In a recent publication, Wu et al. (2022) asked a simple premise: how does aging impact O-GlcNAcylation in the liver? What they discovered, however, requires us to ask a more fundamental question: how does aging alter nutrient-sensing pathways and the messages they communicate? In order to answer this question, we must remember that nutrient sensing is hinged on post-translational modifications (PTMs) and the availability of nutrients necessary for producing PTM metabolites. Adenosine monophosphate (AMP)-regulated protein kinase, which is sensitive to the ratio of AMP to adenosine triphosphate, and mammalian target of rapamycin, an anabolic kinase regulated by mitogen signaling and amino acid availability, are two of the most studied representations of this phenomenon for phosphorylation modifications (Cork et al., 2018).