Sestrin2 Attenuates Cellular Senescence by Inhibiting NADPH Oxidase 4 Expression

• Main Authors: Chae Young Hwang, Ying-Hao Han, Seung-Min Lee, Sang-Mi Cho, Dae-Yeul Yu, Ki-Sun Kwon
• Format: Article
• Language: English
• Published: Korea Geriatrics Society 2020-12-01
• Series: Annals of Geriatric Medicine and Research
• Subjects: nox4; reactive oxygen species; senescence; sestrin2
• Online Access: http://www.e-agmr.org/upload/pdf/agmr-20-0051.pdf

Background Sestrin2 (Sesn2) is involved in the maintenance of metabolic homeostasis and aging via modulation of the 5' AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway. Methods Wild-type and Sesn2 knockout (KO) mice of the 129/SvJ background were maintained in a pathogen-free authorized facility under a 12-hour dark/light cycle at 20°C–22°C and 50%–60% humidity. Mouse embryonic fibroblasts (MEFs) were prepared from 13.5-day-old embryos derived from Sesn2-KO mice mated with each other. Results The MEFs from Sesn2-KO mice showed enlarged and flattened morphologies and senescence-associated β-galactosidase activity, accompanied by an elevated level of reactive oxygen species. These senescence phenotypes recovered following treatment with N-acetyl-cysteine. Notably, the mRNA levels of NADPH oxidase 4 (NOX4) and transforming growth factor (TGF)-β were markedly increased in Sesn2-KO MEFs. Treatment of Sesn2-KO MEFs with the NOX inhibitor diphenyleneiodonium and the TGF-β inhibitor SB431542 restored cell growth inhibited by Sesn2-KO. Conclusion Sesn2 attenuates cellular senescence via suppression of TGF-β- and NOX4-induced reactive oxygen species generation and subsequent inhibition of AMPK.