GeroScienceJul 22, 2026

How cell stress affects aging, cell aging, and brain degeneration

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 23, 2026

Abstract

Chronic endoplasmic reticulum (ER) stress is associated with age-related decline in cellular and tissue function.

Increased oxidative stress, metabolic imbalance, and calcium dysregulation with aging lead to more misfolded proteins in the ER.
Mild or temporary ER stress activates the unfolded protein response (UPR), which helps restore protein folding and cellular resilience.
Persistent ER stress shifts UPR responses towards chronic inflammation and cell loss, contributing to aging and neurodegenerative diseases.
Senescence emerges as a key outcome of sustained ER stress across various tissues.
The context and duration of PERK signaling can initially protect cells but may become maladaptive with prolonged activation.

Simplified

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.

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PubMed

How cell stress affects aging, cell aging, and brain degeneration

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