A novel anti‐aging drug extends longevity by remodeling neutral lipid metabolism

Abstract

We use yeast as a model to understand a mechanism linking longevity and neutral lipid metabolism. Caloric restriction (CR) extends life span across species. We examined 1) the effect of CR and numerous mutations extending yeast life span on the spatiotemporal dynamics of the proteomes and lipidomes of organelles involved in neutral lipid metabolism, including the endoplasmic reticulum (ER), peroxisomes, and lipid bodies; and 2) the chronology of hallmark events of apoptotic and necrotic death pathways in various long‐lived yeast mutants impaired in neutral lipid metabolism. Our findings revealed that a calorie‐rich diet suppresses peroxisomal oxidation of fatty acids (FFA) that originate from neutral lipids synthesized in the ER and deposited within lipid bodies. The resulting age‐related accumulation of arrays of FFA within lipid bodies triggers a programmed necrotic cell death pathway. We designed a chemical genetic screen for small molecules that extend yeast longevity by altering neutral lipid metabolism. Our screen identified lithocholic acid (LCA) as one of such novel anti‐aging drugs. Using a combination of proteomic, lipidomic, metabolomic, and systems biological approaches, we established the mechanism underlying its life‐extending ability. We found that this bile acid remodels neutral lipid metabolism in the ER, lipid bodies, and peroxisomes, thereby postponing age‐related necrosis caused by the buildup of FFA. Our findings revealed two different ways for delaying aging by altering neutral lipid metabolism and thereby impairing the age‐related programmed necrotic death pathway. Supported by NSERC of Canada.