The time required to initiate adaptive increases in the activities of hepatic tyrosine aminotransferase and glucokinase following administration of glucose or adrenocorticotropic hormone, respectively, increases as rats age from 2- to 18- or 24 months. In contrast, no agedependence is demonstrable for these enzyme inductions in response to injection of hormones which interact directly with liver to stimulate their rate of synthesis; insulin for glucokinase and cortisol, insulin or glucagon for tyrosine aminotransferase. Consequently, the age-dependence may reflect an altered responsiveness in the generation of insulin and corticosteroid. Adaptive responsiveness in vivo both of glucokinase and tyrosine aminotransferase to glucose or adrenocorticotropic hormone, respectively, requires insulin and intact adrenal function. In turn, these complex hormonal interactions are susceptible to pituitary control. Localization of an age-dependent step is indicated subsequent to administration of adrenocorticotropic hormone or glucose and prior to accessibility of the appropriate hormones to liver. Although an age-dependent decrease in pancreatic beta cell function is proposed, the degree to which age-dependent enzyme adaptation reflects alterations in hormonal availability in the circulation, production from the appropriate tissue source, responsiveness of tissue source to pituitary or neural control mechanisms, or additional unknown factors remains to be determined. (Endocrinology90: 1551, 1972)