MOTS-c

MOTS-c is a 16-amino acid peptide encoded within the 12S rRNA gene of the mitochondrial genome — discovered in 2015, making it one of the most recently identified endogenous peptides. It is released from mitochondria in response to metabolic stress and acts as a systemic signalling molecule that reaches the nucleus of cells. MOTS-c activates the AMPK pathway (the same pathway targeted by metformin and berberine) while simultaneously inhibiting the folate cycle and methionine metabolism, redirecting cellular metabolism toward greater energy efficiency. In muscle tissue, it promotes glucose uptake independently of insulin — a mechanism directly relevant to age-related insulin resistance. In the brain, it supports mitochondrial biogenesis and reduces neuroinflammation. MOTS-c levels decline significantly with age and are lower in individuals with type 2 diabetes, obesity, and age-related cognitive decline.

Discovered by Changhan Lee at USC in 2015. Initial research demonstrated MOTS-c treatment reversed age-related insulin resistance and obesity in aged mice — results published in Cell Metabolism attracted significant attention. Subsequent work confirmed exercise increases circulating MOTS-c levels, suggesting it partly mediates the metabolic benefits of physical activity. A 2020 study showed MOTS-c improved physical performance in aged mice to levels comparable to young controls. Human studies are limited to observational data confirming the age-related decline in MOTS-c levels and their correlation with metabolic disease markers. MOTS-c and its mitochondrial sibling Humanin are increasingly studied together as the 'mitochondria-derived peptide' (MDP) class — a new category of endogenous longevity signals.

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