Aging-Associated Cognitive Decline is Reversed by D-Serine Supplementation

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-agonis...

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Published ineNeuro Vol. 9; no. 3; p. ENEURO.0176-22.2022
Main Authors Nava-Gómez, L., Calero-Vargas, I., Higinio-Rodríguez, F., Vázquez-Prieto, B., Olivares-Moreno, R., Ortiz-Retana, J., Aranda, P., Hernández-Chan, N., Rojas-Piloni, G., Alcauter, S., López-Hidalgo, M.
Format Journal Article
LanguageEnglish
Published United States Society for Neuroscience 18.05.2022
Subjects
New Research
Aging
fMRI
Cognitive Flexibility
D-serine
Functional brain connectivity
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Summary: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.
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L.N.-G. and I.C.-V. contributed equally to this work.
Author contributions: M.L.-H. designed research; L.N.-G., I.C.-V., F.H.-R., B.V.-P., P.A., and N.H.-C. performed research; J.O.-R., G.R.-P., S.A., and M.L.-H. contributed unpublished reagents/analytic tools; L.N.-G., I.C.-V., F.H.-R., B.V.-P., R.O.-M., G.R.-P., S.A., and M.L.-H. analyzed data; L.N.-G., G.R.-P., S.A., and M.L.-H. wrote the paper.
The authors declare no competing financial interests.
This work was supported by grants from Consejo Nacional de Ciencia y Tecnologia (CONACyT) Ciencia de Frontera 171874 (to M.L.H.), CONACyT Problemas Nacionales 2132 (to N.H.C.), PAPIIT-DGAPA IA208120 (to M.L.H.), PAPIIT-DGAPA IA208022 (to M.L.H.), CONACYT Ciencia Básica A1-S-8686 (to G.R.-P.), and UNAM-DGAPA PAPIIT IN201121 (to G.R.-P.). L.N.-G. and P.A. are doctoral students from the Programa de Doctorado en Biomedicina, from Universidad Autónoma de Querétaro, and received CONACyT Fellowships 472970 and 815419. I.C.-V. is a doctoral student from the Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), and received the CONACyT Fellowship 786125. F.H.-R. and B.V.-P. are master students from the Programa de Maestría en Ciencias (Neurobiología) from UNAM and received CONACyT Fellowships 778405 and 778596.
ISSN:2373-2822
2373-2822
DOI:10.1523/ENEURO.0176-22.2022