Research Paper Volume 2, Issue 9 pp 597—611

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. [1] ROS generated by mitochondrial dysfunction; [2] the ASK1-signalosome responds to changes in levels of oxidative stress (ROS); [3] (SH)₂Trx complexes with ASK1 to form (SH)₂Trx-ASK1 complex, a component of the inASK1-signalosome; [4] 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. [8] Klotho ablation causes increased endogenous ROS, dissociation of the (SH)₂Trx-ASK1 complex to form the actASK1-signalosome. [9] ASK1 activates the p38 MAPK pathway and [10] p38 targeted genes that promote aging. (8 → 12) This is the predominant pathway of Klotho ^(-/-) that promotes accelerated aging and sensitivity to oxidative stress; [13] The activation and nuclear localization of Nrf2 in the Klotho overexpressing mice and decreased Nrf2 activity in Klotho^(-/-).