College of Traditional Chinese Medicine, College of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
National Key Laboratory of Luobing Research and Innovative Chinese Medicine, Shijiazhuang 050035, China; Key Laboratory of State Administration of TCM (Cardio-Cerebral Vessel Collateral Disease), Shijiazhuang 050035, China.
Biomed Pharmacother. 2023 Apr;160:114384. doi: 10.1016/j.biopha.2023.114384. Epub 2023 Feb 8.
Bazi Bushen (BZBS), a traditional Chinese medicine, has been proven effective in the treatment of age-related disease in mouse models. However, whether its therapeutic effects are due to antiaging mechanism has not yet been explored. In the present study, we investigated the antiaging effects of BZBS in naturally aging mice by using behavioral tests, liver DNA methylome sequencing, methylation age estimation, and frailty index assessment. The methylome analysis revealed a decrease of mCpG levels in the aged mouse liver. BZBS treatment tended to restore age-associated methylation decline and prune the methylation pattern toward that of young mice. More importantly, BZBS significantly rejuvenated methylation age of the aged mice, which was computed by an upgraded DNA methylation clock. These results were consistent with enhanced memory and muscular endurance, as well as decreased frailty score and liver pathological changes. KEGG analysis together with aging-related database screening identified methylation-targeted pathways upon BZBS treatment, including oxidative stress, DNA repair, MAPK signaling, and inflammation. Upregulation of key effectors and their downstream effects on elevating Sod2 expression and diminishing DNA damage were further investigated. Finally, in vitro experiments with senescent HUVECs proved a direct effect of BZBS extracts on the regulation of methylation enzymes during cellular aging. In summary, our work has revealed for the first time the antiaging effects of BZBS by slowing the methylation aging. These results suggest that BZBS might have great potential to extend healthspan and also explored the mechanism of BZBS action in the treatment of age-related diseases.
八子补肾（BZBS），一种中药，已被证明在治疗小鼠模型中的与年龄相关的疾病方面有效。然而，其治疗效果是否归因于抗衰老机制尚未得到探索。在本研究中，我们通过行为测试、肝 DNA 甲基组测序、甲基化年龄估计和脆弱性指数评估，研究了 BZBS 在自然衰老小鼠中的抗衰老作用。甲基组分析显示，衰老小鼠肝中 mCpG 水平降低。BZBS 处理倾向于恢复与年龄相关的甲基化下降，并将甲基化模式修整为年轻小鼠的模式。更重要的是，BZBS 显著使衰老小鼠的甲基化年龄年轻化，这是通过升级的 DNA 甲基化时钟计算得出的。这些结果与增强记忆和肌肉耐力、降低脆弱性评分和肝脏病理变化一致。KEGG 分析和与衰老相关的数据库筛选确定了 BZBS 处理后靶向甲基化的途径，包括氧化应激、DNA 修复、MAPK 信号和炎症。进一步研究了上调关键效应物及其对提高 Sod2 表达和减少 DNA 损伤的下游作用。最后，用衰老的 HUVECs 进行的体外实验证明了 BZBS 提取物对细胞衰老过程中甲基化酶调节的直接作用。总之，我们的工作首次揭示了 BZBS 通过减缓甲基化衰老来实现抗衰老作用。这些结果表明，BZBS 可能具有很大的潜力来延长健康寿命，并探索了 BZBS 在治疗与年龄相关的疾病中的作用机制。
