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.
We find that wild-type animals maintain high UPRER activity but low UPRcyto activity, a balance actively enforced by the transcription factor LET-607 (ortholog of mammalian CREBH). Consequently, LET-607 deficiency releases this trade-off, causing a seesaw-like rebalancing: UPRER activity decreases while UPRcyto increases. Strikingly, this rebalancing contributes to longevity: animals lacking LET-607 exhibited extended lifespan in a UPRcyto dependent manner. Mechanistically, LET-607 deficiency downregulates one-carbon cycle, which provides the methyl donor S-adenosylmethionine. This subsequently alleviates H3K9me-mediated repression at the promoters of UPRcyto genes, a process involving the regulators and readers of this histone mark, leading to UPRcyto activation.
Our study reveals a transcriptional mechanism that enforces a proteostatic trade-off and demonstrates that evolutionarily acquired UPR balance in wild-type animals is suboptimal for longevity, supporting the antagonistic pleiotropic theory of aging.
Trending Products
