A novel anti‐aging compound extends longevity by altering the age‐related dynamics of reactive oxygen species

Caloric restriction (CR) extends longevity across species. Our high‐throughput chemical genetic screen identified lithocholic acid (LCA) as a novel anti‐aging drug that further increases the life span of yeast under CR by modulating the homeostasis of reactive oxygen species (ROS). We found that LCA 1) alters mitochondrial oxygen consumption, membrane potential, and ROS generation; 2) protects a subset of proteins and membrane lipids as well as nuclear and mitochondrial DNA from age‐related oxidative damage; 3) alters the proteome of aging yeast by increasing the levels of certain stress response proteins and ROS scavenging enzymes; and 4) enhances the resistance of aging yeast to oxidative and thermal stresses. Based on our findings, we propose a hypothesis on a dual role of mitochondrially produced ROS in regulating longevity. In our hypothesis, if mitochondria are unable (due to the absence of LCA) to maintain ROS concentration below a toxic threshold, ROS promote aging by oxidatively damaging cellular macromolecules. However, if mitochondria can (due to the presence of LCA) maintain ROS concentration at a certain “optimal” level, ROS delay aging by activating four signaling networks that extend life span by increasing the abundance of a compendium of anti‐aging proteins. Our analyses of how various mutations eliminating components of the mitochondrial respiratory chain, stress response proteins, and ROS scavenging enzymes influence the effect of LCA on ROS homeostasis and longevity support the proposed hypothesis. Supported by CIHR and NSERC of Canada.