Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
Biochim Biophys Acta Gen Subj. 2022 Aug;1866(8):130171. doi: 10.1016/j.bbagen.2022.130171. Epub 2022 May 16.
Reactive oxygen species (ROS) acts as a second messenger to trigger biological responses in low concentrations, while it is implicated to be toxic to biomolecules in high concentrations. Mild inhibition of respiratory chain Complex I by metformin at physiologically relevant concentrations stimulates production of low-level mitochondrial ROS. The ROS seems to induce anti-oxidative stress response via activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase (GPx), which results in not only elimination of ROS but also activation of cellular responses including resistance to apoptosis, metabolic changes, cell proliferation, senescence prevention, lifespan extension, and immune T cell activation against cancers, regardless of its effect controlling blood glucose level and T2DM. Although metformin's effect against T2DM, cancers, and ageing, are believed mostly attributed to the activation of AMP-activated protein kinase (AMPK), the cellular responses involving metformin-ROS-Nrf2 axis might be another natural asset to improve healthspan and lifespan.
活性氧（ROS）作为第二信使，在低浓度下触发生物反应，而在高浓度下则对生物分子有毒。二甲双胍在生理相关浓度下轻度抑制呼吸链复合物 I，刺激低水平线粒体 ROS 的产生。ROS 通过激活核因子红细胞 2 相关因子 2（Nrf2）和谷胱甘肽过氧化物酶（GPx）引起抗氧化应激反应，不仅消除了 ROS，还激活了包括抗细胞凋亡、代谢变化、细胞增殖、衰老预防、寿命延长和免疫 T 细胞激活等在内的细胞反应，而不管其控制血糖水平和 T2DM 的效果如何。尽管二甲双胍对 T2DM、癌症和衰老的作用主要归因于 AMP 激活蛋白激酶（AMPK）的激活，但涉及二甲双胍-ROS-Nrf2 轴的细胞反应可能是改善健康寿命和寿命的另一种天然资产。
