Extension of lifespan in C. elegans by naphthoquinones that act through stress hormesis mechanisms

Piper R. Hunt, Tae Gen Son, Mark A. Wilson, Quian Sheng Yu, William H. Wood, Yongqing Zhang, Kevin G. Becker, Nigel H. Greig, Mark P. Mattson, Simonetta Camandola, Catherine A. Wolkow

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere21922
JournalPLoS One
Volume6
Issue number7
DOIs
StatePublished - 2011
Externally publishedYes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Hunt, P. R., Son, T. G., Wilson, M. A., Yu, Q. S., Wood, W. H., Zhang, Y., Becker, K. G., Greig, N. H., Mattson, M. P., Camandola, S., & Wolkow, C. A. (2011). Extension of lifespan in C. elegans by naphthoquinones that act through stress hormesis mechanisms. PLoS One, 6(7), [e21922]. https://doi.org/10.1371/journal.pone.0021922