A number of age-dependent degenerative diseases are caused by chronic endoplasmic reticulum (ER) stress in vital cells. In many cases, the afflicted cells suffer from ER stress since birth, but the death of irreplaceable cells occurs only late in life. Although our understanding of ER stress-induced cell death has advanced significantly, most of the known mechanisms involve pathways that signal within hours, and it remains unclear how these pathways regulate cell death that occurs only decades later. Here, I highlight the conceptual issues and suggest ways to make sense of the age-related effect of ER stress-induced cell death in degenerative diseases.
Excessive endoplasmic reticulum (ER) stress triggers cell death and underlies many degenerative diseases. Many models implicate the rapidly activated Unfolded Response Pathways in triggering caspase activation and cell death. However, such fast acting pathways are not suitable to explain age-related degenerative diseases that manifest only after decades of UPR activity and alternative mechanisms for cell death induction should be considered.