When an individual is under stress, the undesired effect on the brain often exceeds expectations. Additionally, when stress persists for a long time, it can trigger serious health problems, particularly depression. Recent studies have revealed that depressed patients have a higher rate of brain aging than healthy subjects and that depression increases dementia risk later in life. However, it remains unknown which factors are involved in brain aging triggered by chronic stress. The most critical change during brain aging is the decline in cognitive function. In addition, cellular senescence is a stable state of cell cycle arrest that occurs because of damage and/or stress and is considered a sign of aging. We used the chronic unpredictable stress (CUS) model to mimic stressful life situations and found that, compared with nonstressed control mice, CUS-treated C57BL/6 mice exhibited depression-like behaviors and cognitive decline. Additionally, the protein expression of the senescence marker p16^INK4a was increased in the hippocampus, and senescence-associated β-galactosidase (SA-β-gal)-positive cells were found in the hippocampal dentate gyrus (DG) in CUS-treated mice. Furthermore, the levels of SA-β-gal or p16^INK4a were strongly correlated with the severity of memory impairment in CUS-treated mice, whereas clearing senescent cells using the pharmacological senolytic cocktail dasatinib plus quercetin (D + Q) alleviated CUS-induced cognitive deficits, suggesting that targeting senescent cells may be a promising candidate approach to study chronic stress-induced cognitive decline. Our findings open new avenues for stress-related research and provide new insight into the association of chronic stress-induced cellular senescence with cognitive deficits.

当一个人承受压力时，对大脑的不良影响通常会超出预期。此外，当压力持续很长时间时，它可能引发严重的健康问题，尤其是抑郁症。最近的研究表明，抑郁症患者的大脑衰老率高于健康受试者，抑郁症会增加以后生活中痴呆症的风险。但是，尚不清楚哪些因素与慢性压力引发的大脑衰老有关。脑衰老过程中最关键的变化是认知功能下降。另外，细胞衰老是由于损伤和/或应激而发生的细胞周期停滞的稳定状态，并且被认为是衰老的迹象。我们使用慢性不可预测的压力（CUS）模型来模拟压力大的生活状况，并发现与非压力大的对照组小鼠相比，CUS治疗的C57BL / 6小鼠表现出抑郁样行为和认知能力下降。此外，衰老标记p16的蛋白质表达在CUS治疗的小鼠中，海马中的^INK4a增加，并且在海马齿状回（DG）中发现了与衰老相关的β-半乳糖苷酶（SA-β-gal）阳性细胞。此外，SA-β-gal或p16 ^INK4a的水平与经CUS治疗的小鼠的记忆障碍严重程度密切相关，而使用药理学上可接受的鸡尾酒疗法达沙替尼加槲皮素（D + Q）清除衰老细胞则减轻了CUS诱导的认知能力缺陷，表明靶向衰老细胞可能是研究慢性应激诱导的认知功能下降的有前途的候选方法。我们的发现为应激相关研究开辟了新途径，并为慢性应激诱导的细胞衰老与认知缺陷之间的联系提供了新的见解。