Lifespan extension of Caenorhabditis elegans by sulforafane: Sulforafane induces Nrf2 (cSKN-1) via WDR23, but not keap1

Abstract Sulforaphane (SFN) derived from broccoli sprouts reduces oxidative stress by activating Nrf2, a key factor in cellular defenses against oxidative stress. In the present study, the lifespan-extending effects of SFN were investigated using Caenorhabditis elegans as a model organism. SFN induces SKN-1 (Nrf2 homolog) in C. elegans. SFN is also considered to induce Nrf2 by inactivating Keap1, a regulator of Nrf2; however, C. elegans has no Keap1 homolog. We previously showed that WDR23 regulated Nrf2 expression in mammals through a pathway independent of Keap1, which is also present in C. elegans. We herein focused on the Akt-FOXO-WDR23 ubiquitin ligase complex. We used Hep3B and A549 cells, which have wild-type and mutated Keap1, respectively. In both cells, SFN induced Nrf2 by reducing DDB1, a component of the WDR complex. DDB1 expression is regulated by the transcription factor FOXO3, and FOXO3 was phosphorylated and exported from the nucleus when SFN was added to both cells. In addition, we found that SFN did not expand the lifespan of skn-1 or daf-16 (FOXO3 homolog) mutant C. elegans, indicating that SFN induced Nrf2 in a Keap1-independent manner and that a novel mechanism is responsible for the lifespan extension of C. elegans.