Cellular proteostasis collapse 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. Proteostasis collapse upon aging has been discovered in nematodes, and previous studies have established its onset and genetic determinants in aged nematodes. However, whether proteostasis collapse happens in humans has still remained controversial. Furthermore, the question of whether the aging proteostasis collapse occurs at a cell autonomous level has not been explored. Here we sought to tackle the question of proteostasis collapse in the system of human replicative senescence. Using genome-wide characterization of transcription and translation in young vs. senescent human fibroblasts, we asked how these cells respond to heat shock at various gene expression regulatory levels. We found that, indeed, senescent human cells show a marked deterioration in their ability to mount the heat shock response. Interestingly, both transcription and splicing responses are dampened in senescent cells. Examination of the heat shock transcription factor HSF1 revealed that phosphorylated HSF1 nuclear localization, as well as nuclear organization, were hampered in senescent cells. Surprisingly, we observed a decoupling between different regulatory arms of the UPR (the Unfolded Protein Response) in response to heat stress. While young cells initiate both a translational response as well as a transcriptional regulatory response of the different UPR arms, senescent cells show enhanced translational regulation, as well as ER stress sensing, however they were unable to mount the 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.