PT - JOURNAL ARTICLE AU - Nava-Gómez, L. AU - Calero-Vargas, I. AU - Higinio-Rodríguez, F. AU - Vázquez-Prieto, B. AU - Olivares-Moreno, R. AU - Ortiz-Retana, J. AU - Aranda, P. AU - Hernández-Chan, N. AU - Rojas-Piloni, G. AU - Alcauter, S. AU - López-Hidalgo, M. TI - Aging-Associated Cognitive Decline is Reversed by D-Serine Supplementation AID - 10.1523/ENEURO.0176-22.2022 DP - 2022 May 01 TA - eneuro PG - ENEURO.0176-22.2022 VI - 9 IP - 3 4099 - http://www.eneuro.org/content/9/3/ENEURO.0176-22.2022.short 4100 - http://www.eneuro.org/content/9/3/ENEURO.0176-22.2022.full SO - eNeuro2022 May 01; 9 AB - Brain aging is a natural process that involves structural and functional changes that lead to cognitive decline, even in healthy subjects. This detriment has been associated with NMDA receptor (NMDAR) hypofunction because of a reduction in the brain levels of D-serine, the endogenous NMDAR co-agonist. However, it is not clear whether D-serine supplementation could be used as an intervention to reduce or reverse age-related brain alterations. In the present work, we aimed to analyze the D-serine effect on aging-associated alterations in cellular and large-scale brain systems that could support cognitive flexibility in rats. We found that D-serine supplementation reverts the age-related decline in cognitive flexibility, frontal dendritic spine density, and partially restored large-scale functional connectivity without inducing nephrotoxicity; instead, D-serine restored the thickness of the renal epithelial cells that were affected by age. Our results suggest that D-serine could be used as a therapeutic target to reverse age-related brain alterations.