Age-Related Changes in Energy Production in Fresh Senescence-Accelerated Mouse Brain Slices as Revealed by Positron Autoradiography

Abstract

To investigate age-related changes in cerebral energy production, we compared senescence-accelerated prone mice (SAMP8) as an animal model of accelerated aging and senescence-accelerated resistant mice (SAMR1) as a control. Considering that the cerebral glucose metabolic rate (CMRglc) at the time of O₂ deprivation and 2,4-dinitrophenol (DNP) loading would reflect anaerobic glycolytic capacity and mitochondrial function, respectively, we investigated dynamic changes in CMRglc before and after loading with these perturbations. Fresh brain slices were incubated with [¹⁸F]2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) in oxygenated Krebs-Ringer solution at 36°C, and serial two-dimensional time-resolved images of [¹⁸F]FDG uptake in these slices were obtained on the imaging plates. The fractional rate constant (=k₃*) of [¹⁸F]FDG proportional to the CMRglc was evaluated by applying the Gjedde-Patlak graphical method to the image data. The k₃* value before the hypoxic perturbation in all of the brain sites analyzed was higher in SAMP8 than SAMR1 in both the 2- and 10-month-old groups. With O₂ deprivation, k₃* values were higher without site specificity in the 2-month-old SAMP8 than in 2-month-old SAMR1, whereas in 10-month-old mice, there was no significant difference between the two groups. In contrast, with DNP loading, while no significant difference was noted between 2-month-old SAMP8 and 2-month-old SAMR1, in 10-month-old mice, the SAMP8 group showed lower values in certain regions than SAMR1 mice. These results suggest that in the brain tissue of SAMP8, a marked transient enhancement of anaerobic glycolytic capacity in the 2-month-olds and a decrease in mitochondrial function in the subsequent period occur, as a result of which glucose metabolism appears to be enhanced in both the 2- and 10-month-old groups compared to SAMR1 mice.