MOTS-c

Overview

MOTS-c is an investigational mitochondrial-derived peptide studied preclinically for metabolic regulation. It is research-only and not FDA-approved; the CB4211 analog program (CohBar) was discontinued in 2023.

Mechanism of Action

MOTS-c activates AMPK primarily in skeletal muscle, partly via inhibition of the folate cycle and de novo purine biosynthesis (AICAR accumulation), increasing glucose uptake and fatty acid oxidation. Interaction with the folliculin–FNIP complex has been proposed. Serum MOTS-c declines with age, obesity, and type 2 diabetes, supporting a proposed endocrine role.

Research Summary

Evidence is largely preclinical. The modified MOTS-c analog CB4211 (CohBar) completed a Phase 1a/1b study in healthy volunteers and obese NAFLD subjects with mixed exploratory readouts; CohBar subsequently divested from the MOTS-c program and wound down in 2023, so no Phase 2 or Phase 3 data exist. Native MOTS-c has no completed clinical trials demonstrating efficacy in humans.

Dosing Information

Reported Side Effects

• Limited human safety data for native MOTS-c
• Injection-site reactions (anecdotal)
• Theoretical concerns from AMPK activation and altered mitochondrial signaling
• No serious adverse events reported in the Phase 1a/1b study of the analog CB4211, but that program was discontinued and native MOTS-c has not been systematically evaluated in humans

Labs to monitor before & during your MOTS-c protocol

These biomarkers are commonly tracked to assess response and safety. Run baseline labs before starting, mid-cycle labs halfway through, and post-cycle labs 1–2 weeks after the final dose.

Commonly Stacked With

Research References

• Lee C, et al. Cell Metabolism. 2015;21(3):443-454. (PMID 25738459)
• Kim KH, et al. Cell Metabolism. 2018;28(3):516-524. (PMID 29983246)
• Reynolds JC, et al. Nature Communications. 2021;12(1):470. (PMID 33473109)