ε-Viniferin Rejuvenates Senescence via RGS16 Regulation: In Vitro Evidence

Background: Reactive oxygen species (ROS) generated due to mitochondrial dysfunction are one of the primary causes of the initiation and progression of senescence. Although reducing mitochondrial ROS production is known as an effective strategy for the treatment of aging, effective components that reduce mitochondrial ROS production or effective treatments that utilize them have not yet been developed. Methods: Screening of plant-generated secondary metabolites to overcome ROS-mediated stress found that ε-viniferin, a dimer of resveratrol, effectively reduces mitochondrial ROS production. Results: ε-viniferin induced efficient electron transport and reduced mitochondrial ROS, a consequence of inefficient electron transport. In addition, ε-viniferin acted as a senolytic that selectively eliminates senescent fibroblasts, thereby restoring mitochondrial function and senescence-associated phenotypes. RNA sequencing analysis revealed that regulator of G protein signaling 16 (RGS16) was an important gene for ε-viniferin-mediated senescence rejuvenation. Upregulation of RGS16 showed similar effects as ε-viniferin in reducing mitochondrial ROS production and restoring mitochondrial function. Conclusions: This study discovered a novel mechanism by which ε-viniferin rejuvenates senescence by lowering ROS production in mitochondria. The novel mechanism will serve as a basis for developing therapeutics that regulate mitochondrial ROS production to treat aging.