Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species

Zhifan Mao; Wenwen Liu; Yunyuan Huang; Tianyue Sun; Keting Bao; Jiali Feng; Alexey Moskalev; Zelan Hu; Jian Li

Acta Pharmaceutica Sinica B (Feb 2022)

Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species

Zhifan Mao,
Wenwen Liu,
Yunyuan Huang,
Tianyue Sun,
Keting Bao,
Jiali Feng,
Alexey Moskalev,
Zelan Hu,
Jian Li

Affiliations

Zhifan Mao: State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China
Wenwen Liu: State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China
Yunyuan Huang: State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China
Tianyue Sun: State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China
Keting Bao: State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China
Jiali Feng: State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China
Alexey Moskalev: Laboratory of Geroprotective and Radioprotective Technologies, Institute of Biology, Komi Science Centre, Ural Branch, Russian Academy of Sciences, Syktyvkar 167982, Russia
Zelan Hu: State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China; Corresponding authors.
Jian Li: State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, East China University of Science and Technology, Shanghai 200237, China; Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, Dali 671000, China; Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China; Corresponding authors.

Journal volume & issue: Vol. 12, no. 2
pp. 665 – 677

Abstract

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Sulfonylureas are widely used oral anti-diabetic drugs. However, its long-term usage effects on patients’ lifespan remain controversial, with no reports of influence on animal longevity. Hence, the anti-aging effects of chlorpropamide along with glimepiride, glibenclamide, and tolbutamide were studied with special emphasis on the interaction of chlorpropamide with mitochondrial ATP-sensitive K+ (mitoK-ATP) channels and mitochondrial complex II. Chlorpropamide delayed aging in Caenorhabditis elegans, human lung fibroblast MRC-5 cells and reduced doxorubicin-induced senescence in both MRC-5 cells and mice. In addition, the mitochondrial membrane potential and ATP levels were significantly increased in chlorpropamide-treated worms, which is consistent with the function of its reported targets, mitoK-ATP channels. Increased levels of mitochondrial reactive oxygen species (mtROS) were observed in chlorpropamide-treated worms. Moreover, the lifespan extension by chlorpropamide required complex II and increased mtROS levels, indicating that chlorpropamide acts on complex II directly or indirectly via mitoK-ATP to increase the production of mtROS as a pro-longevity signal. This study provides mechanistic insight into the anti-aging effects of sulfonylureas in C. elegans.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/acta-pharmaceutica-sinica-b

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