title: Extension of lifespan in C. elegans by naphthoquinones that act through stress hormesis mechanisms.
abstract: Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap'n'collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Piper R
authors.initials: PR
authors.lastname: Hunt
authors.forename: Tae Gen
authors.initials: TG
authors.lastname: Son
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.forename: Quian-Sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: William H
authors.initials: WH
authors.lastname: Wood
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Simonetta
authors.initials: S
authors.lastname: Camandola
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Wolkow
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D015374:Biosensing Techniques; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008136:Longevity / Q000187:drug effects*; D009154:Mutation / Q000235:genetics; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects*; D016019:Survival Analysis; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology; D014118:Toxins, Biological / Q000737:chemistry / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D024483:Vitamin K 3 / Q000737:chemistry / Q000494:pharmacology
chemical_list: D029742:Caenorhabditis elegans Proteins; D009285:Naphthoquinones; D013764:Tetrahydronaphthalenes; D014118:Toxins, Biological; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; C003020:oxoline; C005503:naphthazarin; D024483:Vitamin K 3; C014758:plumbagin