The ICL1 and MLS1 Genes, Integral to the Glyoxylate Cycle, are Essential and Specific for Caloric Restriction‐Mediated Extension of Lifespan in Budding Yeast

The regulation of complex energy metabolism is intricately linked to cellular energy demands. Caloric restriction (CR) plays a pivotal role in modulating the expression of genes associated with key metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and the glyoxylate cycle. In this study, the chronological lifespan (CLS) of 35 viable single‐gene deletion mutants under both non‐restricted and CR conditions, focusing on genes related to these metabolic pathways is evaluated. CR is found to increase CLS predominantly in mutants associated with the glycolysis and TCA cycle. However, this beneficial effect of CR is not observed in mutants of the glyoxylate cycle, particularly those lacking genes for critical enzymes like isocitrate lyase 1 (icl1Δ) and malate synthase 1 (mls1Δ). This analysis revealed an increase in isocitrate lyase activity, a key enzyme of the glyoxylate cycle, under CR, unlike the activity of isocitrate dehydrogenase, which remains unchanged and is specific to the TCA cycle. Interestingly, rapamycin, a compound known for extending lifespan, does not increase the activity of the glyoxylate cycle enzyme. This suggests that CR affects lifespan through a distinct metabolic mechanism. Caloric restriction (CR) increases lifespan by altering various biological processes. A significant transcriptome contrast between CR and rapamycin in influencing major metabolic pathways, including glycolysis, the tricarboxylic acid cycle, and the glyoxylate cycle is observed. Evaluating relevant 35 genes, these results indicate that the augmentation of the glyoxylate cycle is a specific mechanism for CR‐driven lifespan extension.