Moment-to-moment adjustment of regional cerebral blood flow to neuronal activity via neurovascular coupling (NVC or “functional hyperemia”) has a critical role in maintenance of healthy cognitive function. Aging-induced impairment of NVC responses importantly contributes to age-related cognitive decline. Advanced aging is associated with increased prevalence of senescent cells in the cerebral microcirculation, but their role in impaired NVC responses remains unexplored. The present study was designed to test the hypothesis that a validated senolytic treatment can improve NVC responses and cognitive performance in aged mice. To achieve this goal, aged (24-month-old) C57BL/6 mice were treated with ABT263/Navitoclax, a potent senolytic agent known to eliminate senescent cells in the aged mouse brain. Mice were behaviorally evaluated (radial arms water maze) and NVC was assessed by measuring CBF responses (laser speckle contrast imaging) in the somatosensory whisker barrel cortex evoked by contralateral whisker stimulation. We found that NVC responses were significantly impaired in aged mice. ABT263/Navitoclax treatment improved NVC response, which was associated with significantly improved hippocampal-encoded functions of learning and memory. ABT263/Navitoclax treatment did not significantly affect endothelium-dependent acetylcholine-induced relaxation of aorta rings. Thus, increased presence of senescent cells in the aged brain likely contributes to age-related neurovascular uncoupling, exacerbating cognitive decline. The neurovascular protective effects of ABT263/Navitoclax treatment highlight the preventive and therapeutic potential of senolytic treatments (as monotherapy or as part of combination treatment regimens) as effective interventions in patients at risk for vascular cognitive impairment (VCI).

通过神经血管耦合（NVC 或“功能性充血”）对局部脑血流对神经元活动的即时调整对于维持健康的认知功能具有关键作用。衰老引起的 NVC 反应受损在很大程度上导致了与年龄相关的认知能力下降。晚期衰老与大脑微循环中衰老细胞的患病率增加有关，但它们在 NVC 反应受损中的作用仍未被探索。本研究旨在验证以下假设：经过验证的 senolytic 治疗可以改善老年小鼠的 NVC 反应和认知表现。为了实现这一目标，使用 ABT263/Navitoclax 治疗老年（24 个月大）C57BL/6 小鼠，ABT263/Navitoclax 是一种有效的衰老剂，已知可以消除老年小鼠大脑中的衰老细胞。对小鼠进行行为评估（桡臂水迷宫），并通过测量对侧胡须刺激引起的体感胡须桶皮层的CBF反应（激光散斑对比成像）来评估NVC。我们发现老年小鼠的 NVC 反应明显受损。 ABT263/Navitoclax 治疗改善了 NVC 反应，这与海马编码的学习和记忆功能的显着改善有关。 ABT263/Navitoclax 治疗没有显着影响内皮依赖性乙酰胆碱诱导的主动脉环松弛。因此，衰老大脑中衰老细胞的增加可能会导致与年龄相关的神经血管解偶联，从而加剧认知能力下降。 ABT263/Navitoclax 治疗的神经血管保护作用凸显了 senolytic 治疗（作为单一疗法或作为联合治疗方案的一部分）作为对有血管性认知障碍 (VCI) 风险的患者的有效干预措施的预防和治疗潜力。