AMP-activated protein kinase (AMPK) is a highly conserved enzyme with many important effects, including proposed anti-aging actions. AMPK plays a key role in the control of glucose uptake by skeletal muscle, the tissue that accounts for up to 85% of insulin-induced blood glucose clearance. Insulin resistance (subnormal glucose clearance with a normal insulin level) for muscle glucose uptake is an essential defect for type 2 diabetes. Insulin resistance also confers greater risk for other age-related disorders (hypertension, coronary heart disease, stroke, Alzheimer’s disease, some cancers). Caloric restriction (CR; reducing calorie intake 20-40% below ad libitum, AL, intake) enhances insulin-stimulated glucose uptake in muscle of old rats. We recently discovered that CR by older rats leads to greater AMPK phosphorylation on the key regulatory T172 site (pAMPKThr172) concomitant with greater phosphorylation of multiple AMPK substrates in muscle. Remarkably, this outcome was not attributable to CR-induced changes in ATP or AMP, the major allosteric regulators of AMPK. Because conventional mechanisms cannot explain our striking results, we will probe the possible role of non-canonical mechanisms in this important outcome.