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Aging trajectories vary among individuals, characterized by progressive functional decline, often leading to disease states. One of the central hallmarks of aging is the deterioration of proteostasis, where the function of the endoplasmic reticulum (ER) is dramatically affected. ER stress is monitored and adjusted by the unfolded protein response (UPR); a signaling pathway that mediates adaptive processes to restore proteostasis. Studies in multiple model organisms (yeast, worms, flies, and mice) in addition to human tissue indicates that adaptive UPR signaling contributes to healthy aging. Strategies to improve ER proteostasis using small molecules and gene therapy reduce the decline of organ function during normal aging in mammals. This article reviews recent advances in understanding the significance of the ER proteostasis network to normal aging and its relationship with other hallmarks of aging such as senescence., Competing Interests: Declaration of interests C.H. is inventor on two patent applications to use AAV-XBP1s as an aging intervention, in addition to AAV-ATF6f (unpublished). The AAV-XBP1s technology was licensed to UCB. The remaining author has no interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: None