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

## TL;DR

3,5-Dicaffeoylquinic acid delays aging and improves stress resistance by activating the SKN-1/Nrf2 pathway in worms and human cells.

## Contribution

The study reveals that 3,5-diCQA activates the SKN-1/Nrf2 pathway by binding to Keap1, offering a novel mechanism for its anti-aging effects.

## Key findings

- 3,5-diCQA promotes SKN-1 nuclear translocation and upregulates downstream genes in C. elegans.
- 3,5-diCQA reduces ROS levels and delays senescence in MRC-5 cells via Nrf2 activation.
- Molecular docking shows 3,5-diCQA binds to Keap1, facilitating Nrf2 activation.

## 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.

3,5‐Dicaffeoylquinic acid promoted lifespan and stress tolerance capability of
C. elegans
in a skn‐1‐dependent manner. 3,5‐Dicaffeoylquinic acid reduced the ROS level and delayed senescence of MRC‐5 cells by activating Nrf2. 3,5‐Dicaffeoylquinic acid directly binded to the pocket of Kelch‐like epichlorohydrin‐associated protein 1 (Keap1) to facilitate Nrf2 activation.