MOTS-c

mitochondrial open reading frame of the 12S rRNA type-c; CB4211 (a modified analogue developed by CohBar)

Immune & bioregulators

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Summary

Class: Naturally occurring 16-amino-acid peptide encoded in the mitochondrial 12S rRNA gene (MT-RNR1); a mitochondrial-derived peptide
Mechanism: Acts as a metabolic stress signal: activates AMPK in muscle, alters the folate–methionine cycle, and under stress moves into the nucleus to switch on stress-response genes
Routes studied: Intraperitoneal injection in mice; subcutaneous (CB4211 in humans; community)
Dose range reported: Mouse studies: 0.5–15 mg/kg/day intraperitoneally. CB4211 Phase 1: doses not fully disclosed. Community: 5–10 mg subcutaneous 2–3 times weekly, or ~10 mg once weekly, in cycles. No validated human dose
Half-life: Not well characterised. Circulating MOTS-c appears to be cleared within hours; the exercise-induced rise in human plasma returns to baseline within a few hours
Storage: Lyophilised: refrigerate, protect from light. Reconstituted: refrigerate; community practice is use within ~4 weeks
Regulatory status: Not approved anywhere. FDA placed MOTS-c in Category 2 of its compounding bulk-substances list in 2023

Doses are as reported in studies or by the community — never recommendations.

1What it is

MOTS-c is a short peptide that the body makes from a gene hidden inside mitochondrial DNA, in a region long assumed to code only for a piece of the ribosome. It was described in 2015 by Changhan Lee, Pinchas Cohen and colleagues at the University of Southern California (Lee 2015, Cell Metab). It circulates in blood, is produced by skeletal muscle, and rises sharply during exercise in humans — which is why it is often called an "exercise mimetic" online. That label overstates what has been shown.

A naturally occurring variant of the MOTS-c gene (m.1382A>C, which changes one amino acid) is common in East Asian populations and has been linked to exceptional longevity in Japanese cohorts and, separately, to diabetes risk in men. A pharmaceutical analogue, CB4211, completed an early human trial in 2021; the company has since stopped development.

2How it's thought to work

AMPK activation. MOTS-c raises AMPK activity in skeletal muscle, pushing cells toward burning glucose and fat and away from storage (Lee 2015).

One-carbon metabolism. it inhibits part of the folate cycle, which lowers purine synthesis and builds up AICAR, an AMPK activator.

Nuclear signalling. under metabolic stress (glucose deprivation, oxidative stress), MOTS-c moves from mitochondria into the nucleus and binds stress-response transcription factors such as NRF2, changing gene expression (Kim 2018, Cell Metab).

Muscle adaptation. in mice, it increases expression of genes involved in fat oxidation and improves the muscle's response to exercise.

Proposed: encoded in mitochondrial DNA, it activates AMPK in muscle and increases glucose uptake; under stress it moves into the nucleus.Schematic — not to scale

Mechanistic work is in cells and mice. Whether injected MOTS-c reaches and acts in human muscle at the levels used in mice is unknown.

3What the research shows

Obesity and insulin resistance in mice

Daily MOTS-c prevented high-fat-diet-induced obesity and insulin resistance, and reversed age-dependent insulin resistance in older mice (Lee 2015, Cell Metab). Prevented metabolic dysfunction after ovariectomy in female mice (Lu 2019, J Mol Med). [1][6]

Graded C (mouse) / B (human observational)

Exercise capacity and physical decline

In humans, plasma MOTS-c rose about 12-fold after acute exercise and skeletal-muscle levels increased too. In mice, treatment with MOTS-c doubled running capacity in young animals and improved physical performance in old mice when started late in life (Reynolds 2021, Nat Commun). The human part of that study measured endogenous levels only — nobody was given MOTS-c. [3]

Graded B (observational)

Longevity genetics

The m.1382A>C variant (K14Q MOTS-c) was over-represented in Japanese centenarians (Fuku 2015, Aging Cell) and associated with higher diabetes risk in sedentary men but not in active men (Zempo 2021, Aging Cell). Genetic association, not intervention. [4][5]

Human trial of an analogue

CohBar's CB4211 completed a Phase 1a/1b study in healthy volunteers and people with obesity and fatty liver; the company reported reductions in glucose and liver-enzyme markers and a trend in body weight in a press release (2021). Results were not published in full, and development was discontinued. Treat as "studied, outcome unclear".

Graded C/D

Bone, heart, kidney, inflammation

Rodent and cell studies report protective effects in osteoporosis models, cardiac ischaemia, kidney injury and inflammatory models. Preclinical only.

4Reported side effects and interactions

Literature-reported

CB4211 was reported as well tolerated in Phase 1 with injection-site reactions as the main finding (press release level). No published human safety data for native MOTS-c.

Community-reported

injection-site redness and itching, transient fatigue or a "flat" feeling after dosing, occasional lightheadedness, mild nausea. Some report improved exercise tolerance; this is anecdotal.

Theoretical. AMPK activation can lower blood glucose — anyone on glucose-lowering medicines would be the group most likely to notice. Long-term effects of pushing a stress-response pathway are unknown.

Interactions. none established. Additive glucose-lowering with metformin (also an AMPK activator) is plausible but untested.

Markers researchers commonly monitor

Marker	Why it's watched
Fasting glucose, fasting insulin, HbA1c	the core reported effect in mice is improved insulin sensitivity; also the most likely place for an unwanted drop.
Lipid panel and liver enzymes (ALT, AST)	CB4211's reported human signals were in glucose and liver markers.
Body composition (DEXA or waist measurement)	relevant if the community rationale is fat loss.
Creatine kinase	if used around heavy training, to separate training effects from anything else.
General baseline: CBC, CMP. No MOTS-c-specific clinical assay is in routine use

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Commonly supplied in 5 mg and 10 mg vials. with and swirl; do not shake. The peptide is reported to be sensitive to repeated freeze–thaw.

Open in calculator, pre-loaded →

6Commonly studied alongside

Humanin and SS-31 (grouped as mitochondrial peptides in community discussion; no combined trial), NAD⁺ precursors, exercise protocols (the only context in which human MOTS-c has actually been studied).

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not FDA-approved. Placed in Category 2 of FDA's bulk drug substances list for compounding (2023), citing safety concerns; this restricts compounding pharmacies from using it
European Union	Not authorised
United Kingdom	Not licensed
Australia	Not approved
South Africa	Not registered
Sport	Prohibited by WADA under S0 (non-approved substances); treat as prohibited at all times †

8Open questions

Does MOTS-c in humans reproduce any of the mouse metabolic effects? No published trial.
What is the human pharmacokinetic profile, and does it even reach muscle?
Is the longevity association of the K14Q variant due to MOTS-c function or to linked mitochondrial variants?
Could chronic dosing blunt the body's own exercise-induced MOTS-c response?

9References

1Lee C et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. PubMed · DOI
2Kim KH et al. (2018). The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. PubMed · DOI
3Reynolds JC et al. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. PubMed · DOI
4Fuku N et al. (2015). The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell. PubMed · DOI
5Zempo H et al. (2021). A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging Cell. PubMed · DOI
6Lu H et al. (2019). MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med. PubMed · DOI
7FDA (2023). Certain bulk drug substances for use in compounding that may present significant safety risks — MOTS-c. PubMed
8CohBar Inc. (2021). CB4211 Phase 1a/1b topline results (company announcement; unpublished). PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

25 Oct 2026Profile published — awaiting medical review

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