A novel approach to high‐throughput discovery of anti‐aging drugs identifies lithocholic acid as a longevity‐extending compound

Abstract

Caloric restriction (CR) and dietary restriction (DR) extend life span across species and improve health by delaying the onset of age‐related diseases. All currently known anti‐aging drugs: 1) mimic numerous life‐extending and health‐improving effects of CR and DR without restricting caloric and nutrient intake; and 2) target two signaling pathways that are under the stringent control of calorie and/or nutrient availability. It was believed therefore that all longevity pathways are “adaptable” by nature because they modulate longevity only in response to certain changes in the extracellular and intracellular nutrient and energy status of an organism. However, it is possible that that some longevity pathways could be “constitutive” or “housekeeping” because they control longevity irrespective of calorie and/or nutrient availability. We designed a novel high‐throughput chemical genetic screen for drugs that increase the life span of yeast under CR by modulating such housekeeping longevity pathways and targeting lipid metabolism. Our screen identified lithocholic acid as one of such molecules. We revealed that this bile acid delays aging by suppressing lipid‐induced necrosis, attenuating mitochondrial fragmentation, altering oxidation‐reduction processes in mitochondria, enhancing resistance to oxidative and thermal stresses, suppressing mitochondria‐controlled apoptosis, and enhancing stability of nuclear and mitochondrial DNA. Supported by CIHR and NSERC of Canada.