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A mechanism linking lipid metabolism and longevity

We use the yeast Saccharomyces cerevisiae as a model to study the mechanisms linking lipid metabolism and longevity. Yeast aging can be slowed down by calorie restriction (CR), a low‐calorie diet that extends life span and delays age‐related disorders in a wide spectrum of organisms. We assessed the effect of CR and numerous mutations extending yeast life span on the spatiotemporal dynamics of the proteomes and lipidomes of organelles involved in lipid metabolism. These organelles include the endoplasmic reticulum (ER), peroxisomes and lipid bodies. Our findings imply that 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. Implementing our knowledge, we identified five groups of novel anti‐aging small molecules that greatly extend yeast longevity by remodelling lipid metabolism in the ER, peroxisomes and lipid bodies and by promoting "mitohormesis" through the activation of a distinct set of stress response‐related processes in mitochondria.