Abstract: The ability to protect cellular components in the face of deleterious conditions, such as exposure to chemical poisons, damaging radiation, or excessive heat, is crucial to organismal viability. Several compartmentalized stress response pathways have evolved to mitigate damage and increase cellular fitness in such environments, including the unfolded protein response of the endoplasmic reticulum (UPRER). The UPRER serves a critical protective role by promoting proteome integrity and lipid homeostasis while preventing the accumulation of damaged proteins and protein aggregates. The ability to mount an effective UPRER is a key determinant of organismal lifespan and stress resistance, however, as with other stress responses, it has been shown to decline markedly during the aging process. This leaves the proteomes of aged animals susceptible to dysregulation and dysfunction, which in turn further contributes to an accelerated aging process, development of age-associated pathology, and proteotoxicity (Higuchi-Sanabria et al., 2018).