Oxidative Stress and Antiaging Medicine: Nrf2 Signaling and Antiaging

Nuclear factor erythroid 2-related factor 2 (Nrf2) binds to the antioxidant response element (ARE), a gene expression control sequence, and uniformly controls the gene expression of the second phase detoxification enzymes, antioxidant enzymes, and the biosynthesis pathways of antioxidants [1]. Its activity is mainly regulated tissue-specifically by Nrf2 protein degradation and synthesis (mRNA and protein). The control of Nrf2 protein degradation involves the Keap1 (Kelch-like ECH-associated protein 1)/Cul3 (Cullin 3) system and the ubiquitin-proteasome control system mediated by GSK3β (glycogen synthase kinase 3 β)-SCF (Skp1-Cullin1-F-box protein) βTRCP (Fig. 32.1). Various electrophilic substances and reactive oxygen species/nitrogen species oxidatively modify the reactive cysteine of Keap1, thereby changing the conformation of Keap1 and inhibiting the degradation activity of Nrf2 by the Keap1/Cul3 system. The activation of Nrf2 by growth factors such as insulin-like growth factor 1 (IGF-1) is thought to be due to the inhibition of Nrf2 degradation by GSK3β-SCFβTRCP. In addition, Nrf2 gene expression is positively regulated by myocyte enhancer factor 2 (MEF2) [2] and positive feedback by Nrf2 itself [3]. The autophagy factor p62 is also a target gene of Nrf2, but p62 has an STGE motif similar to the ETGE motif, which is a Keap1 binding motif [4]. When the serine in the STGE motif is phosphorylated under autophagy induction, the STGE motif strongly competes with the binding of Nrf2 and Keap1, activating Nrf2. Phosphorylation of the STGE motif has been reported to be involved in the basal expression of Nrf2 mediated by TGF-β activated kinase 1 (TAK1) in the small intestinal epithelium and the activation of Nrf2 in white muscle [5, 6].