Cellular Senescence Research
Phase 1 Trials
MOTS-c
Also known as: Mitochondrial Open Reading Frame of the 12S rRNA Type-c, MOTS-c mitochondrial peptide, mitochondrial ORF of the 12S rRNA type-c
Mitochondrial derived peptide encoded within the 12S rRNA. Studied in AMPK and metabolic-signalling research.
Research overview
MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a 16-amino-acid peptide encoded by a short stretch of mitochondrial DNA inside the 12S ribosomal RNA gene. It was described in 2015 by Lee, Cohen and colleagues at the University of Southern California (Lee et al., Cell Metab 2015). In that study, mice given MOTS-c did not develop the insulin resistance seen with age or a high-fat diet, and gained less weight on that diet; skeletal muscle appeared to be its main target. Later mouse work reported better physical performance in young, middle-aged and old mice. In people, studies so far are observational: MOTS-c levels in muscle and blood rose after exercise (Reynolds et al., Nat Commun 2021).
A modified version, CB4211, was tested in a phase 1a/1b placebo-controlled study in healthy volunteers and people with fatty liver disease (88 participants, completed 2021); no results are posted on the trial registry. A phase 2a placebo-controlled trial of MOTS-c itself was registered in 2026 and is recruiting. Most published work comes from the discovering group, and long-term human safety is unknown. Supplied for laboratory research use only.
Mechanism of action
In cell and mouse studies, MOTS-c inhibits the folate cycle and the linked pathway that makes purines (building blocks of DNA and RNA), which leads to activation of AMPK, an enzyme that senses cellular energy (Lee et al., 2015). Under metabolic stress such as glucose shortage, it moves into the cell nucleus and changes the activity of many genes, including antioxidant-response genes (Kim et al., Cell Metab 2018). Skeletal muscle appears to be its main target tissue in mice.