Endoplasmic Reticulum Unfolded Protein Response and Aging: Causality, Mechanism, and Interplay

Aging, the progressive decline of physiological integrity, is not an immutable process. Various genetic, physiological, and environmental factors could modulate this process. Maintaining proper conformation, concentration, and subcellular localization of proteins, proteostasis is critical for cellular functions and proteostasis collapse was proposed as one of the aging hallmarks. However, proteostasis is constantly challenged both pathologically and physiologically, especially in the Endoplasmic Reticulum (ER), the cellular protein processing hub. Therefore, Endoplasmic reticulum unfolded protein response (UPRER), a dedicated stress response pathway, was developed to deal with excess unfolded or misfolded protein and ultimately restore ER proteostasis. Here, recent advances in determining UPRER's role in aging were discussed first. Although accumulating evidence has suggested that UPRER contributes to aging causatively, such contribution is complicated and may depend on various factors including intensity, cell type, and duration. After that, several recent advances in determining the mechanisms through which UPRER contributes to aging, both cell autonomously and cell-nonautonomous, were discussed. UPRER's interconnection with other stress response pathways, aging hallmarks, and phenotypical markers of aging are discussed in the third section to provide a more holistic view of aging.