Neuroprotection by caloric restriction is associated with a distinct state of hippocampal energy metabolism linked to PGC-1alpha and GSK3beta

Abstract

The hippocampus is critical for cognition and memory formation and is vulnerable to age-related atrophy and loss of function. These phenotypes are attenuated by caloric restriction (CR), a dietary intervention that delays aging. Here we show significant effects of aging and CR on hippocampal energy metabolism that implicate metabolic pathways in neuronal protection. Using high-resolution quantitative imaging, we detected significant regional differences in activity of the mitochondrial electron transport system (ETS) in mouse hippocampi. Mitochondrial activity was lower in aged mice, and the impact of age was region specific. Multi-photon laser scanning microscopy revealed age- and region-specific differences within the dentate gyrus (DG), where levels of autofluroescence of NAD derived metabolic cofactors declined and chemical properties were altered. There was a significant regional impact of age to decrease levels of PGC-1alpha, a master regulator of ETS gene expression. Rather than reversing the impact of age, we found CR induced a distinct metabolic state. Fluorescence intensity of NAD(P) H was higher in the DG of CR animals, but CR had no impact on fluorescence decay parameters. Levels of PGC-1alpha were lower with CR, as were levels of GSK3beta, a key regulator of PGC-1alpha turnover and activity, and these differences were conserved in rhesus monkeys. These data reveal significant changes in hippocampal energy metabolism with age and suggest CR’s prevention of age-related functional decline involves extensive metabolic reprogramming.