Metabolic Stress—Signaling and Metabolic Adaptation

Abstract Metabolic stress due to nutrient depletion or nutrient excess triggers a number of adaptive responses to restore dynamic homeostasis and to maintain cellular function. This is based on molecular pathways, which sense and subsequently adjust alterations in energy or intermediary metabolism (ATP, NAD + , oxygen). Nutrient sensors include AMPK-activated protein kinase (AMPK), sirtuin 1 (SIRT1), the mechanistic target of rapamycin (mTOR), and the prolyl hydroxylase domain protein (PHD)/hypoxia-inducible factor (HIF) system. Adaptive responses lead to metabolic reprogramming and autophagy due to activation of regulatory enzymes and transcription factors or through epigenetic regulation of gene transcription. Moderate metabolic stress as induced by caloric restriction has been shown to slow down aging via activating AMPK and SIRT1 and inhibiting mTOR. Cancer cells characterized by sustained growth signaling lose the ability to elicit hormetic responses upon starvation, which may sensitize them to chemotherapeutic treatment.