July 17th, 2026
That evolution does not optimize for species longevity is illustrated by the large number of small alterations in gene sequence or protein level that extend life in short-lived laboratory species such as nematode worms. Here, researchers note a trade-off between the activity of the unfolded protein response in various parts of the cell. When errors in protein manufacture and folding occur, unfolded and misfolded proteins emerge to cause harm. The unfolded protein response is triggered and acts to remove the problem proteins. Everything a cell does requires effort, and evolution has led to systems that balance that effort versus all of the other things a cell could instead accomplish. Therefore the unfolded protein response tends to operate at a level that is suboptimal for longevity in an organism. Further, it appears that assignment of that unfolded protein response effort across different parts of the cell is also suboptimal for longevity.
Disruption of proteostasis is a hallmark of aging. Given that cellular resources are limited, this necessitates a coordinated orchestration of different proteostatic subsystems. Yet, the principles governing this process, including the potential role of trade-offs, are not well defined. Here, we report a trade-off between the endoplasmic reticulum unfolded protein response (UPRER) and the cytosolic unfolded protein response (UPRcyto) in C. elegans that influences lifespan.
