinese children and adolescents it was lower in obese boys but not girls [6].
• Diabetes and ageing. In 225 adults, serum MOTS-c was lower in type 2 diabetes and with age [7].

The two obesity papers report concentrations about a thousand-fold apart (0.48 ng/mL versus roughly 470 ng/mL) [5][6]. We did not compare the assay kits, but the gap suggests methods differ.

The P44S question and the variant that exists

We found no MOTS-c variant named “P44S”, and the peptide has only 16 residues [1]. The variant studied is m.1382A>C, which changes lysine 14 to glutamine (K14Q) and is specific to Northeast Asian populations [8].

Fuku and colleagues proposed in 2015 that it might relate to Japanese longevity; that is a hypothesis paper without sample sizes [8]. A 2021 Aging paper, as described in its press release, reported more type 2 diabetes in men carrying the C allele across three cohorts, a link confined to the least active third in one Japanese cohort, and no benefit from the K14Q peptide in high-fat-fed mice [9]. We could not open the full paper, so cohort sizes, effect sizes and disclosures are unverified, and we could not verify any longevity association.

Proposed mechanisms and how well tested

• Folate-purine-AMPK. In cultured human cells, MOTS-c was reported to inhibit the folate cycle and purine synthesis, raising AICAR and activating AMPK, an energy-sensing enzyme. Knocking down AMPK or blocking it cut glucose-stimulated glycolysis by 16% to 40%, which the authors read as a “partial role” [1].
• Nuclear translocation. Under metabolic stress MOTS-c was reported to enter the nucleus, AMPK-dependently, and change nuclear gene expression [2]; the 2021 paper repeated this with a labelled peptide [3].

All of this is cell and mouse work from closely linked authors. We found no independent replication in the sources we opened. FDA wrote that the target “remains unknown” and that MOTS-c is rapidly broken down in human blood in a test tube, so it is undetermined whether injected peptide reaches active levels [16].

CB4211: the analogue trial and what became of it

CohBar describes CB4211 as an analogue of MOTS-c [10]. Its Phase 1a/1b trial (NCT03998514) ran from 2018-07-09 to 2021-04-19; the registry lists 88 participants and no results [11]. Topline results, released by the company on 2021-08-10 [10]:

• Phase 1a: 65 healthy adults, for safety and dose selection.
• Phase 1b: 20 obese adults with at least 10% liver fat, 11 on CB4211 and 9 on placebo, four weeks.
• ALT fell 21% versus a 4% rise on placebo; AST fell 28% versus 11%; glucose fell 6% versus 0% (p < 0.05, unpaired t-test, per the company).
• Liver fat fell by almost the same amount in both arms (5.03 versus 4.88 percentage points). Weight showed only a “trend”.
• No serious adverse events; injection-site reactions in more than 10% of treated people.

This was an exploratory, company-sponsored readout. CohBar’s FY2022 annual report says the trial was suspended in November 2018 over injection-site reactions and delayed again in March 2020 by COVID-19, that the Phase 1b formulation was not judged suitable for further development, and that improved formulations had not succeeded [12]. On 2022-11-17 CohBar retained an adviser to explore strategic alternatives [13]. A merger agreement ended on 2023-11-01 and the company said it intended to liquidate [14]. A Europe PMC search for CB4211 (2026-11-08) returned ten records, all reviews; a ClinicalTrials.gov search for “MOTS-c” returned nine records, one testing MOTS-c [24].

Regulatory status

• United States, as of 2026-11-08. FDA states neither MOTS-c free base nor acetate is a component of an approved drug [16]. MOTS-c does not appear in the category lists of FDA’s 2026-05-14 update [17]. FDA staff evaluated it on their own initiative after a nomination was withdrawn and, in a document dated 2026-05-11, proposed against adding it to the compounding list, citing poor characterization, immunogenicity concerns and no human safety or efficacy data; its adverse event system showed no reports through March 2025 [16]. On 2026-07-23 the Pharmacy Compounding Advisory Committee voted 7 to 5, two abstaining, to recommend it [18][19]. Votes are advisory and rulemaking must follow; as of 2026-07-31 none was added, and we found no later action [20].
• “Research use only.” The label states a non-human purpose, but FDA said in an August 2026 warning letter to a peptide seller (not naming MOTS-c) that such labels do not change its view when marketing shows human use [22].
• Sport. USADA reports that the 2025 WADA Prohibited List names MOTS-c as an example of an AMPK activator [21].
• EMA, UK (MHRA) and Germany (BfArM): not checked.

Risks and unknowns

FDA says the risks of MOTS-c in humans “are unknown” and could not rule out impurities, aggregates and immune reactions in injectable material [16]. CB4211 caused injection-site reactions serious enough to pause the trial [12]. Long-term use, interactions, pregnancy and children are unstudied. Open questions: the molecular target, whether administered MOTS-c acts like the body’s own, and whether mouse effects transfer to people.

What the source post claims and how it holds up

On 2026-10-15 @Hoostethics posted a tier list, “ranking the most cope supplements.” As transcribed in our source notes, it places MOTS-c in “Very cope”, the second of five tiers, beside CLA, multivitamin, pregabalin, kisspeptin-10, Ritalin and berberine [23]. The post defines neither “cope” nor its criteria; we read it as “does little”.

Verdict: partly supported. That no human data show MOTS-c works is supported: FDA found none and the one human trial used a different molecule [10][16]. But the tier implies a tested failure. MOTS-c is untested in people, a different state, and a Phase 2 trial is running [15]. For the wider list see our cope supplements tier list check. Prices for this research peptide are on the MOTS-c compound page.

Frequently asked questions

Is MOTS-c approved? No. FDA states it is not a component of any approved drug [16]. We did not check the EMA, MHRA or BfArM.

Has MOTS-c been tested in people? Only as a blood marker and in exercise studies. The one completed intervention trial tested the analogue CB4211 in 20 people for four weeks [10]. A Phase 2 trial of MOTS-c in prediabetes has been recruiting since February 2026 [15].

What is the MOTS-c P44S variant? We found no variant by that name. The studied variant is m.1382A>C (K14Q), linked to diabetes in Japanese men in a 2021 study we could read only through a press release [9].

Is MOTS-c banned in sport? USADA says the 2025 WADA list names it as an example of an AMPK activator among metabolic modulators [21].

Sources

1. Lee C et al., Cell Metabolism, “The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance” (2015-03-03). https://doi.org/10.1016/j.cmet.2015.02.009 (full text read from a CohBar-hosted copy; record on Europe PMC, PMID 25738459)
2. Kim KH et al., Cell Metabolism, “The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress” (2018). PMID 29983246 (abstract only, via Europe PMC)
3. Reynolds JC et al., Nature Communications, “MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis” (2021). https://doi.org/10.1038/s41467-020-20790-0 (full text via eScholarship)
4. von Walden F et al., Journal of Applied Physiology, “Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans” (2021). PMID 34351816 (abstract only)
5. Cataldo LR et al., Journal of Investigative Medicine, “Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals” (2018). PMID 29593067 (abstract only)
6. Du C et al., Pediatric Diabetes, “Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance” (2018). PMID 29691953 (abstract only)
7. Ramanjaneya M et al., Frontiers in Endocrinology, “Mitochondrial-derived peptides are down regulated in diabetes subjects” (2019). PMID 31214116 (abstract only)
8. Fuku N et al., Aging Cell, “The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity?” (2015). PMID 26289118 (abstract only)
9. Aging-US via EurekAlert, news release on “A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c” (2021-02-02). https://www.eurekalert.org/news-releases/477698 (full paper not opened)
10. CohBar, Inc., “CohBar Announces Positive Topline Results from the Phase 1a/1b Study of CB4211 Under Development for NASH and Obesity” (2021-08-10). https://www.biospace.com/cohbar-announces-positive-topline-results-from-the-phase-1a-1b-study-of-cb4211-under-development-for-nash-and-obesity
11. ClinicalTrials.gov, NCT03998514, “A Phase 1a/1b Study of CB4211 in Healthy Non-obese Subjects and Subjects With NAFLD” (record last updated 2021-05-11). https://clinicaltrials.gov/study/NCT03998514
12. CohBar, Inc., Form 10-K for fiscal year 2022 (share-count date 2023-03-06), SEC EDGAR. https://sec.gov/Archives/edgar/data/1522602/000121390023018882/f10k2022_cohbarinc.htm (first 100,000 characters read)
13. CohBar, Inc., Form 8-K (2022-11-17), SEC EDGAR. https://www.sec.gov/Archives/edgar/data/1522602/000121390022073317/ea168878-8k_cohbar.htm
14. CohBar, Inc., Form 8-K (2023-11-01), SEC EDGAR. https://www.sec.gov/Archives/edgar/data/1522602/000121390023081954/ea187569-8k_cohbar.htm
15. ClinicalTrials.gov, NCT07505745, “MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity” (posted 2026-04-01). https://clinicaltrials.gov/study/NCT07505745
16. FDA, “FDA Evaluation of MOTS-c-Related Bulk Drug Substances,” briefing document for the Pharmacy Compounding Advisory Committee (evaluation dated 2026-05-11). https://www.fda.gov/media/193347/download
17. FDA, “Bulk Drug Substances Nominated for Use in Compounding Under Section 503A” (updated 2026-05-14). https://www.fda.gov/media/94155/download (MOTS-c does not appear in its category lists)
18. Pharmaceutical Executive, “FDA votes to loosen restrictions on four peptides” (2026-07-24). https://www.pharmexec.com/view/fda-votes-loosen-restrictions-four-peptides
19. Pharmaceutical Technology, “Peptide compounding vote raises questions for drug developers” (2026-07-24). https://www.pharmtech.com/view/peptide-compounding-vote-raises-questions-drug-developers
20. AJMC, “FDA panel backs 6 peptides for compounding” (2026-07-31). https://ajmc.com/view/fda-panel-backs-6-peptides-for-compounding
21. USADA, “Athlete Advisory: What’s New on the 2025 WADA Prohibited List?” (2024-10-16). https://www.usada.org/athlete-advisory/new-2025-wada-prohibited-list/ (WADA’s own list not opened)
22. FDA, Warning Letter to Peak Performance Peptides, ref. 735127 (2026-08-24). https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/peak-performance-peptides-735127-08242026
23. @Hoostethics, “ranking the most cope supplements.” (2026-10-15). https://x.com/Hoostethics/status/2110728908735979632 (X blocked access; post text read through the fxtwitter mirror; tier placement read from the image by Peptilyze)
24. Europe PMC search for “CB4211” and ClinicalTrials.gov search for “MOTS-c” (both run 2026-11-08). https://www.ebi.ac.uk/europepmc/ and https://clinicaltrials.gov/

This article is information, not medical advice.