title: Benzimidazole derivative M084 extends the lifespan of Caenorhabditis elegans in a DAF-16/FOXO-dependent way.
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.
authors.affiliation: 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.|University of Chinese Academy of Sciences, Beijing, 100039, China.
authors.forename: Ai-Jun
authors.initials: AJ
authors.lastname: Ding
authors.affiliation: 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.|School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China.
authors.forename: Gui-Sheng
authors.initials: GS
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Tang
authors.affiliation: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, Hubei, China.
authors.forename: Xuechuan
authors.initials: X
authors.lastname: Hong
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
authors.forename: Michael X
authors.initials: MX
authors.lastname: Zhu
authors.affiliation: 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. luohuairong@mail.kib.ac.cn.|School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, China. luohuairong@mail.kib.ac.cn.
authors.forename: Huai-Rong
authors.identifier: http://orcid.org/0000-0001-8912-6694
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000187:drug effects* / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D024101:Mitochondrial Proteins; C108831:daf-16 protein, C elegans
keywords: Aging; Benzimidazole derivative M084; Caenorhabditis elegans; Lifespan