2-Methoxystypandrone from Polygonum cuspidatum Rejuvenates Senescence by Reducing Mitochondrial ROS

Oxidative stress induced by reactive oxygen species (ROS) is a major contributor to senescence. Although strategies to mitigate ROS are considered crucial for reversing this process, effective interventions remain limited. Extracts from Polygonum cuspidatum (P. cuspidatum) have shown protective effects against senescence by suppressing mitochondrial ROS production; however, the specific bioactive compound responsible for these effects has not yet been identified. This study aimed to identify the active compound in P. cuspidatum responsible for reducing mitochondrial ROS and to elucidate its mechanism of action in rejuvenating senescence. Bioactive components of P. cuspidatum extract were screened for their ability to decrease mitochondrial ROS production. The most potent compound, 2-methoxystypandrone (2-MS), was further examined for its effects on oxidative phosphorylation (OXPHOS) efficiency, mitochondrial ROS generation, and senescence-associated phenotypes in a skin cell-based model. 2-MS was identified as the most effective compound for reducing mitochondrial ROS. Mechanistically, 2-MS enhanced OXPHOS efficiency, thereby minimizing ROS production resulting from inefficient respiration. Reduction in mitochondrial ROS by 2-MS restored senescence-associated phenotypes and rejuvenated senescence by suppressing ROS-driven melanogenesis and inflammatory responses in skin cells. This study identifies 2-MS as a key active ingredient of P. cuspidatum that exerts anti-aging effects through the reduction in mitochondrial ROS generation. These findings highlight 2-MS as a promising therapeutic and cosmetic candidate for rejuvenating senescence.