Metabolic Biomarkers for Lifespan Extension and Cellular Stress in <i>Saccharomyces cerevisiae</i> during Calorie Restriction and Quercetin Treatment

As life expectancy increases, age-related diseases pose significant challenges in modern medicine. The molecular mechanisms of aging have been widely explored in mice, nematodes, human cells, and yeast. The budding yeast <i>Saccharomyces cerevisiae</i> has become the most widely employed eukaryotic model due to its short lifespan and well-characterized genetic and molecular profiles. However, research into the metabolite perturbations associated with lifespan extension has tended to focus on mutant or engineered yeast cells, and information regarding these processes in normal yeast cells remains scant. In this study, therefore, we investigated how aging affects the intracellular metabolites of <i>S. cerevisiae</i> during its growth and how these changes relate to lifespan extension induced by calorie restriction (CR) and quercetin treatment using a ¹H nuclear magnetic resonance (NMR)-based metabolomic approach. The results revealed clear relationships between intracellular metabolites and aging, CR, and quercetin treatment in yeast cells. The intracellular trehalose levels were found to increase with aging, CR, and dimethyl sulfoxide (DMSO) treatment, indicating that yeast cells activate protective responses against cellular stress. Meanwhile, quercetin treatment was able to clear the metabolic stress caused by DMSO treatment. The treatment of both CR and quercetin significantly increased the intracellular proline levels, which are known to regulate mitochondrial function and decline with age. The findings of this study suggest that CR and quercetin promote the longevity of <i>S. cerevisiae</i> through a shared metabolic pathway and highlight intracellular trehalose and proline as potentially valuable biomarkers of cellular stress and longevity in yeast cells.