MOTS-c in Humans: The K14Q Variant, Japanese Longevity and the CB4211 Trial

LynxLab · 24 October 2026 · 9 min read

What is known about MOTS-c in people: the m.1382A>C variant, Japanese longevity data, blood levels in diabetes, CohBar's CB4211 trial and the 2026 FDA review.

Photo: National Cancer Institute, Unsplash

The mouse data on MOTS-c are striking. The human data are thinner, odder and far more interesting to read carefully.

There is a single-letter change in mitochondrial DNA, carried by a slice of the Japanese population, that alters the peptide. There is one small clinical trial, of a modified version, run by a company that no longer exists in that form. And in July 2026 the US Food and Drug Administration convened a committee to ask whether mots-c should be compounded for patients at all.

A single base change that rewrites the peptide

MOTS-c is coded by a 51-base-pair open reading frame in the mitochondrial 12S rRNA gene, running from position 1,343 to 1,393 of the mitochondrial genome. Position 1,382 sits inside it. In most people that base is an adenine. In a subset of people of Northeast Asian ancestry it is a cytosine, a variant written m.1382A>C.

Noriyuki Fuku of Juntendo University and colleagues at Keio and in Madrid laid this out in a short paper in Aging Cell in August 2015, five months after the peptide was discovered. The A-to-C change swaps the fourteenth amino acid of MOTS-c from lysine to glutamine, abbreviated K14Q or Lys14Gln.

The authors argued the swap was unlikely to be harmless. The physicochemical distance between lysine and glutamine scores 53 on the Grantham scale, above the 50 that separates radical from conservative substitutions, and a protein-variant prediction tool scored it well below its cutoff for a neutral change.

The Japanese longevity connection

Why did a Japanese group care about one mitochondrial base? Because they had already found it in their centenarians. The m.1382A>C variant marks the mitochondrial haplogroup D4b2, and earlier work by the same researchers had associated D4b2 and related haplogroups with exceptional longevity in Japan.

Japan has the longest life expectancy in the world and the largest number of supercentenarians, people aged 110 or over. Fuku and colleagues suggested that a variant in the MOTS-c reading frame "may be among the putative biological mechanisms explaining the high longevity of Japanese people".

The paper was explicit that this was a hypothesis. Its conclusion called for "further mechanistic research" to determine what the variant does. For anyone reading mots-c peptide marketing that cites "Japanese longevity", this two-page commentary is the entire original basis for the claim, and its authors were careful about what it did and did not show.

What the K14Q variant actually does

The follow-up arrived in the journal Aging in January 2021, from Hirofumi Zempo, Su-Jeong Kim, Fuku, Pinchas Cohen and colleagues. Its title gives the game away: "A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c".

The team pooled three Japanese-ancestry cohorts, J-MICC, MEC and TMM, totalling 27,527 people. Men carrying the C allele had a higher prevalence of type 2 diabetes. Women did not. In J-MICC, which alone included 4,963 men and 6,889 women, the excess risk was confined to men in the lowest third of physical activity.

The laboratory work explained why. In high-fat-fed male mice, normal MOTS-c reduced body weight and improved glucose tolerance, while the K14Q version did not. In cell culture the variant peptide was a weaker insulin sensitiser. Female mice, like the women in the cohorts, were unaffected by either.

Carriers also had nearly 20-fold higher circulating MOTS-c than matched controls in a Tsukuba cohort. Infusion studies in mice suggested the K14Q peptide was cleared 2.6 times more slowly but produced 7.4 times faster, which the authors read as the body overproducing a partly inactive hormone to compensate. Researchers who buy mots-c for variant work should note that the standard synthetic sequence carries lysine at position 14, the common form.

So the one human genetic variant in MOTS-c is associated with more diabetes in sedentary men, not with longer life. The 2021 paper noted that the earlier longevity association for haplogroup D4b2 came from a study of 96 centenarians, and its abstract reports no link to lifespan.

What blood levels show in people

If MOTS-c is a metabolic hormone, its levels in blood should track metabolic health. Several groups have measured it, with results that depend uncomfortably on the assay.

The largest study came from Qatar. Ramanjaneya and colleagues measured serum MOTS-c in 225 adults, published in Frontiers in Endocrinology in 2019: 68 healthy controls, 33 with prediabetes, 31 with well-controlled type 2 diabetes and 93 with poor control. MOTS-c was significantly lower in people with type 2 diabetes, lowest in those with the worst glycaemic control, and fell as HbA1c and glucose rose.

The same paper flagged a problem. Two earlier studies had disagreed about whether obesity changed MOTS-c, and the one that found a difference reported levels nearly 1,000-fold higher than the one that did not, because they used different kits. The Qatar authors concluded the kits were probably detecting different molecules. Until a validated assay exists, every human blood-level study of mots c carries that caveat.

The one human finding that has held up is the exercise response. In the 2021 Nature Communications study from the Lee laboratory, muscle MOTS-c rose nearly 12-fold after a single bout of cycling in sedentary young men, as described in our companion piece on the discovery and mouse studies of MOTS-c.

The CB4211 trial: the only clinical test so far

No native MOTS-c has ever been given to humans in a registered trial. The closest thing is CB4211, which its developer CohBar described as "a novel and improved analog of MOTS-c". CohBar was co-founded by Pinchas Cohen, the co-discoverer of the peptide.

The programme had a rough start. In November 2018 CohBar told investors in an SEC filing that the phase 1 study had been temporarily suspended to address mild but unexpectedly persistent injection site reactions, described by the chief scientific officer as "persistent painless bumps" where some of the dose remained under the skin. The formulation was changed and the study resumed.

Topline results came on 10 August 2021, filed with the SEC as a press release. The phase 1a stage tested single and multiple ascending doses over one week in 65 healthy adults. The phase 1b stage gave 25 mg of CB4211 or placebo once daily by subcutaneous injection for four weeks to 20 obese adults with non-alcoholic fatty liver disease and at least 10% liver fat, all of them confined to the clinical unit for the four weeks.

The primary endpoint was safety, and it was met: no serious adverse events, with the only common side effect being transient injection site reactions. On the exploratory endpoints, 11 people on CB4211 showed a 21% fall in the liver enzyme ALT against a 4% rise on placebo, a 28% fall in AST against 11%, and a 6% fall in glucose against no change, all statistically significant. There was a trend towards lower body weight.

Liver fat, the measure that matters most in fatty liver disease, told a different story. It fell by 5.03 percentage points on CB4211 and by 4.88 on placebo, and the share of patients achieving a 30% relative reduction was 36% against 33%. Four weeks in a supervised clinical unit had done as much as the drug.

What happened to CohBar

CB4211 never reached phase 2. On 23 May 2023 CohBar announced in an SEC-filed press release an all-stock merger with Morphogenesis, a private cancer immunotherapy company, to form TuHURA Biosciences. The combined company's stated focus was Morphogenesis's cancer vaccine platform. The announcement does not describe any plan to continue CB4211.

That leaves a single 20-patient, four-week, phase 1b study of a modified analogue as the entire human interventional record for the MOTS-c family. Anyone searching for mots-c uk suppliers and reading claims about human weight loss or liver benefit should hold them against that record.

The 2026 FDA compounding review

The newest development is regulatory. US compounding pharmacies had nominated MOTS-c for the FDA's 503A bulk drug substances list, which would allow it to be compounded for individual patients. The FDA brought the nomination to its Pharmacy Compounding Advisory Committee on 23 and 24 July 2026, alongside three other research peptides.

The agency's briefing document, dated 11 May 2026, records that MOTS-c had been nominated for insulin resistance, obesity, osteoporosis, vascular calcification, muscle and fat metabolism, and longevity, as 5 mg and 10 mg subcutaneous injections. The FDA evaluated only obesity and osteoporosis, and stated that it "did not identify clinical studies evaluating these uses of MOTS-c". It also noted that no United States Pharmacopeia monograph exists for the substance.

Advisory committees give non-binding advice and the FDA had not issued a final determination when the briefing was published. The US Anti-Doping Agency's position is that during the evaluation there is no legal basis to include MOTS-c in any compounded medication, and the peptide remains on the WADA Prohibited List as an AMPK activator.

In the UK, MOTS-c has no MHRA marketing authorisation and is supplied for laboratory research only. LynxLab stocks mots-c 10mg for research use at £24.99 a vial, tested to 99% purity with the lab report on the product page. Batch lab reports are published for every product. The honest summary for 2026 is that MOTS-c in humans is a genetics story, an assay problem and one small trial of a different molecule.

Frequently asked questions

What is the MOTS-c K14Q variant?

A mitochondrial DNA change, m.1382A>C, found mainly in people of Northeast Asian ancestry, that swaps lysine for glutamine at position 14 of the MOTS-c peptide. A 2021 study of 27,527 Japanese-ancestry people linked it to higher type 2 diabetes prevalence in sedentary men, and showed the variant peptide was a weaker insulin sensitiser in mice.

Is MOTS-c linked to Japanese longevity?

A 2015 Aging Cell commentary proposed that the m.1382A>C variant, found in the long-lived haplogroup D4b2, might contribute to Japanese longevity. The 2021 follow-up found the variant was associated with more diabetes in inactive men and reported no link to lifespan. The longevity connection remains a hypothesis.

Has MOTS-c been tested in a human clinical trial?

Not the native peptide. CohBar's analogue CB4211 completed a phase 1a/1b study in 2021: 65 healthy adults in phase 1a and 20 obese adults with fatty liver in phase 1b. It was safe over four weeks and lowered liver enzymes and glucose, but liver fat fell about equally on drug and placebo. No phase 2 followed.

Is MOTS-c FDA approved?

No. In July 2026 the FDA's Pharmacy Compounding Advisory Committee reviewed a nomination to allow MOTS-c compounding for obesity and osteoporosis. The FDA's briefing stated it had identified no clinical studies for those uses. MOTS-c is not approved or licensed as a medicine in the US, the UK or the EU.

Sources

Research use only

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