MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
J Proteome Res. 2022 Jul 1;21(7):1759-1770. doi: 10.1021/acs.jproteome.2c00167. Epub 2022 Jun 14.
Altered adaptive homeostasis contributes to aging and lifespan regulation. In the present study, to characterize the mechanism of aging in mouse liver, we performed quantitative proteomics and found that the most upregulated proteins were related to the oxidation-reduction process. Further analysis revealed that malondialdehyde (MDA) and protein carbonyl (PCO) levels were increased, while nuclear Nrf2 and downstream genes were significantly increased, indicating that oxidative stress induced Nrf2 activation in aged mouse liver. Importantly, nicotinamide mononucleotide (NMN) administration decreased the oxidative stress and the nuclear Nrf2 and Nrf2 downstream gene levels. Indeed, aged mice treated with NMN improved stress resistance against acetaminophen (APAP)-induced liver injury, indicating that NMN restored Nrf2-mediated adaptive homeostasis. Further studies found that NMN increased Sirt3 activities to deacetylate age-associated acetylation at K68 and K122 in Sod2, while its effects on nuclear Nrf2 levels were diminished in Sirt3-deficient mice, suggesting that NMN-enhanced adaptive homeostasis was Sirt3-dependent. Taken together, we demonstrated that Nrf2-regulated adaptive homeostasis was decreased in aged mouse liver and NMN supplementation restored liver redox homeostasis via the Sirt3-Nrf2 axis and protected aged liver from oxidative stress-induced injury.
改变的适应性稳态有助于衰老和寿命调节。在本研究中，为了研究小鼠肝脏衰老的机制，我们进行了定量蛋白质组学研究，发现上调最明显的蛋白质与氧化还原过程有关。进一步分析表明，丙二醛（MDA）和蛋白羰基（PCO）水平升高，而核 Nrf2 和下游基因显著增加，表明氧化应激诱导了衰老小鼠肝脏中 Nrf2 的激活。重要的是，烟酰胺单核苷酸（NMN）的给药降低了氧化应激和核 Nrf2 及 Nrf2 下游基因的水平。事实上，用 NMN 处理的老年小鼠增强了对乙酰氨基酚（APAP）诱导的肝损伤的应激抵抗能力，表明 NMN 恢复了 Nrf2 介导的适应性稳态。进一步的研究发现，NMN 增加了 Sirt3 的活性，使 Sod2 中与年龄相关的 K68 和 K122 乙酰化去乙酰化，而在 Sirt3 缺陷型小鼠中，其对核 Nrf2 水平的影响减弱，表明 NMN 增强的适应性稳态是依赖于 Sirt3 的。总之，我们证明了衰老小鼠肝脏中 Nrf2 调节的适应性稳态降低，NMN 通过 Sirt3-Nrf2 轴补充恢复肝脏氧化还原稳态，并保护衰老肝脏免受氧化应激诱导的损伤。
