Senescent Cells Fail to Maintain Proteostasis
Given the newfound consensus in the research community regarding the importance of senescent cells to degenerative aging, it isn't surprising to see a great deal more fundamental research into the biochemistry of cellular senescence now taking place than was previously the case. In many cases it isn't all that clear as to whether an incrementally greater understanding of mechanism A or mechanism B will at any point be helpful to the development of senolytic therapies to selectively destroy senescent cells, but that is the way of fundamental research. It is hard to say in advance what will turn out to be a big deal at the end of the day.
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.
This article gives a layman's explanation of current senolytic efforts including the big stumble by Unity.
https://www.nature.com/articles/s41587-020-00750-1
It would be interesting to see a map or a catalog of all the groups around the world that are working on senescence and what their current focus is on. Surely this must already exist, otherwise how would you know what to work on as a scientist? How could you be sure that someone isn't working on the same thing?
Thanks for the link August. Good read. The article is the likely explanation for UBXs 30% jump in price over a 3 week period following the article.