Deep-diving mammals routinely experience hypoxia and ischemia-reperfusion as part of their life history. Adaptations to diving include increased blood oxygen stores and high antioxidant capacity. In addition, marine mammals produce high levels of endogenous carbon monoxide (CO), which has been shown in laboratory systems to protect cells and tissues from damage caused by ischemia-reperfusion. Northern elephant seals, one of the deepest diving pinnipeds, produce and maintain CO at concentrations higher than those of human cigarette smokers, and thus provide a natural study system for examining the role of CO in hypoxia tolerant mammals. The primary source of endogenous CO production occurs from the breakdown of heme by heme oxygenase enzymes. Levels of endogenous CO and heme stores are also known to increase with age in elephant seals. We measured the expression of heme oxygenase genes (HMOX1 and HMOX2) and other genes associated with CO signaling (BVR, NRF2, GPX3, PGC1A, ESRRA) in skeletal muscle and blood of northern elephant seals of various age classes (weaned pup, juvenile, and adult). We found that the expression of HMOX1 and HMOX2 genes increased with age and was significantly correlated with the expression of genes associated with mitochondrial biogenesis (ESRRA) and antioxidant defense (GPX3, NRF2; p< 0.05). These data suggest that increased heme oxygenase expression may underlie high CO production, antioxidant expression, and diving capacity in adult seals, providing insights into cellular mechanisms underpinning hypoxia and ischemia-reperfusion tolerance in deep-diving mammals.