Mao Zhifan, Liu Wenwen, Zou Rong, Sun Ling, Huang Shuman, Wu Lingyu, Chen Liru, Wu Jiale, Lu Shijie, Song Zhouzhi, Li Xie, Huang Yunyuan, Rao Yong, Huang Yi-You, Li Baoli, Hu Zelan, Li Jian
State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materialbiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan, Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
Signal Transduct Target Ther. 2025 Feb 17;10(1):67. doi: 10.1038/s41392-025-02157-3.
Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention. Mitochondrial malate dehydrogenase (MDH2), an enzyme in the TCA cycle, was identified as an anti-aging target through activity-based protein profiling in present study. The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts. Glibenclamide (Gli), a classic anti-glycemic drug, was found to inhibit the activity of MDH2 and relieve fibroblast senescence in an MDH2-dependent manner. The anti-aging effects of Gli were also further validated in vivo, as it extended the lifespan and reduced the frailty index of naturally aged mice. Liver specific Mdh2 knockdown eliminated Gli's beneficial effects in naturally aged mice, reducing p16 expression and hepatic fibrosis. Mechanistically, MDH2 inhibition or knockdown disrupted central carbon metabolism, then enhanced the methionine cycle flux, and subsequently promoted histone methylation. Notably, the tri-methylation of H3K27, identified as a crucial methylation site in reversing cellular senescence, was significantly elevated in hepatic tissues of naturally aged mice with Mdh2 knockdown. Taken together, these findings reveal that MDH2 inhibition or knockdown delays the aging process through metabolic-epigenetic regulation. Our research not only identified MDH2 as a potential therapeutic target and Gli as a lead compound for anti-aging drug development, but also shed light on the intricate interplay of metabolism and epigenetic modifications in aging.
线粒体代谢调节的表观遗传修饰是衰老的驱动力，也是治疗干预的一个有前景的靶点。线粒体苹果酸脱氢酶（MDH2）是三羧酸循环中的一种酶，在本研究中通过基于活性的蛋白质谱分析被确定为抗衰老靶点。在Mdh2基因敲低或过表达的成纤维细胞中，MDH2的表达水平与细胞衰老呈正相关。格列本脲（Gli）是一种经典的抗糖尿病药物，被发现以MDH2依赖的方式抑制MDH2的活性并减轻成纤维细胞衰老。Gli的抗衰老作用也在体内得到进一步验证，因为它延长了自然衰老小鼠的寿命并降低了虚弱指数。肝脏特异性Mdh2基因敲低消除了Gli对自然衰老小鼠的有益作用，降低了p16的表达和肝纤维化。机制上，MDH2抑制或基因敲低破坏了中心碳代谢，进而增强了甲硫氨酸循环通量，随后促进了组蛋白甲基化。值得注意的是，H3K27的三甲基化被确定为逆转细胞衰老的关键甲基化位点，在Mdh2基因敲低的自然衰老小鼠的肝组织中显著升高。综上所述，这些发现表明MDH2抑制或基因敲低通过代谢-表观遗传调节延缓了衰老过程。我们的研究不仅确定MDH2为潜在的治疗靶点，Gli为抗衰老药物开发的先导化合物，还揭示了衰老过程中代谢与表观遗传修饰之间的复杂相互作用。
