The effect of aging on beta-adrenergically mediated substrate utilization was investigated in nine young (25.2 +/- 1.7 yr old) and eight older males (52.9 +/- 2.1 yr old), matched for body weight and body composition. In a first experiment, the nonselective beta-agonist isoprenaline (ISO) was infused in increasing standardized doses, and during each infusion period energy expenditure and substrate utilization were determined by indirect calorimetry. In a second experiment, forearm skeletal muscle metabolism was studied during a standardized infusion dose of ISO (19 ng/kg fat-free mass x min). During beta-adrenergic stimulation there was an increased carbohydrate oxidation (at an ISO infusion dose of 24 ng/kg fat-free mass x min, 31% vs. 21% of total energy expenditure; P < 0.05) and a decreased fat oxidation (51 vs. 62 of total energy expenditure; P < 0.05) in older compared to young subjects. Skeletal muscle lactate release significantly increased in the older subjects (from -175 +/- 32 to -366 +/- 66 nmol/100 mL forearm tissue x min), whereas there was no change in young subjects (from -32 +/- 21 to 23 +/- 57 nmol/100 mL forearm tissue x min; interaction group x ISO, P < 0.01). Additionally, there was a tendency toward a blunted ISO-induced increase in nonesterified fatty acid uptake in the older subjects (interaction group x ISO, P = 0.062). Thus, middle-aged subjects have a blunted ability to oxidize fat during beta-adrenergic stimulation compared to young subjects. This diminished fat oxidation may be an important etiological factor in the age-related increase in body fatness and obesity by favoring fat storage above oxidation.