Synergistic ROS Reduction Through the Co-Inhibition of BRAF and p38 MAPK Ameliorates Senescence

Reactive oxygen species (ROS)-mediated damage to macromolecules and cellular organelles is one of the major causes of senescence. Therapeutic strategies that lower ROS levels have been proposed as important treatments for senescence, but effective mechanisms for reducing ROS levels have not been discovered. Here, we aimed to find a combination that has a synergistic effect on ROS reduction using senomorphics known to reduce ROS. Combination treatment with BRAF inhibitor SB590885 and p38 MAPK inhibitor SB203580 showed a synergistic effect on ROS reduction compared to treatment with either drug alone. The synergistic effect of ROS reduction through this combination led to a synergistic effect that restored mitochondrial function and ameliorated senescence-associated phenotypes. To elucidate the underlying mechanism by which the synergistic effect of the two drugs reverses senescence, we performed RNA sequencing and identified <i>metallothionein 2A</i> (<i>MT2A</i>) as a key gene. <i>MT2A</i> was upregulated in response to combination therapy, and overexpression of <i>MT2A</i> led to a decrease in ROS and subsequent recovery of senescence-associated phenotypes, similar to the effects of combination therapy. Taken together, we found a drug combination that showed synergistic effects on ROS reduction, which contributed to the recovery of senescence-associated phenotypes through <i>MT2A</i> gene regulation. This study opens up a new avenue in aging research by demonstrating that combination therapy with existing senomorphics can enhance the ability to reverse senescence and that similar reversal effects can be achieved through gene regulation regulated by combination therapy.