Proteostasis Rebalancing by LET-607 Deficiency Promotes 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 (UPR^ER) and the cytosolic UPR (UPR^cyto) in C. elegans that influences lifespan. We find that wild-type animals maintain high UPR^ER activity but low UPR^cyto 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: UPR^ER activity decreases while UPR^cyto increases. Strikingly, this rebalancing contributes to longevity: animals lacking LET-607 exhibited extended lifespan in a UPR^cyto 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 UPR^cyto genes, a process involving the regulators and readers of this histone mark, leading to UPR^cyto 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.