The PERK paradox in aging: how ER stress shapes senescence and neurodegeneration

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are now recognized as integral components of the proteostasis network that preserves cellular and tissue function across the lifespan. With aging, increasing oxidative load, metabolic imbalance, and Ca²⁺ dysregulation elevate the burden of misfolded proteins in the ER, leading to progressive UPR engagement. When ER stress is mild or transient, UPR signaling restores folding capacity, restrains translation, and enhances redox and degradative programs, thereby promoting cellular resilience. In contrast, persistent or repeatedly unresolved ER stress narrows this adaptive window and biases UPR outputs toward chronic inflammation, stable growth arrest, and cell loss processes that collectively drive inflammaging, stem/progenitor exhaustion, tissue degeneration, and vulnerability to neurodegenerative disease. This review synthesizes evidence that ER stress is not merely a correlation of aging but a mechanistic contributor to age-related decline, with senescence emerging as a major downstream fate in multiple tissues. It also highlights how context- and duration-dependent PERK signaling can be protective early, yet maladaptive when chronically engaged, shaping senescence programs and influencing neuronal survival and neurodegenerative disease progressions. Finally, this review discusses therapeutic opportunities and open questions centered on restoring adaptive PERK/ISR dynamics to support healthy aging.