Cellular proteostasis decline in mammalian senescence

Collapse of proteostasis, the decline in the ability to cope with protein misfolding stresses and maintain protein homeostasis in the face of external challenges, has been established as a hallmark of aging in nematodes. However, whether proteostasis decline occurrs in humans still remains an open question. Here we sought to tackle the question of proteostasis collapse in human cellular senescence. Using RNA-seq and ribosome footprint profiling, we performed genome-wide characterization of transcription and translation in young vs. senescent primary human fibroblasts, and asked how these cells respond to heat shock at various gene expression regulatory levels. We found that, indeed, senescent human cells showed a marked deterioration in their ability to mount the heat shock response. Interestingly, both transcription and splicing responses were dampened in senescent cells. Accordingly, phosphorylated HSF1 nuclear localization, as well as nuclear organization, were hampered in senescent cells. Surprisingly, we observed a decoupling between different arms of the UPR in senescent cells. While young cells initiated both a translational regulatory response as well as a transcriptional regulatory response of the different UPR arms, senescent cells showed enhanced translational regulation, as well as ER stress sensing and XBP1 splicing, however they were unable to mount a UPR related transcriptional response. Together our data establishes a first genome-wide characterization of a cellular senescence proteostasis collapse at various regulatory levels, and reveals a general deterioration in the ability of cells to mount stress response transcriptional programs upon senescence.