A time to fast

Abstract

Nutrient composition and caloric intake have traditionally been used to devise optimized diets for various phases of life. Adjustment of meal size and frequency have emerged as powerful tools to ameliorate and postpone the onset of disease and delay aging, whereas periods of fasting, with or without reduced energy intake, can have profound health benefits. The underlying physiological processes involve periodic shifts of metabolic fuel sources, promotion of repair mechanisms, and the optimization of energy utilization for cellular and organismal health. Future research endeavors should be directed to the integration of a balanced nutritious diet with controlled meal size and patterns and periods of fasting to develop better strategies to prevent, postpone, and treat the socioeconomical burden of chronic diseases associated with aging.

Fig. 1.. Experimental approaches used to improve fitness and promote health span.

Description of different feeding regimens, their macronutrient balance, and feeding time during a 24-hour period. The feeding time represented in the day-night diagrams refers to eating time in humans and nonhuman primates. Mice undergoing a CR regimen tend to finish their food allotment quickly, self-imposing a continuous form of TRF. In human studies, people voluntarily reduce their food intake and mostly adhere to a three-meals-per-day schedule. Mean life-span extension is documented for all the treatments in the species depicted in the box, whereas maximum life span is only achieved after CR and IF or PF.

Fig. 2.. Fasting time and energy restriction share biological responses implicated in metabolite-controlled longevity pathways.

Reduction of calories by continuous energy restriction or prolonged fasting periods trigger metabolic adaptations characterized by increased amounts of circulating ketones, whereas circulating fatty acids, amino acids, glucose, and insulin are maintained at low concentrations. Adaptive cellular responses involve alterations in the ratios of adenosine monophosphate (AMP) to adenosine triphosphate (ATP), of oxidized nicotinamide adenine dinucleotide (NAD⁺) to the reduced form NADH, and of acetyl-CoA to CoA. After a few hours of fasting, increased AMP to ATP ratios activate AMPK, which triggers repair and inhibits anabolic processes. Acetyl-CoA and NAD⁺ serve as cofactors for epigenetic modifiers such as histone acetyltransferases and NAD⁺-dependent deacetylases, the sirtuins, thus linking nutrition, energy metabolism, and post-translational modifications of histone proteins. Sirtuins deacetylate FOXOs and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), factors respectively involved in stress resistance and mitochondrial biogenesis. Production of ketone bodies such as β-hydroxybutyrate from fatty-acid catabolism may operate as endogenous histone deacetylase (HDAC) inhibitors and may contribute to epigenetic control of gene expression, DNA repair, and genome stability. Ketogenesis also promotes synaptic plasticity and neurogenesis by increasing the expression of brain-derived neurotrophic factor (BDNF). Periodic cycles of fasting have systemic anti-inflammatory effects and increase progenitor stem cells. Down-regulation of the insulin–IGF-1 signaling (IIS) pathway and reduction of circulating amino acids repress the activity of mTOR and its downstream effector, the ribosomal protein S6 kinase beta-1 (S6K). This mechanism inhibits global protein synthesis and promotes recycling of macromolecules by stimulation of autophagy. CR promotes the expression and activity of NRF2, which induces a number of antioxidative and carcinogen-detoxifying enzymes. Collectively, the organism responds to a low-energy challenge by minimizing anabolic processes (synthesis, growth, and reproduction), favoring maintenance systems, and enhancing stress resistance, tissue repair, and recycling of damaged molecules. Improvement in resilience, metabolic homeostasis, tissue repair, and organismal function can act as direct modifiers of the four domains of the aging phenotype: body composition (1); balance between energy availability and energy demand (27); signaling networks that maintain homeostasis (81); and neurodegeneration (4). Each of these domains can be assessed readily by routine clinical tests.

Fig. 3.. Integration of the circadian rhythms and feeding-fasting cycles with metabolism.

(Left) The transcriptional activators BMAL1 and CLOCK are at the core of a cell-autonomous molecular circuit that governs circadian rhythms. Fasting increases hunger, the extent of which depends on the overall energy intake, diet composition, and length of fasting. The internal circadian clock also increases hunger independent of food intake and other behaviors. Intermittent energy restriction increases concentrations of the plasma membrane redox system enzymes, NADH-cytochrome b5 reductase and NAD(P)H-quinone oxidoreductase, contributing to oscillations in the NAD(P)H [reduced form of NAD(P)⁺] to NAD(P)⁺ (nicotinamide adenine dinucleotide phosphate) ratio (82). The circadian rhythmicity of CLOCK and BMAL1 expression regulates the transcription of NAMPT, a key regulatory enzyme involved in the generation of NAD⁺, a metabolite required for the deacetylase activity of SIRT1. Active SIRT1 influences metabolism through its effects on catabolic and anabolic reactions and mediates BMAL1 deacetylation, which inhibits the circadian clock machinery. During the active phase (yellow boxes), increased production of ATP sustains anabolic pathways. During the resting phase (green boxes), a shift toward AMP gears metabolism toward catabolic processes. These intermediate energy carriers activate downstream transcription factors, kinases, and deacetylases like NRF2, AMPK, PGC-1α, sirtuins, and FOXOs, whose activation influences health and survival. (Right) At the organismal level, fasting or feeding states are paralleled by changes in the metabolic rate. AL–fed animals set their RERs at around 0.9, showing an intermediate preference between fat and carbohydrate metabolism. Both CR and TRF regimens increase the amplitude of RER oscillations, characterized by higher RER (utilization of carbohydrates) during feeding and lower RER (utilization of lipids) during fasting. Under prolonged fasting, lipids are the only source of energy, as opposed to feeding time. The FMD diet results in lower RER with a slight peak after the meal. The RER traces are idealized and may be close to what is seen in nocturnal rodents.

Fig. 4.. Systemic effects of caloric restriction or intermittent fasting.

The balance between reduction in total food intake and timing contributes to differences in energy consumption, leading to changes in circulating factors and organ function. The height of each arrow does not reflect the intensity level but instead highlights a grouping. Down arrows indicate decreased levels, and up arrows indicate increased levels.