MOTS-c, a mitochondrially encoded open reading frame-derived peptide recently discovered by Lee et al. 2015 (this issue of Cell Metabolism) promotes biosynthesis of an endogenous AMP analog, AICAR. As AICAR activates AMPK, the discovery of MOTS-c offers an unexpected therapeutic option to be exploited toward the prevention of type 2 diabetes and delaying of the aging processes.