COMPOUND

Compounds / Anti-aging

MOTS-c

Mitochondrial Open Reading Frame of the 12S rRNA-c

Anti-aging SubQ Not FDA approved

16-amino-acid mitochondrial-derived peptide encoded within the 12S rRNA gene, discovered 2015 by the Lee/Cohen lab at USC. Endogenous MOTS-c rises ~12x in skeletal muscle after exercise. Exogenous administration is positioned as an exercise mimetic. Improves insulin sensitivity, glucose uptake, fatty acid oxidation, and mitochondrial respiratory capacity in animal models. CB4211 analog reached phase 1a/1b in NAFLD via CohBar (now defunct). That program supplies the only published human exposure data for the mechanism.

At a glance

Half-life
~1.5 h Endogenous MOTS-c returns to baseline within ~4 hours post-exercise, suggesting plasma t½ of 1-2h. Exogenous PK in humans not formally established (CB4211 analog PK proprietary). Tmax ~30 min.
Routes
SubQ
Vial sizes
10 mg · 25 mg
Evidence base
3 studies 3 preclinical

Mechanism

Translocates from mitochondria to the nucleus under metabolic stress, inhibits the folate-methionine cycle to deplete AICAR substrate, and activates AMPK. AMPK activation drives GLUT4-mediated glucose uptake, fatty acid oxidation, and PGC-1α-mediated mitochondrial biogenesis. Also acts as a stress-responsive transcription factor for nuclear DNA-encoded mitochondrial genes. MOTS-c rises ~12x in muscle post-exercise; exogenous administration restored physical capacity in aged mice. Confirmed insulin-sensitizing effect and AMPK-consistent plasma metabolite shifts.

Dosing

No standardized human dosing has been established. Every catalogued study for MOTS-c is preclinical or a literature review. Amounts used in animal models do not translate directly to humans.

Published evidence

  1. Animal in vivo 2021

    MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis

    Reynolds JC, Lai RW, Woodhead JST, et al. Nature Communications

    MOTS-c rises ~12x in muscle post-exercise; exogenous administration in aged mice restored physical capacity and grip strength to young-mouse levels.

    PMID 33623024

  2. Animal in vivo 2019

    The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity

    Kim SJ, Mehta HH, Wan J, et al. Physiological Reports

    Confirmed insulin-sensitizing effect; modulates plasma amino acids and lipid metabolites consistent with AMPK activation.

    PMID 31293078

  3. Animal in vivo 2015

    The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance

    Lee C, Zeng J, Drew BG, et al. Cell Metabolism

    Original discovery: MOTS-c administration in mice prevented age- and HFD-induced insulin resistance, improved glucose tolerance, enhanced muscle glucose uptake.

    PMID 25738459

Reported side effects

Injection site reaction
Common Mild · Local redness, mild pain. Resolves within hours.
Transient hypoglycemia
Occasional Mild · AMPK activation can lower blood glucose. Particularly relevant for diabetics on insulin or sulfonylureas.
Transient fatigue (early weeks)
Occasional Mild · Reported on r/Peptides during first 1-2 weeks; resolves with continued use.
Headache
Occasional Mild · Reported in CB4211 phase 1 NAFLD trial.

Interactions

  • Metformin Synergy

    Both activate AMPK. Additive activation may amplify hypoglycemia risk and GI effects.

  • Insulin Caution

    MOTS-c improves insulin sensitivity. Insulin-dependent diabetics may experience exaggerated glucose drop.

Reconstitution and storage

Lyophilized. Typical: 2mL BAC water per 10mg vial = 5 mg/mL. Gentle swirl, do not shake.

Lyophilized: -20°C long term, 4°C short term. Reconstituted: refrigerate 2-8°C, use within 30 days. Protect from light.

Open the reconstitution calculator for MOTS-c