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-MESSAGES 1. Biochemical 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. 2. Ketones reduce appetite and help maintain effective fasting. 3. Application of fasting patterns increases healthy life span and defences against oxidative and metabolic stresses. 4. 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. 5. Long-term fasting, with durations between 5 and 21 days can be successfully repeated in the course of a year.

Interplay between oxidative damage, the redox status, and metabolic biomarkers during long-term fasting

“…Analysis of correlations between the redox status and clinical parameters confirmed the link between markers of metabolic health and the antioxidant status established in our first study ( Wilhelmi de Toledo et al, 2020a , Wilhelmi de Toledo et al, 2020b ). The strongest correlation observed was between uric acid levels and the TAC ( Fig.…”

“…In addition, it would be important to improve our oxidative status and strengthen defense mechanisms against various diseases including those caused by viruses like covid-19. A possible approach to achieve these objectives could be long-term fasting, that is defined as voluntary food abstinence from 2 days to several weeks ( Wilhelmi de Toledo et al, 2020b ). The study of various forms of fasting on metabolic health has been gaining ground in recent years with more and more studies showing beneficial effects such as inactivating of the mechanistic target of rapamycin (mTOR) signaling pathways as well as several others resulting in metabolic normalization, enhanced autophagy and apoptosis followed by cell regeneration, increased brain-derived neurotrophic factor (BDNF) levels in brain leading to enhanced cognition, mood as well as increased neuronal plasticity and regeneration.…”

“…The study of various forms of fasting on metabolic health has been gaining ground in recent years with more and more studies showing beneficial effects such as inactivating of the mechanistic target of rapamycin (mTOR) signaling pathways as well as several others resulting in metabolic normalization, enhanced autophagy and apoptosis followed by cell regeneration, increased brain-derived neurotrophic factor (BDNF) levels in brain leading to enhanced cognition, mood as well as increased neuronal plasticity and regeneration. Fasting also enhanced the transcription of cytoprotective enzymes, mitochondrial biogenesis all of these effects leading to restoration and conservation of functional integrity of cells and tissues ( de Cabo and Mattson, 2019 ; Wilhelmi de Toledo et al, 2020b ). Moreover, it has been shown that long-term fasting improved dysmetabolism as well as the antioxidant capacity ( Drinda et al, 2019 ; Wilhelmi de Toledo et al, 2019 , 2020a ).…”

Influence of Long-Term Fasting on Blood Redox Status in Humans

“…LF, also called sometimes periodic fasting [ 5 , 6 ], refers to total abstinence or a strong reduction in energy intake for from 2 to 21 days or more [ 7 ]. It has been extensively studied in free-living animals which survive on body energy stores, such as in migrating birds, hibernating animals and penguins [ 8 , 9 ].…”

“…LF in humans has been practiced for decades under medical supervision in specialized centers [ 10 ]. LF has been used to treat several pathologies [ 7 ]. In contrast to LF, intermittent fasting (IF) is defined as periods of fasting lasting from 12 to 48 h, and is the most studied fasting regimen [ 11 , 12 , 13 ].…”