MOTS-c

MOTS-c (Mitochondrial Open Reading Frame of the 12S rRNA-c) is a 16-amino acid peptide encoded within the mitochondrial 12S rRNA gene. Its discovery by Changhan David Lee's group at USC in 2015 demonstrated that the mitochondrial genome encodes functional signaling peptides — peptides that act systemically beyond the organelle.

MOTS-c activates AMPK (AMP-activated protein kinase), the master metabolic regulator, driving downstream effects on glucose uptake, fatty acid oxidation, and mitochondrial biogenesis. Mouse studies showed improved insulin sensitivity, reduced obesity-related metabolic dysfunction, and enhanced exercise performance — effects resembling the molecular response to physical activity, earning it designation as a potential exercise mimetic.

Longevity research interest stems from observed age-related decline in circulating MOTS-c levels and from animal studies showing healthspan extension in treated cohorts. Research groups examine MOTS-c in models of insulin resistance, age-related metabolic decline, and exercise physiology. Its mitochondrial origin and AMPK-activating mechanism position it at the intersection of metabolic and longevity research.