Novel anti‐aging small molecules greatly extend yeast life span by specifically targeting a mechanism underlying the essential role of cellular lipid movement and compartmentalized metabolism in regulating longevity

Abstract

We use the yeast Saccharomyces cerevisiae as a model to study the mechanisms linking lipid dynamics and longevity. Yeast aging can be slowed down by calorie restriction (CR), a diet that extends life span and delays age‐related disorders in various organisms. We assessed the effect of CR and numerous life‐extending mutations on the spatiotemporal dynamics of the proteomes and lipidomes of organelles involved in lipid metabolism, including the endoplasmic reticulum (ER), peroxisomes and lipid bodies. Our findings revealed a mechanism underlying the essential role of lipid dynamics in regulating longevity. In this mechanism, a calorie‐rich diet suppresses peroxisomal oxidation of free fatty acids (FFA) that originate from neutral lipids synthesized in the ER and deposited within lipid bodies. The resulting accumulation of FFA initiates several negative feedback loops regulating the metabolism of neutral lipids, ultimately leading to the accumulation of diacylglycerol (DAG). The buildup of FFA promotes necrotic cell death, whereas the accumulation of DAG hampers a stress response‐related signal transduction network. We identified 25 novel anti‐aging small molecules that greatly extend yeast longevity by remodelling compartmentalized lipid metabolism and preventing the FFA‐induced necrotic cell death. Our findings revealed two different ways for delaying aging by altering cellular lipid dynamics.