Alanine-Metabolizing Enzyme Alt1 Is Critical in Determining Yeast Life Span, As Revealed by Combined Metabolomic and Genetic Studies

Abstract

Alterations in metabolic pathways are gaining attention as important environmental factors affecting life span, but the determination of specific metabolic pathways and enzymes involved in life span remains largely unexplored. By applying an NMR-based metabolomics approach to a calorie-restricted yeast (<i>Saccharomyces cerevisiae</i>) model, we found that alanine level is inversely correlated with yeast chronological life span. The involvement of the alanine-metabolizing pathway in the life span was tested using a deletion mutant of <i>ALT1</i>, the gene for a key alanine-metabolizing enzyme. The mutant exhibited increased endogenous alanine level and much shorter life span, demonstrating the importance of <i>ALT1</i> and alanine metabolic pathways in the life span. <i>ALT1</i>’s effect on life span was independent of the TOR pathway, as revealed by a <i>tor1</i> deletion mutant. Further mechanistic studies showed that <i>alt1</i> deletion suppresses cytochrome <i>c</i> oxidase subunit 2 expression, ultimately generating reactive oxygen species. Overall, <i>ALT1</i> seems critical in determining yeast life span, and our approach should be useful for the mechanistic studies of life span determinations