MOTS-c: the monograph

MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. It is a 16-amino-acid peptide (sequence H-Met-Arg-Trp-Gln-Glu-Met-Gly-Tyr-Ile-Phe-Tyr-Pro-Arg-Lys-Leu-Arg-OH, molecular weight 2174.6 g/mol) encoded not in the cell nucleus but inside the mitochondrial genome, within the 12S ribosomal RNA gene MT-RNR1 ^1,41. It belongs to a family of eight known mitochondrial-derived peptides; MOTS-c is the one encoded by the 12S gene, while humanin and the six small humanin-like peptides come from the 16S gene ³³.

The biology is genuinely interesting and the discovery is real. Researchers have measured MOTS-c circulating in humans and rodents and expressed in skeletal muscle, heart and brain, and the peptide appears to be conserved across species ³⁵. The research literature itself, not only marketing copy, calls it an exercise mimetic ^31,29.

This site exists because of a gap between two things that are both true. The discovery science is strong and continuing. The record of giving MOTS-c to human beings and measuring what happens is, as of this page's verification date, empty of published results. Every row in the evidence table below names the species it came from and, just as importantly, which molecule was actually studied: MOTS-c given as a drug, MOTS-c measured as a natural hormone, a MOTS-c genotype, or a chemically different analog.

The fact chips beside this section carry their evidence grade and link to the source that establishes each one. Three of them record documented absences rather than findings, because in this compound's file the absences are the most decision-relevant facts available.

The proposed mechanism is specific and testable. In the discovery work, MOTS-c inhibited the folate cycle and the de novo purine synthesis tethered to it, causing accumulation of AICAR, an established activator of AMP-activated protein kinase, with skeletal muscle as the apparent target organ ¹. A 2018 paper showed MOTS-c translocating into the nucleus under metabolic stress and regulating nuclear genes in an AMPK-dependent way, interacting with antioxidant-response transcription factors including NRF2 ². A 2024 study identified casein kinase 2 as a direct binding target, with muscle effects blunted when CK2 was suppressed ⁴.

That is real mechanistic work, and it is why the compound is taken seriously in the laboratory. It is also why FDA's assessment of the same literature is worth quoting rather than paraphrasing: nonclinical pharmacology of MOTS-c "have been limited to in-vivo and in-vitro rodent models and have not evaluated the dose-response relationships for the effects of MOTS-c in vivo", and "the molecular target(s) through which MOTS-c acts remains unknown. As such, it is difficult to predict which organs might be targeted and affected by MOTS-c" ³⁵.

A mechanism explains how something could work. It is not evidence that it does work in people at any particular dose.

Almost every argument made for buying MOTS-c draws on one of four literatures. They are not interchangeable, and the study table below labels every row with which one it belongs to.

One: MOTS-c administered as a drug. Every published study in this category is in mice, rats or cells. This is where the impressive results live, including the lifespan and treadmill data.

Two: endogenous MOTS-c measured in human blood or muscle. These are real human studies, but nobody was given anything; the peptide was measured as a naturally occurring hormone, and the findings point in different directions depending on the population.

Three: MOTS-c genotype. The K14Q association studies are human genetics in large Japanese and Korean cohorts. They can show that carrying a less active version of the peptide travels with a health outcome. They cannot show that injecting the peptide changes that outcome.

Four: CB4211, a chemically different analog developed from licensed MOTS-c intellectual property, which did complete a Phase 1 program in humans ^32,40.

Set against those four literatures is the finding FDA reported after its own search, in its own words: "We performed our own search of published medical literature and did not identify clinical studies evaluating administration of MOTS-c-related BDSs in human subjects" ³⁵. Our independent check agrees: 248 records mention MOTS-c in their title or abstract on PubMed, and none of them reports giving it to human participants ³². Reviewers in the field put the state of play plainly: whether these peptides can be harnessed into therapies "remains to be fully determined" ³³.

This is the strongest part of the file, and it deserves to be stated at full strength before it is qualified. In the 2015 discovery paper, mice on a 60 percent fat diet given 0.5 mg/kg/day of MOTS-c for eight weeks weighed about 20 percent less than vehicle-treated mice, with higher energy expenditure and less liver fat; at 5 mg/kg/day, clamped mice needed about 30 percent more glucose to stay euglycemic, and seven days of treatment restored the insulin sensitivity of 12-month-old soleus muscle to that of 3-month-old muscle ^35,1.

The 2021 Nature Communications study is the one behind most exercise-mimetic marketing. A single 5 mg/kg dose improved treadmill performance in young, middle-aged and old mice, and intermittent dosing started at 23.5 months of age, very late in a mouse life, raised median lifespan from 912 to 970 days and maximal lifespan from 1047 to 1120 days ^35,3.

Elsewhere in rodents: 5 mg/kg daily for 12 weeks reduced ovariectomy-induced bone loss on micro-CT ⁵; local injection reduced particle-induced calvarial osteolysis ⁷; 5 mg/kg/day for four weeks attenuated vascular calcification and myocardial remodeling in rats ⁹; treatment improved cold tolerance and browning of white fat ⁸; 15 mg/kg/day held immobilization muscle loss to about 5 percent instead of about 15 percent ¹¹; and 15 mg/kg twice daily preserved quadriceps mass in cancer cachexia by 12 percent while failing to prevent overall weight or fat loss ¹².

Two honest qualifications belong beside all of it. The doses are large by peptide standards and were given intraperitoneally in most studies, a route nobody uses at home. And FDA's reviewers noted that this body of work has never established a dose-response relationship in vivo ³⁵, which is exactly the information a person would need to reason from a mouse dose to anything else.

No published study has given MOTS-c to a human being and reported the result. FDA searched for one and did not find it ³⁵; so did we ³². FDA also reports that outsourcing facilities filed no reports of compounding MOTS-c products between January 2017 and December 2025 ³⁵.

One registered trial would change this page if it reports. NCT07505745 is a Phase 2a randomized, double-blind, placebo-controlled study of subcutaneous MOTS-c once daily for 12 weeks in 120 planned adults with prediabetes and overweight or obesity, sponsored by Hudson Biotech and recruiting at Peking University Shenzhen Hospital since February 2026, with insulin sensitivity by Matsuda index and treatment-emergent adverse events as its primary endpoints ³⁹. It has posted no results, and its public record does not state the dose ³⁹. A registered trial is a plan, not a finding.

What does exist in humans is measurement of the peptide people already make. Those studies are real and they disagree in an interesting way. Plasma MOTS-c was no different between lean and obese adults in one small study but tracked insulin resistance in the lean group ²⁰; it was lower in obese boys ²¹; it was higher in adults with obesity at the Mayo Clinic and did not budge six months after bariatric surgery ²⁶; and a meta-analysis of 602 participants found it decreased in diabetes yet increased in obesity, which the authors describe as opposite results ²⁷. In healthy aging men, blood levels fell with age while muscle expression rose ²².

Read together, those studies suggest MOTS-c behaves like a stress-responsive signal rather than a simple fuel gauge that is low in illness and high in health. None of them tested whether adding more of it helps.

The longevity story attached to MOTS-c starts with genetics, not dosing. An East-Asian-specific mitochondrial variant, m.1382A>C, swaps the 14th amino acid from lysine to glutamine, producing a variant called K14Q that has less biological activity ^17,18.

The cohorts are large and the findings are specific. A meta-analysis of three Japanese cohorts totalling 27,527 people found men, but not women, with the C allele had a higher prevalence of type 2 diabetes, and in one cohort only among men in the lowest tertile of physical activity ¹⁷. In 211 Japanese adults the C allele tracked a higher proportion of fast-twitch fibers, and across 721 athletes and 873 controls it was most common in sprint and power athletes (6.5 percent), then controls (5.1 percent), then endurance athletes (2.9 percent) ¹⁸. In 683 older Korean adults, men with the C allele had more muscle mass and stronger grip ¹⁹.

Here is the limit of what that design can establish. Association genetics compares people who inherited different versions of a peptide across a lifetime. It can support the claim that MOTS-c activity matters for human metabolism. It cannot establish that injecting MOTS-c into an adult produces the outcome associated with the more active genotype, any more than a gene associated with height means an injection makes an adult taller. The same 2021 paper made the distinction concrete inside one study: male mice given MOTS-c lost weight and improved glucose tolerance, mice given the K14Q variant peptide did not, and female mice were unaffected by either ¹⁷.

The Japanese-longevity framing traces back to a two-page 2015 hypothesis article that proposed the polymorphism "may be among the putative biological mechanisms explaining the high longevity of Japanese people" and said in the same sentence that more research is needed ¹⁶. That is a hypothesis paper doing its job, and it is not a finding about supplementation.

Sales pages sometimes point to a completed Phase 1 program as evidence that MOTS-c has been through human trials. That program tested CB4211, which a peer-reviewed review describes as "the MOTS-c analog CB4211", developed after MOTS-c intellectual property was licensed by CohBar and used to build potent analogs ³². An analog is a different molecule designed to behave similarly. It is not the peptide in a research vial.

The trial itself is a real, well-designed study: NCT03998514, a three-part Phase 1a/1b randomized, double-blind, placebo-controlled evaluation of single and multiple ascending subcutaneous doses in healthy non-obese subjects and in subjects with nonalcoholic fatty liver disease, 88 participants, completed on 19 April 2021 ⁴⁰.

Two facts finish the story. The registry record has no results posted, and a PubMed search for CB4211 returns zero records, so that human dataset has never been published in the peer-reviewed literature ^40,32. And the registry record never mentions MOTS-c at all: its condition is nonalcoholic fatty liver disease and its interventions are labeled only as CB4211 dose levels and placebo ⁴⁰.

So the sentence "MOTS-c has been in human trials" fails twice over: the trial tested a different molecule, and it reported nothing. FDA classifies even the free base and the acetate salt of MOTS-c as distinct substances with potentially different safety and efficacy profiles ³⁵; an analog is further away still.

There is no pharmacokinetic profile for MOTS-c in any species. FDA states it "did not identify in-vivo pharmacokinetic or toxicokinetic studies of MOTS-c", and separately that no clinical study provided pharmacokinetic data ³⁵. No half-life, no bioavailability, no dose-exposure curve exists to cite, in humans or in animals.

The one relevant experiment is a test-tube study built for anti-doping purposes. MOTS-c at 5 micrograms per mL was incubated in human whole blood at 37 degrees C, and within 15 minutes mass spectrometry showed it cut into shorter fragments: MOTS-c(2-16), (3-16), (4-16) and (5-16) ^35,15. Degradation was described as rapid and not requiring long incubation.

FDA draws the honest conclusion from that observation rather than an alarming one: "It remains to be determined whether exogenous administration of MOTS-c to humans can generate pharmacologically active concentrations of the peptide over time" ³⁵. Anyone quoting a half-life for MOTS-c, in hours or in minutes, is quoting something that has not been measured.

MOTS-c is sold as a lyophilized powder in vials, typically labeled 5 mg or 10 mg, for reconstitution and subcutaneous injection. That matches what was nominated to FDA: "5 mg and 10 mg for subcutaneous (SC) injection" ³⁵.

The published animal work mostly used intraperitoneal injection, and one bone study used local injection into the treated area ⁷. No published study establishes what subcutaneous dosing does in any species, and FDA notes subcutaneous administration is generally associated with greater immunogenicity risk than intravenous ³⁵.

Oral, nasal and topical MOTS-c products appear online. There is no published human or animal study of any of those routes, and the peptide's rapid breakdown in blood makes any oral claim particularly unsupported ¹⁵.

There is no established human dose of MOTS-c. No human dose-finding study has been published, the one registered trial does not state its dose in the public record, and FDA reports that the animal literature never established a dose-response relationship in vivo ^39,35.

What does exist are the doses used in animals, which our study-dose explorer lists with species attached: 0.5 mg/kg/day and 5 mg/kg/day intraperitoneally in the discovery mouse work ¹, 5 mg/kg acutely and 15 mg/kg three times weekly in the lifespan study ³, 5 mg/kg/day for 12 weeks in the ovariectomy bone model ⁵, 5 mg/kg/day for four weeks in the rat vascular model ⁹, 15 mg/kg/day in the immobilization model ¹¹ and 15 mg/kg twice daily in cachexia ¹².

Those numbers are mouse and rat doses. Converting them into a human dose requires pharmacokinetic data that does not exist for this peptide in any species, which is why this site publishes no conversion and no suggested amount.

Is MOTS-c known to be dangerous? No. Is it known to be safe? Also no, and that is the accurate answer. FDA states plainly: "The nomination did not include, and FDA has not identified, any clinical studies or human exposure data for MOTS-c via any route of administration. Therefore, potential safety risks associated with the use of MOTS-c-related BDSs in humans are unknown" ³⁵.

What about side-effect reports? FDA searched its adverse event reporting system for MOTS-c through March 2025 and the searches "retrieved no reports" ³⁵. That is weaker reassurance than it sounds: FDA notes in the same document that compounders under section 503A generally do not report adverse events to the agency, so an empty database mostly reflects a reporting pathway that barely exists here ³⁵.

What about animal toxicity studies? None were found. FDA reports identifying no acute toxicity, repeat-dose toxicity, genotoxicity, developmental and reproductive toxicity, or carcinogenicity studies of MOTS-c free base or acetate ³⁵. The usual preclinical safety package for a drug entering humans does not exist for this peptide.

What is the specific risk FDA names? Immunogenicity. Compounded MOTS-c "may pose significant risk for immunogenicity for certain routes of administration and may have complexities with regard to peptide-related impurities and API characterization" ³⁴, and FDA cannot rule out immune responses driven by impurities and peptide aggregates because the quality-control data needed to do so were not found in public literature or in the certificates of analysis reviewed ³⁵.

Who has not been studied? Everyone. With zero human administration studies published, there is no data on pregnancy, breastfeeding, children, older adults, or people with kidney, liver, cardiac or oncologic disease.

Is it a doping risk? Yes, unambiguously. MOTS-c is named on the 2026 WADA Prohibited List under S4.4.1, and a validated mass-spectrometry method for detecting it in plasma has existed since 2019 ^42,15.

No interaction study of MOTS-c with any medication has been published in any species. No contraindication list exists because contraindications are derived from clinical experience that has not been collected.

One indirect signal is worth stating precisely. In a randomized trial where metformin was added to breast cancer treatment, circulating MOTS-c did not change significantly ³¹. That is a study of metformin's effect on natural MOTS-c levels, not a study of a drug interaction with injected MOTS-c, and it should not be quoted as one.

Anyone considering this compound while taking prescription medication is reasoning without data, and the right place to take that problem is a clinician who can see the whole medication list.

FDA's chemistry review of MOTS-c is the most useful document in existence for anyone evaluating a vial, because it lists exactly what a certificate of analysis usually leaves out. FDA found no impurity limits, no aggregate testing, no microbial bioburden and no bacterial endotoxin testing in the certificates it reviewed or in the public literature, and concluded both the free base and the acetate salt are "not well-characterized" ³⁵. Endotoxin testing is described as a critical quality attribute for an injectable product.

Naming is its own hazard. FDA notes that MOTS-c is a common name, not a United States Adopted Name, and that it has encountered "multiple salts, and derivatives, including different active moieties, sold commercially under the same common name", a situation in which someone may be dosed with a different substance than intended ³⁵. In the nomination FDA reviewed, the certificate of analysis named one substance in its title and a different one by CAS number.

The storage guidance circulating online traces to supplier pages, not stability studies: lyophilized peptide below -20 degrees C, desiccated and protected from light; reconstituted solution at about 4 degrees C for 2 to 7 days or below -18 degrees C for longer ³⁵. Those are handling conventions, and no validated shelf life for a finished MOTS-c product exists.

MOTS-c is sold online as a research chemical and appears in some clinic offerings, including combination infusions. FDA's own survey of the market records claims that it regulates mitochondrial energy, promotes metabolic homeostasis, improves glucose regulation, promotes weight loss and improves physical performance, and notes it is unclear whether compounded products are involved in all of those instances ³⁵.

There is no approved MOTS-c product to buy anywhere ³⁸, no pharmacopeial monograph in the United States, Europe or Japan, and no product authorized by the European Medicines Agency ³⁵. Outsourcing facilities reported no MOTS-c compounding to FDA across a nine-year window ³⁵.

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The questions below are the ones this compound actually generates. Each answer states its evidence grade in the first sentence.

Every citation below was fetched and verified during pack production. The machine-readable citation manifest carries the same list with source types, identifiers and verification dates.