The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging
Figure 7.The oxidative stress-Chronic stress cycle of aging. Integration of the Role of the ASK1-Signalosome in ROS-Mediated Regulation of the p38 MAPK Pathway and Physiological Characteristics of Aging.  ROS generated by mitochondrial dysfunction;  the ASK1-signalosome responds to changes in levels of oxidative stress (ROS);  (SH)2Trx complexes with ASK1 to form (SH)2Trx-ASK1 complex, a component of the inASK1-signalosome;  the (SH)2Trx-ASK1 complex (inASK1-siganlosome) inhibits p38 MAPK activity; (5 → 7) inhibition of p38 MAPK activity attenuates stress response gene expression and favors expression of longevity assurance genes. This is the predominating pathway of the long-lived Klotho overexpressing, Snell and Ames mice that favors resistance to oxidative stress.  Klotho ablation causes increased endogenous ROS, dissociation of the (SH)2Trx-ASK1 complex to form the actASK1-signalosome.  ASK1 activates the p38 MAPK pathway and  p38 targeted genes that promote aging. (8 → 12) This is the predominant pathway of Klotho (-/-) that promotes accelerated aging and sensitivity to oxidative stress;  The activation and nuclear localization of Nrf2 in the Klotho overexpressing mice and decreased Nrf2 activity in Klotho(-/-).