Aging-related cognitive disorders have been increasingly linked to maladaptive stress pathways that persistently impair synaptic protein synthesis and plasticity. The integrated stress response (ISR) links various stressors to downstream translational reprogramming through the phosphorylation of eIF2α. Acute ISR activation can be protective, while chronic ISR activation may confine neurons and glial cells to hypo-plastic states, impairing learning and memory function. ISRIB is a prototype small molecule that activates eIF2B and restores translation homeostasis, providing a viable framework for “tuning” ISR output rather than indiscriminately blocking stress signaling. This review summarizes ISR biology in the aging brain, emphasizes cell-type heterogeneity, and evaluates the evidence for ISRIB across various conditions, including normal aging, Alzheimer’s disease, vascular cognitive impairment, synucleinopathies, perioperative neurocognitive disorders, and related conditions with shared ISR pathology. We then discuss dosing, safety, optimization, limitations, translational biomarkers, and lessons from emerging clinical-stage eIF2B activators. Finally, we propose precision and combination strategies to tailor ISR modulation to disease stage, pathological context, and therapeutic window, aiming to provide new directions and a theoretical basis for the treatment of aging-related cognitive disorders. • Reframes aging-related cognitive decline as potentially reversible dysfunction driven by chronic ISR-linked translational braking. • Positions ISRIB as the prototype for pharmacological eIF2B activation in the CNS. • Integrates cross-disease evidence, emphasizing cell-type context as key determinants of ISRIB efficacy. • Outlines biomarkers, safety risks, and trial lessons for next-generation eIF2B activators. • Proposes precision stratification and rational combination strategies to align ISR modulation with disease stage and biology.
Zhu et al. (Fri,) studied this question.