A novel mechanism of exercise-induced cognitive protection in ageing: D-amino acid oxidase /D-serine-dependent modulation of NMDAR signalling

Age-related cognitive impairment poses a significant public health challenge. Although exercise interventions have been shown to ameliorate cognitive deficits, the underlying molecular mechanisms remain incompletely understood. This review therefore proposes a novel framework, based on current evidence, integrating exercise interventions with the D-amino acid oxidase (DAO)/D-serine-N-methyl-D-aspartate receptor (NMDAR) axis. This review explores the potential mechanisms by which exercise modulates this metabolic axis to maintain central D-serine homeostasis, potentiate NMDAR signalling, and subsequently activate the downstream Calcium/Calmodulin-dependent Kinase II (CaMKII) -cAMP Response Element-Binding protein (CREB) -Brain-Derived Neurotrophic Factor (BDNF) pathway, thereby restoring synaptic plasticity and reversing cognitive decline. Furthermore, this article highlights the translational potential of the DAO/D-serine metabolic axis for early intervention strategies. Given the currently limited direct evidence supporting the targeted effects of exercise on this central axis, rigorous in vivo and in vitro experimental validation will be essential in future studies to substantiate these conclusions.