Chikusetsu saponin IVa (CHS) is an essential active triterpenoid saponin found in various medicinal herbs, such as Aralia taibaiensis, Panax japonicus, and Aralia elata. While multiple health benefits have been documented, the effect of CHS on aging remains unclear. By employing the D-galactose-induced aging mice and the replicative senescence of primary mouse embryonic fibroblasts (MEFs) as the aging models, we found that CHS significantly attenuated aging both in vitro and in vivo. RNA sequencing analysis revealed that CHS greatly improved autophagy and mitophagy. Corresponding to the improved mitophagy, CHS remarkably reduced mitochondrial ROS and enhanced mitochondrial respiratory function. Mitophagy inhibition and Atg 7 genetic knockout (KO) almost abolished the anti-aging effect of CHS. AMPK pathway was activated during the attenuation of aging by CHS treatment, and a specific AMPK inhibitor reversed the induction of mitophagy and autophagy, as well as the attenuation of aging by CHS. Molecular docking data indicated AMPK as the direct binding target of CHS. In conclusion, our study initially demonstrates that CHS exhibits a potent anti-aging effect both in vitro and in vivo. CHS may directly bind to AMPK and activate the AMPK-dependent pathway to enhance autophagy and mitophagy, thereby reducing mitochondrial ROS and improving mitochondrial respiratory function, contributing to the anti-aging effect. These findings offer a new clue for the promising application of CHS in the improvement of aging and aging-related diseases in the future.
