D tier · weak
MOTS-c has a coherent preclinical mechanism and one small phase 1a/1b safety trial of an analogue, but no randomised efficacy trial of MOTS-c itself in humans, a failed liver-fat endpoint for its lead analogue, a discontinued development programme and an FDA compounding restriction.
mots-c
MOTS-c is a 16-amino-acid mitochondrial-derived peptide that activates AMPK and shows metabolic and exercise-mimetic effects in rodent models. Human evidence is essentially absent: the only clinical data come from a phase 1a/1b trial of the analogue CB4211 in 88 subjects that met safety endpoints but showed liver fat reduction no better than placebo, and the developing company subsequently dissolved.
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available as a research reagent
≥ 99% HPLC · lyophilised powder · batch certificate published. Grade D above is our own and is not adjusted because we stock it.
the explanation
MOTS-c is a tiny peptide encoded inside mitochondria that in mice improves insulin sensitivity, boosts running endurance and slightly extends lifespan. In the one human study of a modified version, it was safe but did not reduce liver fat any better than a placebo, and the company developing it shut down.
regulatory status
Not approved — research use only
No approval in any jurisdiction. Placed in FDA section 503A category 2 in September 2023, then removed from that list on 22 April 2026 when the nomination was withdrawn. Removal from category 2 is not an approval: the substance reverts to an unapproved new drug and remains unlawful to compound in the United States. Prohibited in sport by WADA, and clinical development of the lead analogue CB4211 was discontinued when CohBar dissolved. At the Pharmacy Compounding Advisory Committee meeting of 23 July 2026 the panel voted 7 to 5 with two abstentions to recommend adding MOTS-c to the section 503A bulks list, against FDA staff advice. A recommendation is non-binding, confers no approval and is not a finding of efficacy; implementation would require notice-and-comment rulemaking. FDA has not published meeting minutes and these tallies are trade-press reporting from the room.
how it works · proposed mechanism
MOTS-c is a signal sent from the mitochondrion to the rest of the cell during metabolic stress.
Activates the AMPK energy sensor
MOTS-c activates AMP-activated protein kinase, the cell's central low-energy sensor, which shifts metabolism toward glucose uptake and fat oxidation. This is the same pathway metformin engages, though by a different upstream route.
Blocks the folate cycle
MOTS-c inhibits the folate-dependent purine biosynthesis pathway, causing accumulation of AICAR, an endogenous AMPK activator. This indirect route explains AMPK activation without direct kinase binding.
Moves into the nucleus
Under metabolic stress MOTS-c translocates from mitochondria to the nucleus, where it associates with stress-responsive transcription factors and antioxidant response elements. This makes it one of the clearest examples of mitochondrial-to-nuclear retrograde signalling.
Exercise-induced in muscle
MOTS-c expression rises in skeletal muscle and plasma following exercise in both rodents and humans, and treated aged mice showed roughly two-fold increased treadmill endurance. Whether exogenous administration reproduces this in humans is untested.
what’s reported
evidence shape
5 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
The single human programme tested an analogue, not MOTS-c, and its headline efficacy endpoint failed: MRI-PDFF liver fat fell 5.03% with CB4211 versus 4.88% with placebo, an essentially null result, with only ALT and AST differing. Persistent injection-site reactions, poor bioavailability and a short circulating half-life have stalled development entirely, and the FDA has explicitly barred compounding on immunogenicity grounds.
key published findings
- Lee et al. (Cell Metabolism, 2015) first characterised MOTS-c as a 16-amino-acid mitochondrial-derived peptide that activates AMPK via folate-cycle inhibition and AICAR accumulation, reducing obesity and insulin resistance in diet-induced obese mice.
- Reynolds et al. (Nature Communications, 2021) reported MOTS-c is exercise-induced, that treatment roughly doubled treadmill endurance in aged mice, and that late-life treatment beginning at 23.5 months increased median lifespan by approximately 6.4%.
- The CB4211 phase 1a/1b trial (NCT03998514; 65 healthy adults plus 20 obese NAFLD subjects, 4 weeks at 25 mg daily) met its primary safety endpoint with no serious adverse events but frequent transient injection-site reactions.
- In the CB4211 phase 1b stage, MRI-PDFF liver fat reduction was −5.03% with drug versus −4.88% with placebo, an effectively null difference; ALT fell 21% versus 4% and AST 28% versus 11%.
- In September 2023 the FDA placed MOTS-c in Section 503A Category 2, barring compounding for human use on grounds of immunogenicity risk and absent safety data; WADA prohibits it in sport.
limitations of the evidence
- No randomised controlled trial of MOTS-c itself has ever been completed in humans; all clinical data derive from the structurally modified analogue CB4211.
- The CB4211 phase 1b enrolled only 20 subjects for four weeks, far too small and short to detect or exclude meaningful metabolic effects.
- Rodent longevity and endurance findings come from single laboratories and have not been independently replicated at scale, and MOTS-c does not meaningfully cross the blood-brain barrier after peripheral administration.
- Eight ClinicalTrials.gov records naming research peptides — including BPC-157, TB-500, MOTS-c, GHK-Cu and melanotan II — share one sponsor, Hudson Biotech, and one site. A July 2026 investigation established that all eight are fabricated: at least two declare themselves fictional or mock in their own text, and two reproduce an Eli Lilly protocol design and compound code that Eli Lilly states it never authorised. The records were still listed as recruiting after the investigation was published. A registry entry is a form submission, not peer review, and this index does not treat one as evidence.
identity
| full name | MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA type-c) |
| category | Metabolic |
| modality | peptide |
| formula | C101H152N28O22S2 |
| molar mass | 2174.6 g/mol |
| cas | 1627580-64-6 |
| half-life | Short; circulating estimates on the order of 1–2 hours |
| sequence | MRWQEMGYIFYPRKLR |
laboratory handling
| storage | Lyophilised material is typically stored at −20 °C in desiccated, light-protected vials, with vendor stability data commonly citing up to 3 years; stock solutions are generally held at −80 °C for up to about a year or −20 °C for roughly a month. |
| solubility | Readily soluble in water (approximately 40 mg/mL) and in DMSO (approximately 100 mg/mL); insoluble in ethanol. |
| co-studied with | Because MOTS-c converges on AMPK, overlapping pharmacology with other AMPK-activating agents such as metformin is expected but has not been characterised in humans. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
8 citedAlzheimer's Drug Discovery Foundation (Cognitive Vitality) · 2024 · review
International Journal of Molecular Sciences (eScholarship) · 2022 · review
Cell Metabolism · 2015 · preclinical
Nature Communications · 2021 · preclinical
Dr Noc (Morgan McSweeney PhD) · 2026 · investigation
U.S. Food and Drug Administration · 2026 · regulatory
Regulatory Affairs Professionals Society · 2026 · trade press
CohBar / GlobeNewswire · 2021 · press release
Sources marked tertiary or press release are the weakest citations on this page.
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