Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished ATF6 nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

蛋白质稳态丧失，维持蛋白质稳态的能力下降已被确定为线虫衰老的标志。但是，尚不清楚人类中是否发生蛋白质变形塌陷。在这里，我们证明蛋白稳态下降是人类衰老的内在原因。使用基因表达，剪接和翻译的转录组范围内的表征，我们发现应激衰老细胞中热休克反应的转录激活显着恶化。此外，磷酸化HSF1核的本地化和分布被削弱衰老。有趣的是，替代的拼接规则也受到了抑制。出乎意料的是，我们发现应激衰老细胞中不同的未折叠蛋白反应（UPR）分支之间存在脱钩。年轻细胞启动了UPR相关的翻译和转录调控反应，而衰老细胞则显示出增强的翻译调控和内质网（ER）压力感测。但是，他们无法触发与UPR相关的转录反应。这伴随着在衰老细胞中ATF6核定位的减少。最后，我们发现在衰老细胞中热应激后蛋白酶体功能受损，并且在恢复正常温度后不能恢复。总之，我们的数据揭示了在人类衰老时安装动态应激转录程序的能力的下降，这对蛋白稳态控制和相关蛋白稳态下降对人类衰老具有广泛影响。衰老细胞表现出增强的翻译调控和内质网（ER）应力感测；但是，他们无法触发与UPR相关的转录反应。这伴随着在衰老细胞中ATF6核定位的减少。最后，我们发现衰老细胞受热应激后蛋白酶体功能受损，恢复正常温度后仍未恢复。总之，我们的数据揭示了在人类衰老时安装动态应激转录程序的能力的下降，这对蛋白稳态控制和相关蛋白稳态下降对人类衰老具有广泛影响。衰老细胞表现出增强的翻译调控和内质网（ER）应力感测；但是，他们无法触发与UPR相关的转录反应。这伴随着在衰老细胞中ATF6核定位的减少。最后，我们发现在衰老细胞中热应激后蛋白酶体功能受损，并且在恢复正常温度后不能恢复。总之，我们的数据揭示了在人类衰老时安装动态应激转录程序的能力的下降，这对蛋白稳态控制和相关蛋白稳态下降对人类衰老具有广泛影响。我们发现，蛋白酶体功能在衰老细胞受热应激后会受损，并且在恢复正常温度后不会恢复。总之，我们的数据揭示了在人类衰老时安装动态应激转录程序的能力的下降，这对蛋白稳态控制和相关蛋白稳态下降对人类衰老具有广泛影响。我们发现衰老细胞受热应激后蛋白酶体功能受损，并且恢复正常温度后无法恢复。总之，我们的数据揭示了在人类衰老时安装动态应激转录程序的能力的下降，这对蛋白稳态控制和相关蛋白稳态下降对人类衰老具有广泛影响。