The cyclic metabolic switching theory of intermittent fasting

Abstract

Intermittent fasting (IF) and ketogenic diets (KDs) have recently attracted much attention in the scientific literature and in popular culture and follow a longer history of exercise and caloric restriction (CR) research. Whereas IF involves cyclic metabolic switching (CMS) between ketogenic and non-ketogenic states, KDs and CR may not. In this Perspective, I postulate that the beneficial effects of IF result from alternating between activation of adaptive cellular stress response pathways during the fasting period, followed by cell growth and plasticity pathways during the feeding period. Thereby, I establish the cyclic metabolic switching (CMS) theory of IF. The health benefits of IF may go beyond those seen with continuous CR or KDs without CMS owing to the unique interplay between the signalling functions of the ketone β-hydroxybutyrate, mitochondrial adaptations, reciprocal activation of autophagy and mTOR pathways, endocrine and paracrine signalling, gut microbiota, and circadian biology. The CMS theory may have important implications for future basic research, clinical trials, development of pharmacological interventions, and healthy lifestyle practices. In this Perspective, Mattson discusses that the beneficial effects of intermittent fasting (IF) are mediated by cyclic metabolic switching between ketogenic (fasting) and non-ketogenic (fed) states and that this explains the added health benefits of IF over caloric restriction and ketogenic diets.