Gcn4 impacts metabolic fluxes to promote yeast chronological lifespan

Abstract

Aging is characterized by a gradual decline in physiological integrity, which impairs functionality and increases susceptibility to mortality. Dietary restriction, mimicking nutrient scarcity without causing malnutrition, is an intervention known to decelerate the aging process. While various hypotheses have been proposed to elucidate how dietary restriction influences aging, the underlying mechanisms remain incompletely understood. This project aimed to investigate the role of the primary regulator of the general amino acid control (GAAC) pathway, the transcription factor Gcn4, in the aging process of S. cerevisiae cells. Under conditions of amino acid deprivation, which activate Gcn4, the deletion of GCN4 led to a diverse array of physiological changes in the cells. Notably, the absence of Gcn4 resulted in heightened mitochondrial activity, likely contributing to the observed increase in reactive oxygen species (ROS) accumulation. Furthermore, these mutant gcn4Δ cells exhibited reduced ethanol production despite maintaining similar glucose consumption rates, suggesting a pivotal role for Gcn4 in regulating the Crabtree effect. Additionally, there was a marked reduction in trehalose, the storage carbohydrate, within the mutant cells compared to the wild-type strain. The intracellular content of free amino acids also exhibited disparities between the wild-type and GCN4-deficient strains. Taken together, our findings indicate that the absence of GCN4 disrupts cellular homeostasis, triggering significant alterations in interconnected intracellular metabolic pathways. These disruptions have far-reaching metabolic consequences that ultimately culminate in a shortened lifespan.