Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, School of Medical Technology, Xinxiang Medical University, Xinxiang 453003, China.
School of Public Health, Xinxiang Medical University, Xinxiang 453003, China.
Int Immunopharmacol. 2024 Aug 20;137:112468. doi: 10.1016/j.intimp.2024.112468. Epub 2024 Jun 20.
Prolonged or excessive oxidative stress can lead to premature cellular and body aging. Mannan-binding lectin (MBL) is synthesized by the liver and plays an important role in innate immunity, anti-inflammation, and anti-oxidation, and has a positive impact on health and longevity. To date, few studies investigated the role of MBL in attenuating oxidative stress-induced senescence. In this study, we evaluated the role of MBL in oxidative stress-induced premature aging and explored its underlying mechanism in C57BL/6 mice and mouse embryonic fibroblasts (NIH/3T3). First, we established an oxidative premature senescence model induced by D-galactose in C57BL/6 mice. We found that MBL-deficient mice had a marked aging-like appearance, reduced learning and spatial exploration abilities, severe liver pathological damage, and significantly upregulated expression of Senescence-associated proteins (p53 and p21), inflammatory kinesins (IL-1β and IL-6), and the senescence β-galactosidase (SA-β-Gal) positive rate as compared with WT mice. In the HO-induced oxidative senescence model of NIH/3T3 cells, consistent results were obtained after MBL intervention. In addition, MBL effectively inhibited G1 phase arrest, ROS levels, DNA damage, and mitochondrial dysfunction in premature senescent cells. Mechanistically, we found that oxidative stress inhibited the nicotinamide adenine dinucleotide (NAD+)/ silent information regulator 1 (Sirt1) signaling pathway, while MBL activated the NAD+/Sirt1 signaling pathway inhibited by oxidative stress. In addition, MBL could activate the NAD+/Sirt1 pathway by upregulating NAMPT, which in turn inhibited p38 phosphorylation by activating the NAD+/Sirt1 pathway. In conclusion, MBL inhibits oxidative aging, which may facilitate the development of therapeutics to delay oxidative aging.
长期或过度的氧化应激可导致细胞和机体过早衰老。甘露聚糖结合凝集素（MBL）由肝脏合成，在先天免疫、抗炎和抗氧化中发挥重要作用，对健康和长寿有积极影响。迄今为止，很少有研究探讨 MBL 在减轻氧化应激诱导的衰老中的作用。在本研究中，我们评估了 MBL 在氧化应激诱导的过早衰老中的作用，并探讨了其在 C57BL/6 小鼠和小鼠胚胎成纤维细胞（NIH/3T3）中的潜在机制。首先，我们建立了 D-半乳糖诱导的 C57BL/6 小鼠氧化应激性过早衰老模型。我们发现，MBL 缺陷小鼠表现出明显的衰老样外观，学习和空间探索能力下降，肝病理损伤严重，衰老相关蛋白（p53 和 p21）、炎症因子（IL-1β 和 IL-6）表达显著上调，衰老β-半乳糖苷酶（SA-β-Gal）阳性率明显升高。在 HO 诱导的 NIH/3T3 细胞氧化衰老模型中，MBL 干预后也得到了一致的结果。此外，MBL 可有效抑制早发性衰老细胞的 G1 期阻滞、ROS 水平、DNA 损伤和线粒体功能障碍。在机制上，我们发现氧化应激抑制了烟酰胺腺嘌呤二核苷酸（NAD+）/沉默信息调节因子 1（Sirt1）信号通路，而 MBL 激活了氧化应激抑制的 NAD+/Sirt1 信号通路。此外，MBL 可通过上调 NAMPT 激活 NAD+/Sirt1 通路，进而通过激活 NAD+/Sirt1 通路抑制 p38 磷酸化。综上所述，MBL 抑制氧化衰老，可能有助于开发延缓氧化衰老的治疗方法。
