MOTS-C

MOTS-c is naturally produced and released from skeletal muscle during exercise — levels increase 11.9-fold in muscle after a bout of exercise. When administered exogenously, it activates the same AMPK signaling pathways triggered by physical activity, leading to improved glucose uptake, enhanced fat oxidation, and better insulin sensitivity without actual exercise. In aged mice, MOTS-c treatment doubled running time and increased running distance 2.16-fold.

MOTS-c itself has not been tested in formal human clinical trials. However, CohBar developed a MOTS-c peptide analog called CB4211, which completed Phase 1a trials in healthy adults and demonstrated safety and tolerability after 7 days of dosing. CB4211 is currently in Phase 1b trials for the treatment of obesity and non-alcoholic fatty liver disease (NAFLD). The trial expects to measure effects on liver fat, body weight, and metabolic biomarkers.

Endogenous MOTS-c levels decline with age — by ages 70-81, levels in skeletal muscle are approximately 21% lower than in young adults. Preclinical studies showed that MOTS-c supplementation in elderly mice (starting at 23.5 months) improved physical performance, restored youthful metabolic function, and showed a trend toward increased lifespan (6.4% median, 7% maximum lifespan extension). MOTS-c appears to rejuvenate aging phenotypes across multiple tissues.

Preclinical data suggests a favorable safety profile with no serious adverse events. The analog CB4211 was safe and well-tolerated in human Phase 1a trials. Potential side effects based on limited data include temporary fatigue, mild nausea, and headaches. MOTS-c primarily activates AMPK, similar to metformin, and may interact with other AMPK-activating drugs. Long-term safety in humans has not been established.

MOTS-c is extremely temperature-sensitive and unstable. At room temperature, peptide levels can decrease by 85-90% within 2-3 hours. Even at 4°C, levels decrease by one-quarter after 24 hours. For this reason, MOTS-c should be stored frozen as a lyophilized powder and reconstituted immediately before use. This instability also makes measuring endogenous MOTS-c levels challenging in clinical settings.

MOTS-c is not approved for human use by the FDA or any regulatory agency — it remains a research compound only. It is prohibited by the World Anti-Doping Agency (WADA) and is listed as a performance-enhancing substance. Athletes have been known to use MOTS-c illegally, and detection methods using LC/MS have been developed to identify MOTS-c and its metabolites in doping control.