Cellular proteostasis decline in human senescence

Abstract

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.

Interphase Chromosomes in Replicative Senescence: Chromosome Positioning as a Senescence Biomarker and the Lack of Nuclear Motor-Driven Chromosome Repositioning in Senescent Cells

“…In young proliferating cells (positive for Ki67) significantly relocate chromosome 11 to a new nuclear location, more towards the nuclear interior than the intermediate location in cells after heat shock ( Figure 6I ). However, there is no movement of chromosome 11 at all in senescent cells when responding to heat-shock ( Figure 6J ), this correlates with heat shock gene transcription failing in senescent cells ( Sabath et al, 2020 ).…”

Regulation of Age-Related Protein Toxicity

“…This decline in ability occurs early in adulthood, at the onset of oocyte biomass production, and seems a consequences of a reduced expression of the H3K27 demethylase jmjd-3.1 (Shemesh et al, 2013;Labbadia and Morimoto, 2015). A decline in the ability to induce chaperone expression with increasing age, was also found in senescent human lung fibroblasts (Sabath et al, 2020). In contrast, Walther and colleagues did not observe major changes in Hsp70 and Hsp90 expression in C. elegans throughout life, while sHsp expression even increased dramatically during aging (Walther et al, 2015).…”

“…At the same time, enhanced lipid biogenesis increases protein folding and protein degradation in the ER ( Chalmers et al, 2017 ; Frakes and Dillin, 2017 ). However, the ability to induce the UPR ER and its downstream targets decline with increasing age ( Sabath et al, 2020 ; Taylor and Hetz, 2020 ). In addition, absolute UPR ER -induced chaperone levels decrease during aging and the UPR ER -regulated chaperones that are still present, accumulate increasing amounts of oxidative damage ( Taylor, 2016 ).…”

Endoplasmic Reticulum Stress Signaling and the Pathogenesis of Hepatocarcinoma

“…The ER in hepatocytes has a remarkable capacity to adapt to extracellular and intracellular challenges [ 5 , 6 , 7 ]. However, in humans, numerous disturbances impair hepatocytes’ ability to handle protein folding and proteostasis, which disrupts ER homeostasis and leads to misfolded protein accumulation, ER stress and unfolded protein response (UPR) [ 8 , 9 , 10 , 11 , 12 ]. ER stress and subsequent adaptive UPR activation are important in the pathogenesis of chronic liver disease, ranging from steatosis and nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) [ 13 , 14 , 15 , 16 , 17 ].…”