Understanding the Role of the Endoplasmic Reticulum Stress Sensor IRE1α in Aging

Aging is a progressive biological process that leads to a decline in multiple organ functions and finally to disease. A key feature of aging is the breakdown of proteostasis, particularly affecting the endoplasmic reticulum (ER). As an adaptation to ER stress, the unfolded protein response (UPR) is activated to maintain ER homeostasis. Among the three arms of the UPR, IRE1α is the most ancient pathway involved in maintaining proteostasis. As such, multiple studies demonstrate IRE1α's significance in ensuring healthy aging. The process of aging can be delayed through various strategies, including genetic modifications, dietary adjustments, and pharmacological interventions, which are correlated with improved ER proteostasis, activation of the UPR and IRE1α. This article reviews the latest progress in understanding the role of the UPR and IRE1α signaling in the aging process and its interconnection with other aging biomarkers, including cellular senescence.