ODC1-associated astrocytic urea cycle dysregulation in age-related memory impairment.

Aging is an inevitable physiological process characterized by progressive functional decline and degenerative alterations across organ systems. Metabolic disturbance, particularly the disruption of substance and energy metabolism, is increasingly recognized as a central hallmark of aging. Emerging evidence suggests that dysregulation of the urea cycle (UC) contributes to aging-related pathological processes, including cognitive impairment; however, its role in astrocyte-mediated brain aging remains unclear. In this study, we used a D-galactose-induced mouse aging model to investigate the involvement of UC activation in age-related cognitive decline. Aging mice exhibited marked cognitive impairment, accompanied by an increased proportion of reactive astrocytes in the hippocampus, a key pathological feature of brain aging. Metabolic analysis and molecular validation revealed enhanced UC activity and increased urea production in aging mice. Inhibition of UC activation reduced urea production and decreased the proportion of hippocampal reactive astrocytes. Mechanistically, the expression of key UC-related enzymes, including ornithine decarboxylase 1 (ODC1) and arginase 1 (ARG1), was significantly downregulated, accompanied by improved mitochondrial dynamics, particularly the restoration of mitochondrial fusion and fission balance. Furthermore, ODC1 knockdown confirmed its critical role in mediating UC activation in astrocytes and significantly alleviated aging-like cellular phenotypes. Notably, Ganoderma lucidum polysaccharide peptides (GLPs) effectively suppressed UC activation in aging astrocytes by downregulating ODC1 and ARG1. Collectively, this study identifies dysregulated astrocytic UC activity as a novel metabolic mechanism linking astrocyte reactivity, mitochondrial dysfunction, and age-related cognitive decline, suggesting that targeting ODC1-mediated UC activation and mitochondrial dynamics may provide a promising dual strategy for combating brain aging.