Comprehensive metabolic profiling across five lifespan stages in murine hippocampus and cortex reveals sex-related variation in age-related cognitive decline

This study employs Barnes maze behavioral assessments, untargeted liquid chromatography-mass spectrometry metabolomics, and ¹³C₆-glucose isotopic tracing to systematically investigate cognitive function and metabolic profiles in hippocampal and cortical tissues of male and female mice across five distinct age-ranges. Behavioral analyses reveal significant cognitive decline in both sexes by 16-months-of-age, with females exhibiting more severe impairment by 23-months, demonstrating a sex-related variation. ¹³C₆-glucose tracing analyses reveals that glucose is rapidly and preferentially metabolized toward the Tricarboxylic acid cycle over glycolysis and the pentose phosphate pathway (PPP), with metabolism rates increasing from juvenility to meet developmental demands and maintaining homeostasis into pre-elderly. Surprisingly, glucose metabolism continues to rise in elderly males but declines in females. Developmental shifts from purine biosynthesis to degradation display sex-related variation, highlighting sustained synthesis in elderly males versus degradation in aging females. Finally, age and sex- related differences in amino acids, neurotransmitters, histidine-derived antioxidants, and the arginine-urea cycle further underscore complex metabolic reprogramming in the CNS. Overall, our study elucidates from a metabolic perspective the molecular basis of sex-related variation in age-related cognitive decline by characterizing sex-related variation in reprogramming of glucose, purine, and amino acid metabolic networks.