Glibenclamide targets MDH2 to relieve aging phenotypes through metabolism-regulated epigenetic modification.

Zhifan Mao, Wenwen Liu, Rong Zou, Ling Sun, Shuman Huang, Lingyu Wu, Liru Chen, Jiale Wu, Shijie Lu, Zhouzhi Song, Xie Li, Yunyuan Huang, Yong Rao, Yi-You Huang, Baoli Li, Zelan Hu, Jian Li

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.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. · pubmed

Paper

Abstract

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

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Research summary

Glibenclamide inhibits MDH2 activity to relieve fibroblast senescence and extend lifespan in aged mice. The study addresses a potential mechanism of aging through mitochondrial metabolism and epigenetic modification, which is directly related to the root causes of aging.

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