The endoplasmic reticulum (ER) is the first compartment in the protein secretory pathway. The ER responds to the accumulation of unfolded proteins in its lumen by activating signal transduction pathways cumulatively called the unfolded protein response (UPR). The UPR regulates the expression of genes that function within the secretory pathway, but also affect broad physiological aspects. Ultimately, activation of the UPR remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress, allowing persistent ER function.

Strikingly, the responsiveness of the UPR pathways declines with age, indicating that “older” organisms have a more vulnerable and unprotected ER, that is likely to become dysfunctional, and to perturb normal physiology. Accordingly, diseases associated with increased ER stress, such as:
Alzheimer’s, Huntington, Parkinson’s disease are a major cause of age-related morbidity and mortality. Hence, finding novel ways to maintain ER homeostasis specifically in the old should have major health benefits.

Given the collapse in the responsiveness of the UPR with age, the cellular tools dedicated for assuring ER homeostasis in the young and in the old are vastly different. Still, the majority of the studies in the ER stress response field are conducted in isolated cells devoid of age-related context. Here, using the model organism C. elegans, we present a new platform for genetically dissecting genes and pathways that maintain ER function in aging animals. Such genes and pathways have the potential to become targets for the development of therapeutic drugs for age-related proteostasis-related diseases.