3,5‐Dicaffeoylquinic Acid Delayed Aging and Promoted Oxidative Stress Tolerance via Activation of the SKN ‐1/Nrf2 Signaling Pathway

ABSTRACT 3,5‐Dicaffeoylquinic acid (3,5‐diCQA), as a plant‐derived polyphenol, exhibits multiple bioactivities, including anti‐inflammation, antioxidation, and anti‐diabetes. A previous report demonstrated that 3,5‐diCQA increased the lifespan and promoted the healthspan in Caenorhabditis elegans . Nevertheless, the molecular mechanisms underlying the function of 3,5‐diCQA remain to be further determined. In this study, 3,5‐diCQA promoted the transfer of SKN‐1 to nucleus and upregulated the expressions of its downstream genes. Moreover, 3,5‐diCQA enhanced oxidative stress tolerance and decreased ROS level in a skn‐1 ‐dependent manner. Consistently, 3,5‐diCQA remarkably reduced the ROS level and delayed senescence of MRC‐5 cells by activating Nrf2. Notably, molecular docking results revealed that 3,5‐diCQA was found to occupy the binding pocket of Keap 1 (Kelch‐like epichlorohydrin‐associated protein 1), a cytoplasmic repressor of Nrf2, thereby promoting Nrf2 activation. Overall, this study demonstrated that SKN‐1/Nrf2 signaling is essential for 3,5‐diCQA to exert its anti‐aging and stress resistance‐enhancing effects. Our findings elucidate novel mechanisms by which 3,5‐diCQA activates the SKN‐1/Nrf2 pathway, highlighting its promise as candidate for delaying aging and attenuating oxidative stress‐related disorders.