Caloric restriction creates a metabolic pattern of chronological aging delay that in budding yeast differs from the metabolic design established by two other geroprotectors

// Karamat Mohammad 1 and Vladimir I. Titorenko 1 1 Department of Biology, Concordia University, Montreal, Quebec H4B 1R6, Canada Correspondence to: Vladimir I. Titorenko, email: [email protected] Keywords: cellular aging; geroprotectors; caloric restriction(definition); metabolism; methionine Received: January 11, 2021     Accepted: March 15, 2021     Published: March 30, 2021 Copyright: © 2021 Mohammad and Titorenko. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Caloric restriction and the tor1Δ mutation are robust geroprotectors in yeast and other eukaryotes. Lithocholic acid is a potent geroprotector in Saccharomyces cerevisiae . Here, we used liquid chromatography coupled with tandem mass spectrometry method of non-targeted metabolomics to compare the effects of these three geroprotectors on the intracellular metabolome of chronologically aging budding yeast. Yeast cells were cultured in a nutrient-rich medium. Our metabolomic analysis identified and quantitated 193 structurally and functionally diverse water-soluble metabolites implicated in the major pathways of cellular metabolism. We show that the three different geroprotectors create distinct metabolic profiles throughout the entire chronological lifespan of S. cerevisiae . We demonstrate that caloric restriction generates a unique metabolic pattern. Unlike the tor1Δ mutation or lithocholic acid, it slows down the metabolic pathway for sulfur amino acid biosynthesis from aspartate, sulfate and 5-methyltetrahydrofolate. Consequently, caloric restriction significantly lowers the intracellular concentrations of methionine, S -adenosylmethionine and cysteine. We also noticed that the low-calorie diet, but not the tor1Δ mutation or lithocholic acid, decreases intracellular ATP, increases the ADP:ATP and AMP:ATP ratios, and rises intracellular ADP during chronological aging. We propose a model of how the specific remodeling of cellular metabolism by caloric restriction contributes to yeast chronological aging delay.