Differences in the cerebral cortex metabolome of young adult and geriatric dogs

Abstract Text: Aging is responsible for chemical and morphological alterations in the brain (e.g., decreased brain mass, increased ventricular size, demyelination, neuroaxonal degeneration, decreased cholinergic activity, etc.) that lead to cognitive decline and neurodegenerative diseases. The longer lifespan of the canine pet population has increased the prevalence of cognitive dysfunction.  A better understanding of the brain aging process would aid in preventing or reversing the progression of cognitive decline and improve the quality of life of geriatric dogs.  Therefore, the objective of this experiment was to use untargeted GC-LC-MS to assess the impact of age on the metabolome of the cerebral cortex of dogs. Cerebral cortex samples were collected from 12 geriatric (12-year old) and 12 young adult (1-year old) beagles and stored at -80°C until GC-MS and LC-MS/MS analyses.  A total of 239 named biochemicals were identified, with 101 being altered (P < 0.05)  geriatric and young adult dogs.  Prior transcriptomics analysis of these samples showed that 963 genes were altered due to age, with old dogs having increased expression of genes associated with inflammation, stress response, and calcium homeostasis and decreased expression of genes associated with neuropeptide signaling and synaptic transmission.  In the current study, the cerebral cortex of geriatric dogs had a relative deficiency of excitatory amino acids, such as glutamate and gamma-aminobutyrate (GABA), compared to young adult dogs. In addition, geriatric dogs had increased concentrations of palmitoylethanolamide (PEA), suggesting greater levels of oxidative stress or inflammation in the brain of these animals. Glutathione metabolism also differed (P < 0.05) between geriatric and young adult dogs, with the former having greater concentrations of reduced glutathione. A relative hyperglycemia in the cerebral cortex of geriatric dogs seemed to drive elevations in glycolytic pathway intermediates; lactate, and sorbitol which, over long periods of time, could drive undesirable pathological events such as protein glycation and aggregation. Overall, the data suggest that the brains of geriatric dogs have reduced neurotransmitter metabolism and increased inflammation, possibly contributing to the altered neural functional capacity and health status of these animals. Futures studies should investigate whether a metabolic signature of the aging brain may be detected  in the plasma or serum of geriatric dogs. Identification of circulating metabolic biomarkers would allow for more frequent sampling using a non-invasive method and be useful in disease diagnosis and the development of nutritional interventions.

Keywords: Age, dog, metabolome