Chlorogenic Acid Activates Nrf2/SKN-1 and Prolongs the Lifespan of Caenorhabditis elegans via the Akt-FOXO3/DAF16a-DDB1 Pathway and Activation of DAF16f.

Chlorogenic acid (CGA) is the most abundant polyphenol in coffee. It has been widely reported to exhibit antioxidant activity by activating nuclear factor erythroid 2-related factor 2 (Nrf2) potentially via the canonical Kelch-like-ECH-associated protein 1 (Keap1)-Nrf2 pathway. We herein demonstrated that the knockdown of WD40 repeat protein 23 (WDR23), but not Keap1, abolished the effects of CGA on the activation of Nrf2. CGA decreased the expression of DDB1, an adaptor for WDR23-Cullin 4A-RING ligase (CRL4AWDR23). FOXO3, a major target for inactivation by the PI3K/Akt pathway, was identified as the transcription factor responsible for the basal and CGA-inhibited expression of the DDB1 gene. CGA blocked FOXO3 binding to importin-7 (IPO7), thereby inhibiting the nuclear accumulation of FOXO3, down-regulating the expression of DDB1, inhibiting the activity of CRL4WDR23, and ultimately increasing that of Nrf2. This pathway was conserved in Caenorhabditis elegans, and CGA extended the lifespan partly through this pathway. We found that in C. elegans, the isoform DAF-16a, but not DAF-16f, regulated the expression levels of ddb-1 mRNA and SKN-1 protein. CGA prolonged the mean lifespan of DAF-16a- and DAF-16f-rescued worms by 24% and 9%, respectively, suggesting that both isoforms involve in lifespan-extending effects of CGA, with DAF-16a being more important than DAF-16f. Based on these results, we established a novel Akt-FOXO3/DAF16a-DDB1 axis that links nutrient sensing and oxidative stress response pathways. Our results also provide a novel molecular mechanism for Nrf2/SKN-1 activation by CGA and the increased lifespan of C. elegans by CGA via this pathway.