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
Escuela Nacional de Estudios Superiores, Unidad Juriquilla. UNAM.
Facultad de Medicina. UAQ.
eNeuro. 2022 May 18;9(3). doi: 10.1523/ENEURO.0176-22.2022.
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 N-methyl-D-aspartate receptor (NMDAR) hypofunction due to a reduction in the brain levels of D-serine, the endogenous NMDAR co-agonist. However, it is not clear if 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.Age-related behavioral changes in cognitive performance occur as a physiological process of aging. Then, it is important to explore possible therapeutics to decrease, retard or reverse aging effects on the brain. NMDA receptor hypofunction contributes to the aging-associated cognitive decline. In the aged brain, there is a reduction in the brain levels of the NMDAR co-agonist, D-Serine. However, it is unclear if chronic D-serine supplementation could revert the age-detriment in brain functions. Our results show that D-serine supplementation reverts the age-associated decrease in cognitive flexibility, functional brain connectivity, and neuronal morphology. Our findings raise the possibility that restoring the brain levels of D-serine could be used as a therapeutic target to recover brain alterations associated with aging.
大脑老化是一个自然过程，即使在健康个体中，也会涉及导致认知能力下降的结构和功能变化。这种损害与N-甲基-D-天冬氨酸受体（NMDAR）功能减退有关，原因是内源性NMDAR协同激动剂D-丝氨酸的脑内水平降低。然而，尚不清楚补充D-丝氨酸是否可作为一种干预措施来减少或逆转与年龄相关的大脑改变。在本研究中，我们旨在分析D-丝氨酸对大鼠细胞和大规模脑系统中与衰老相关的改变的影响，这些改变可能支持认知灵活性。我们发现，补充D-丝氨酸可逆转与年龄相关的认知灵活性下降、额叶树突棘密度下降，并部分恢复大规模功能连接，且不会诱发肾毒性；相反，D-丝氨酸恢复了受年龄影响的肾上皮细胞厚度。我们的结果表明，D-丝氨酸可作为一个治疗靶点来逆转与年龄相关的大脑改变。与年龄相关的认知能力行为变化是衰老的生理过程。因此，探索可能的治疗方法以减少、延缓或逆转衰老对大脑的影响非常重要。NMDA受体功能减退导致与衰老相关的认知能力下降。在老年大脑中，NMDAR协同激动剂D-丝氨酸的脑内水平降低。然而，尚不清楚长期补充D-丝氨酸是否能逆转大脑功能的年龄损害。我们的结果表明，补充D-丝氨酸可逆转与年龄相关的认知灵活性、脑功能连接和神经元形态的下降。我们的发现增加了一种可能性，即恢复D-丝氨酸的脑内水平可作为一个治疗靶点，以恢复与衰老相关的大脑改变。
