Cellular senescence, a stress‐induced irreversible cell cycle arrest, has been defined for mitotic cells and is implicated in aging of replicative tissues. Age‐related functional decline in the brain is often attributed to a failure of protein homeostasis (proteostasis), largely in postmitotic neurons, which accordingly is a process distinct by definition from senescence. It is nevertheless possible that proteostasis failure and cellular senescence have overlapping molecular mechanisms. Here, we identify postmitotic cellular senescence as an adaptive stress response to proteostasis failure. Primary rat hippocampal neurons in long‐term cultures show molecular changes indicative of both senescence (senescence‐associated β‐galactosidase, p16, and loss of lamin B1) and proteostasis failure relevant to Alzheimer's disease. In addition, we demonstrate that the senescent neurons exhibit resistance to stress. Importantly, treatment of the cultures with an mTOR antagonist, protein synthesis inhibitor, or chemical compound that reduces the amount of protein aggregates relieved the proteotoxic stresses as well as the appearance of senescence markers. Our data propose mechanistic insights into the pathophysiological brain aging by establishing senescence as a primary cell‐autonomous neuroprotective response.

中文翻译：

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长期培养的有丝分裂后大鼠神经元的蛋白稳态失败和细胞衰老。

细胞衰老是一种应力诱导的不可逆的细胞周期停滞，已被定义为有丝分裂细胞，并与复制组织的衰老有关。大脑中与年龄相关的功能衰退通常归因于蛋白质稳态（蛋白稳态）的失败，这主要是在有丝分裂后的神经元中发生的，因此，从定义上讲，这是一个与衰老不同的过程。然而，蛋白稳态失败和细胞衰老可能具有重叠的分子机制。在这里，我们确定有丝分裂后细胞衰老为对蛋白稳态失败的适应性应激反应。长期培养的原代大鼠海马神经元显示出指示阿尔茨海默氏病相关的衰老（衰老相关的β-半乳糖苷酶，p16和层粘连蛋白B1丢失）和蛋白稳态失败的分子变化。此外，我们证明了衰老的神经元表现出对压力的抵抗力。重要的是，用mTOR拮抗剂，蛋白质合成抑制剂或减少蛋白质聚集体数量的化合物对培养物进行处理，可以减轻蛋白毒性压力以及衰老标记的出现。我们的数据通过将衰老确立为主要的细胞自主神经保护反应，提出了对病理生理性大脑衰老的机制性见解。