Fig. 7

Model for proteostasis control by the ISR. Different pathologies may have distinct hormetic set points that relate to phenotypic fitness, such as cognition and behavior. As considered here, either reduced or increased ISR activation can be maladaptive. Therefore, depending on the disease or pathology and the optimal hormetic 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 optimal homeostatic cell fitness. Costa-Mattioli and Walter, 2020, p. 7, [106]. "Reprinted from Science. 2020 Apr 24; 368(6489). Costa-Mattioli M, Walter P. The integrated stress response: From mechanism to disease. p. 7, 2018, with permission from the American Association for the Advancement of Science via STM guidelines."