The aim of the present study was to investigate the neuronal structures that mediate the antiaging properties of acetyl-l-carnitine (ALCAR). The regional cerebral metabolic rates for glucose (rCMRglc) have been determined with the quantitative autoradiographic [(14)C]2-deoxyglucose procedure at different times after i.v. administration of saline or ALCAR 500 mg/kg to naïve, non pretreated 3-, 12- and 24-month-old rats and to 24-month-old rats pretreated with ALCAR (100 mg/kg/day, for 3 months). rCMRglc increased maximally at 30 min after ALCAR in 3-, 12- and 24-month old rats (14, 15 and 15 areas affected, 19, 24 and 22% mean increments). Peak metabolic activations occurred with similar magnitude in motor, visual, limbic and thalamic areas in all age rats and with larger magnitude in hippocampal and thalamic areas in aged rats. Cerebral metabolic activations subsided by 60 min after ALCAR in 3-month rats (3 brain regions affected, 4% decrease) and persisted by that time in 12- and 24-month-old rats (14 and 12 regions affected, 15 and 20% increases). Cerebral activations were enhanced in aged rats after chronic treatment with ALCAR (24 brain regions affected, 20% mean increase). Hence, during aging, metabolic responsivity to ALCAR is maintained in most brain areas and increased in limbic and thalamic regions. Increased responsivity to ALCAR may result from undetermined pharmacokinetic factors and/or from a higher sensitivity and contribute to the aging reversal properties of ALCAR.