Impaired capacity to restore proteostasis in the aged brain after ischemia: Implications for translational brain ischemia research

Brain ischemia induced by cardiac arrest or ischemic stroke is a severe form of metabolic stress that substantially disrupts cellular homeostasis, especially protein homeostasis (proteostasis). As proteostasis is fundamental for cellular and organismal health, cells have developed a complex network to restore proteostasis impaired by stress. Many components of this network - including ubiquitination, small ubiquitin-like modifier (SUMO) conjugation, autophagy, and the unfolded protein response (UPR) - are activated in the post-ischemic brain, and play a crucial role in cell survival and recovery of neurologic function. Importantly, recent studies have shown that ischemia-induced activation of these proteostasis-related pathways in the aged brain is impaired, indicating an aging-related decline in the self-healing capacity of the brain. This impaired capacity is a significant factor for consideration in the field of brain ischemia because the vast majority of cardiac arrest and stroke patients are elderly. In this review, we focus on the effects of aging on these critical proteostasis-related pathways in the brain, and discuss their implications in translational brain ischemia research.