Different pathologies may have distinct homeostatic set points that relate to phenotypic fitness, such as cognition. As considered here, either reduced or increased ISR activation can be maladaptive. Therefore, depending on the disease or pathology and the optimal homeostatic set point for a particular phenotype, activation of the ISR (e.g., with sephin1) or inhibition of the ISR (e.g., with ISRIB) would restore homeostasis to optimal cell fitness.