Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging

Abstract

Aging is a complex process in which the accumulation of molecular, cellular, and organism dysfunction increases the probability of death. Several pieces of evidence have revealed a contribution of stress responses in aging and in aging-related diseases, in particular, the key role of signaling pathways associated to nutritional stress. Here, we review the possible interplay between amino acid sensing and redox balance maintenance mediated by the nutritional sensor general control nonderepressive 2 (GCN2). We discuss this new dimension of nutritional stress sensing consequences, standing out GCN2 as a central coordinator of key cellular processes that assure healthy homeostasis in the cell, raising GCN2 as a novel interesting target, that when activated, could imply pleiotropic benefits, particularly GCN2 intervention and its new unexplored therapeutic role as a player in the aging process.

Figure 1

Main aging hallmarks studied in chordates. In the diagram, the nine-group aging hallmarks were grouped into four: mitochondrial dysfunction, DNA alterations (containing epigenetic alterations and genomic stability), impaired adaptive/stress response (containing loss of proteostasis and nutrient sensing deregulation), and cell cycle state dependent in function if they are differentiated or not, proliferative tissue alterations (telomere attrition, senesce), or nonproliferative cell disturbances such as synaptic loss.

Figure 2

GCN2-dependent nutrient sensing along aging. Amino acid deprivation activates GCN2, a kinase that induces a nutrient stress response transcriptional program through ATF4 action. GCN2 also regulates other cell processes such as autophagy, cell cycle through p53 function, and redox status by transcriptionally modulating GPX1; this homeostatic balance can be altered throughout aging. ROS: reactive oxygen species; GPX1: glutathione peroxidase 1; GCN2: general control nonderepressive 2; eIF2α: eukaryotic initiation factor 2 alpha; ATF4: activating transcription factor 4.