Folic acid ameliorates myelination deficits and cognitive-emotional impairments in offspring of advanced maternal age

Advanced maternal age (AMA), defined as pregnancy at 35 years of age or older, has been associated with adverse neurodevelopmental outcomes in offspring. However, its long-term effects and underlying mechanisms remain incompletely understood. Folic acid, a key nutrient in one-carbon metabolism essential for nervous system development, plays an established role in early neural tube formation, while its contribution to postnatal brain development has received increasing attention. In this study, Sprague-Dawley rat models of AMA and age-appropriate maternal age were established to investigate potential alterations in folate levels in offspring associated with AMA and to explore the effects of postnatal folic acid supplementation on myelination. Untargeted metabolomic analysis revealed that offspring of AMA dams exhibited reduced folate levels during early postnatal development compared with controls. These alterations were accompanied by impairments in learning, memory, and emotional behaviors, as well as deficits in hippocampal myelination. Continuous postnatal folic acid supplementation significantly improved behavioral abnormalities and partially restored myelin-related protein expression and myelination levels. These findings suggest that AMA may impair myelination by affecting early folate availability in offspring, thereby contributing to neurodevelopmental and behavioral abnormalities. Postnatal folic acid intervention partially alleviates AMA-associated myelination deficits, highlighting the potential value of perinatal and early postnatal nutritional regulation in reducing neurodevelopmental risks associated with AMA.