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Benzimidazole derivative M084 extends the lifespan of Caenorhabditis elegans in a DAF-16/FOXO-dependent way

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Abstract

With the growth of aging population, there is increasing demand to develop strategy to improve the aging process and aging-related diseases. Benzimidazole and its derivatives are crucial heterocyclic backbone of many drugs and compounds with diverse therapeutic applications, including alleviation of aging-related diseases. Here, we investigate if the benzimidazole derivative n-butyl-[1H]-benzimidazol-2-amine (M084), a novel inhibitor of TRPC4 and TRPC5 channels and antidepressant, could affect the lifespan of Caenorhabditis elegans (C. elegans). Our results showed that M084 could extend the lifespan of C. elegans, delay age-related decline of phenotypes, and improve stress resistance. M084 could not extend the lifespan of the loss-of-function mutants of daf-16, daf-2, pdk-1, aak-2, clk-1, isp-1, sir-2.1, and skn-1. M084 could decrease the ATP level and increase the gene expression of mitochondrial unfolded protein response factors. Thus, M084 might inhibit the mitochondrial respiration, activate mitochondrial unfolded protein response and AMPK, recruite SIR-2.1 and SKN-1, and finally through the transcription factor DAF-16, delay the aging process of C. elegans. Our findings reveal the new pharmaceutical potential of benzimidazole derivatives and provide clue for developing novel anti-aging agents.

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Acknowledgements

C. elegans strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was partially supported by the Natural Science Foundation of China (Grant Nos. 81671405 and 81370453) and Natural Science Foundation of Yunnan province (Grant Nos. 2013FA045 and 2015FB172).

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Authors and Affiliations

  1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, Yunnan, China

    Ai-Jun Ding, Gui-Sheng Wu & Huai-Rong Luo

  2. University of Chinese Academy of Sciences, Beijing, 100039, China

    Ai-Jun Ding

  3. School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China

    Gui-Sheng Wu, Bin Tang & Huai-Rong Luo

  4. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, Hubei, China

    Xuechuan Hong

  5. Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

    Michael X. Zhu

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  1. Ai-Jun Ding
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Correspondence to Huai-Rong Luo.

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Ding, AJ., Wu, GS., Tang, B. et al. Benzimidazole derivative M084 extends the lifespan of Caenorhabditis elegans in a DAF-16/FOXO-dependent way. Mol Cell Biochem 426, 101–109 (2017). https://doi.org/10.1007/s11010-016-2884-x

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