Impact of Aging on Metabolic Changes in the Ketotic Rat Brain: Glucose, Oxidative and 4-HNE Metabolism.

Neuroprotection by ketosis is thought to be associated with improved mitochondrial function, decreased reactive oxygen species (ROS) and apoptotic and inflammatory mediators, and increased protective pathways. Oxidative injury to cells is often associated with lipid peroxidation. Accumulation of intermediary products of lipid peroxidation includes 4-hydroxynonenal (HNE; a toxic lipid peroxidation intermediate). We investigated the metabolic effects of diet-induced ketosis on cerebral metabolic rate of glucose (CMRglc), Acetyl-coA, and HNE concentrations in young and aged rats. Rats (3 months old and 18 months old) were randomly assigned to two groups, ketogenic (high fat, carbohydrate restricted; KG) or standard lab-chow (STD) diet for 4 weeks. CMRglc was measured using 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (PET). Cerebral metabolic rates of glucose (μmol/min per 100 g) was determined in the brain using Gjedde-Patlak analysis. Acetyl-coA, glutamate and HNE concentrations in cortical tissues were measured using mass spectrometry. We observed a 30% reduction of CMRglc in young ketotic rats, whereas CMRglc in the aged on the KG diet was similar to the STD groups. We observed no differences in cortical Acetyl-coA concentrations between the groups. Glutamate concentrations were significantly reduced in the aged STD group, but recovered in the KG group, compared to the young. Brain ketone body concentrations were highest in the young KG rats (tenfold vs STD), whereas ketone body levels in the aged KG brains were 30% of the young KG. The lack of KG diet effect on CMRglc in the aged rats was not expected. Also noted was that, in the aged rats, HNE levels were not elevated as we had expected. Together these findings suggest that oxidative metabolism may be reduced in the aged.