BACKGROUND: Results of studies in experimental animals have shown that, with age, myocardial fatty acid metabolism decreases, and glucose metabolism increases. Whether similar changes occur in humans is unknown. METHODS: Seventeen healthy younger normal volunteers (six males, 26 ± 5 years) and 19 healthy older volunteers (nine males, 67 ± 5 years) underwent positron emission tomography (PET) under resting conditions in the fasted state. Myocardial blood flow (MBF), myocardial oxygen consumption (MVO2), myocardial fatty acid utilization (MFAU) and oxidation (MFAO), and myocardial glucose utilization (MGU) were quantified by PET with 15O-water, 11C-acetate, 11C-palmitate, and 11C-glucose, respectively. RESULTS: Although MBF was similar between the groups, MVO2 was higher in the older subjects (5.6 ± 1.6 μmol/g/min) compared with younger subjects (4.6 ± 1.0 μmol/g/min, p < 0.04). Rates of MFAU and MFAO (corrected for MVO2) were significantly lower in older subjects than in younger subjects (MFAU/MVO2: 35 ± 10 vs. 51 ± 20 nmol free fatty acids (FFA)/nmol O2 × 10-3, p < 0.005, and MFAO/MVO2: 33 ± 10 vs. 48 ± 18 nmol FFA/nmol O2 × 10-3, p < 0.004). In contrast, the rates of MGU corrected for MVO2 did not differ between the groups. CONCLUSIONS: With aging, humans exhibit a decline in MFAU and MFAO. Although absolute rates of MGU do not increase, by virtue of the decline in MFAU there is likely an increase in relative contribution of MGU to substrate metabolism. The clinical significance of this metabolic switch awaits further study.