Unravelling the health effects of fasting: a long road from obesity treatment to healthy life span increase and improved cognition

Abstract

In recent years a revival of interest has emerged in the health benefits of intermittent fasting and long-term fasting, as well as of other related nutritional strategies. In addition to meal size and composition a new focus on time and frequency of meals has gained attention. The present review will investigate the effects of the main forms of fasting, activating the metabolic switch from glucose to fat and ketones (G-to-K), starting 12-16 h after cessation or strong reduction of food intake. During fasting the deactivation of mTOR regulated nutrient signalling pathways and activation of the AMP protein kinase trigger cell repair and inhibit anabolic processes. Clinical and animal studies have clearly indicated that modulating diet and meal frequency, as well as application of fasting patterns, e.g. intermittent fasting, periodic fasting, or long-term fasting are part of a new lifestyle approach leading to increased life and health span, enhanced intrinsic defences against oxidative and metabolic stresses, improved cognition, as well as a decrease in cardiovascular risk in both obese and non-obese subjects. Finally, in order to better understand the mechanisms beyond fasting-related changes, human studies as well as non-human models closer to human physiology may offer useful clues.KEY-MESSAGESBiochemical changes during fasting are characterised by a glucose to ketone switch, leading to a rise of ketones, advantageously used for brain energy, with consequent improved cognition.Ketones reduce appetite and help maintain effective fasting.Application of fasting patterns increases healthy life span and defences against oxidative and metabolic stresses.Today's strategies for the use of therapeutic fasting are based on different protocols, generally relying on intermittent fasting, of different duration and calorie intake.Long-term fasting, with durations between 5 and 21 days can be successfully repeated in the course of a year.

Keywords: Glucose-to-ketones metabolic switch; intermittent fasting; long-term fasting; periodic fasting; prolonged fasting; zero calorie diet.

Figure 1.

Metabolic switch from carbohydrates to fatty acids and ketones induced by 10 days of fasting (daily energy intake of about 250 kcal and multidisciplinary programme). A regression spline was fitted on individual acetoacetic values to show the variations in ketosis during the course of the study. T: transition to the fasting mode; RF: progressive reintroduction of food [40].

Figure 2.

Representationof signalling pathways modulated fasting. The reduced levels of circulating amino acids and of IGF-1 consequent to fasting repress the activity of mTOR and its downstream effector leading to an inhibition of global protein synthesis and promote recycling of macromolecules by autophagy stimulation. There is a rise in the AMP-to-ATP ratio leading to the activation of AMPK. SIRT1-driven deacetylation of PGC-1α and FOXO1 transcription factors provides a mechanism by which mitochondrial and lipid oxidation genes can be dynamically controlled in response to energy demand. AMPK: AMP-activated protein kinase; FOXO1: forkhead box O1; IGF: insulin-like growth factor; NAD+: nicotinamide adenine dinucleotide; PGC-1α: peroxisome proliferator–activated receptor γ coactivator 1α; mTOR: mammalian target of Rapamycin; SIRT: sirtuin.