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F R E E A C C E S S P R I M A L S O U R C E A F T E R R E G I S T R A T I O N : The NEW ENGLAND JOURNAL of MEDICINE (Effects of Intermittent Fasting on Health, Aging, and Disease)
According to Weindruch and Sohal in a 1997 article in the Journal, reducing food availability over a lifetime (caloric restriction) has remarkable effects on aging and the life span in animals.1 The authors proposed that the health benefits of caloric restriction result from a passive reduction in the production of damaging oxygen free radicals. At the time, it was not generally recognized that because rodents on caloric restriction typically consume their entire daily food allotment within a few hours after its provision, they have a daily fasting period of up to 20 hours, during which ketogenesis occurs. Since then, hundreds of studies in animals and scores of clinical studies of controlled intermittent fasting regimens have been conducted in which metabolic switching from liver-derived glucose to adipose cell–derived ketones occurs daily or several days each week. Although the magnitude of the effect of intermittent fasting on life-span extension is variable (influenced by sex, diet, and genetic factors), studies in mice and nonhuman primates show consistent effects of caloric restriction on the health span (see the studies listed in Section S3 in the Supplementary Appendix, available with the full text of this article at NEJM.org).
Figure 1. Cellular Responses to Energy Restriction That Integrate Cycles of Feeding and Fasting with Metabolism.
Total energy intake, diet composition, and length of fasting between meals contribute to oscillations in the ratios of the levels of the bioenergetic sensors nicotinamide adenine dinucleotide (NAD+) to NADH, ATP to AMP, and acetyl CoA to CoA. These intermediate energy carriers activate downstream proteins that regulate cell function and stress resistance, including transcription factors such as forkhead box Os (FOXOs), peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), and nuclear factor erythroid 2–related factor 2 (NRF2); kinases such as AMP kinase (AMPK); and deacetylases such as sirtuins (SIRTs). Intermittent fasting triggers neuroendocrine responses and adaptations characterized by low levels of amino acids, glucose, and insulin. Down-regulation of the insulin–insulin-like growth factor 1 (IGF-1) signaling pathway and reduction of circulating amino acids repress the activity of mammalian target of rapamycin (mTOR), resulting in inhibition of protein synthesis and stimulation of autophagy. During fasting, the ratio of AMP to ATP is increased and AMPK is activated, triggering repair and inhibition of anabolic processes. Acetyl coenzyme A (CoA) and NAD+ serve as cofactors for epigenetic modifiers such as SIRTs. SIRTs deacetylate FOXOs and PGC-1α, resulting in the expression of genes involved in stress resistance and mitochondrial biogenesis. Collectively, the organism responds to intermittent fasting by minimizing anabolic processes (synthesis, growth, and reproduction), favoring maintenance and repair systems, enhancing stress resistance, recycling damaged molecules, stimulating mitochondrial biogenesis, and promoting cell survival, all of which support improvements in health and disease resistance. The abbreviation cAMP denotes cyclic AMP, CHO carbohydrate, PKA protein kinase A, and redox reduction–oxidation.
Studies in animals and humans have shown that many of the health benefits of intermittent fasting are not simply the result of reduced free-radical production or weight loss.2-5 Instead, intermittent fasting elicits evolutionarily conserved, adaptive cellular responses that are integrated between and within organs in a manner that improves glucose regulation, increases stress resistance, and suppresses inflammation. During fasting, cells activate pathways that enhance intrinsic defenses against oxidative and metabolic stress and those that remove or repair damaged molecules (Figure 1).5 During the feeding period, cells engage in tissue-specific processes of growth and plasticity. However, most people consume three meals a day plus snacks, so intermittent fasting does not occur.2,6
Preclinical studies consistently show the robust disease-modifying efficacy of intermittent fasting in animal models on a wide range of chronic disorders, including obesity, diabetes, cardiovascular disease, cancers, and neurodegenerative brain diseases.3,7-10 Periodic flipping of the metabolic switch not only provides the ketones that are necessary to fuel cells during the fasting period but also elicits highly orchestrated systemic and cellular responses that carry over into the fed state to bolster mental and physical performance, as well as disease resistance.11,12
Here, we review studies in animals and humans that have shown how intermittent fasting affects general health indicators and slows or reverses aging and disease processes. First, we describe the most commonly studied intermittent-fasting regimens and the metabolic and cellular responses to intermittent fasting. We then present and discuss findings from preclinical studies and more recent clinical studies that tested intermittent-fasting regimens in healthy persons and in patients with metabolic disorders (obesity, insulin resistance, hypertension, or a combination of these disorders). Finally, we provide practical information on how intermittent-fasting regimens can be prescribed and implemented. The practice of long-term fasting (from many days to weeks) is not discussed here, and we refer interested readers to the European clinical experience with such fasting protocols.13
Intermittent Fasting and Metabolic Switching
Figure 2. Metabolic Adaptations to Intermittent Fasting.
Energy restriction for 10 to 14 hours or more results in depletion of liver glycogen stores and hydrolysis of triglycerides (TGs) to free fatty acids (FFAs) in adipocytes. FFAs released into the circulation are transported into hepatocytes, where they produce the ketone bodies acetoacetate and β-hydroxybutyrate (β-HB). FFAs also activate the transcription factors peroxisome proliferator–activated receptor α (PPAR-α) and activating transcription factor 4 (ATF4), resulting in the production and release of fibroblast growth factor 21 (FGF21), a protein with widespread effects on cells throughout the body and brain. β-HB and acetoacetate are actively transported into cells where they can be metabolized to acetyl CoA, which enters the tricarboxylic acid (TCA) cycle and generates ATP. β-HB also has signaling functions, including the activation of transcription factors such as cyclic AMP response element–binding protein (CREB) and nuclear factor κB (NF-κB) and the expression of brain-derived neurotrophic factor (BDNF) in neurons. Reduced levels of glucose and amino acids during fasting result in reduced activity of the mTOR pathway and up-regulation of autophagy. In addition, energy restriction stimulates mitochondrial biogenesis and mitochondrial uncoupling.
Glucose and fatty acids are the main sources of energy for cells. After meals, glucose is used for energy, and fat is stored in adipose tissue as triglycerides. During periods of fasting, triglycerides are broken down to fatty acids and glycerol, which are used for energy. The liver converts fatty acids to ketone bodies, which provide a major source of energy for many tissues, especially the brain, during fasting (Figure 2). In the fed state, blood levels of ketone bodies are low, and in humans, they rise within 8 to 12 hours after the onset of fasting, reaching levels as high as 2 to 5 mM by 24 hours.14,15 In rodents, an elevation of plasma ketone levels occurs within 4 to 8 hours after the onset of fasting, reaching millimolar levels within 24 hours.16 The timing of this response gives some indication of the appropriate periods for fasting in intermittent-fasting regimens.2,3
In humans, the three most widely studied intermittent-fasting regimens are alternate-day fasting, 5:2 intermittent fasting (fasting 2 days each week), and daily time-restricted feeding.11 Diets that markedly reduce caloric intake on 1 day or more each week (e.g., a reduction to 500 to 700 calories per day) result in elevated levels of ketone bodies on those days.17-20 The metabolic switch from the use of glucose as a fuel source to the use of fatty acids and ketone bodies results in a reduced respiratory-exchange ratio (the ratio of carbon dioxide produced to oxygen consumed), indicating the greater metabolic flexibility and efficiency of energy production from fatty acids and ketone bodies.3
Ketone bodies are not just fuel used during periods of fasting; they are potent signaling molecules with major effects on cell and organ functions.21 Ketone bodies regulate the expression and activity of many proteins and molecules that are known to influence health and aging. These include peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α), fibroblast growth factor 21,22,23 nicotinamide adenine dinucleotide (NAD+), sirtuins,24 poly(adenosine diphosphate [ADP]–ribose) polymerase 1 (PARP1), and ADP ribosyl cyclase (CD38).25 By influencing these major cellular pathways, ketone bodies produced during fasting have profound effects on systemic metabolism. Moreover, ketone bodies stimulate expression of the gene for brain-derived neurotrophic factor (Figure 2), with implications for brain health and psychiatric and neurodegenerative disorders.5
How much of the benefit of intermittent fasting is due to metabolic switching and how much is due to weight loss? Many studies have indicated that several of the benefits of intermittent fasting are dissociated from its effects on weight loss. These benefits include improvements in glucose regulation, blood pressure, and heart rate; the efficacy of endurance training26,27; and abdominal fat loss27 (see Supplementary Section S1).
Intermittent Fasting and Stress Resistance
In contrast to people today, our human ancestors did not consume three regularly spaced, large meals, plus snacks, every day, nor did they live a sedentary life. Instead, they were occupied with acquiring food in ecologic niches in which food sources were sparsely distributed. Over time, Homo sapiens underwent evolutionary changes that supported adaptation to such environments, including brain changes that allowed creativity, imagination, and language and physical changes that enabled species members to cover large distances on their own muscle power to stalk prey.6
Figure 3. Cellular and Molecular Mechanisms Underlying Improved Organ Function and Resistance to Stress and Disease with Intermittent Metabolic Switching.
Periods of dietary energy restriction sufficient to cause depletion of liver glycogen stores trigger a metabolic switch toward use of fatty acids and ketones. Cells and organ systems adapt to this bioenergetic challenge by activating signaling pathways that bolster mitochondrial function, stress resistance, and antioxidant defenses while up-regulating autophagy to remove damaged molecules and recycle their components. During the period of energy restriction, cells adopt a stress-resistance mode through reduction in insulin signaling and overall protein synthesis. Exercise enhances these effects of fasting. On recovery from fasting (eating and sleeping), glucose levels increase, ketone levels plummet, and cells increase protein synthesis, undergoing growth and repair. Maintenance of an intermittent-fasting regimen, particularly when combined with regular exercise, results in many long-term adaptations that improve mental and physical performance and increase disease resistance. HRV denotes heart-rate variability.
The research reviewed here, and discussed in more detail elsewhere,11,12 shows that most if not all organ systems respond to intermittent fasting in ways that enable the organism to tolerate or overcome the challenge and then restore homeostasis. Repeated exposure to fasting periods results in lasting adaptive responses that confer resistance to subsequent challenges. Cells respond to intermittent fasting by engaging in a coordinated adaptive stress response that leads to increased expression of antioxidant defenses, DNA repair, protein quality control, mitochondrial biogenesis and autophagy, and down-regulation of inflammation (Figure 3). These adaptive responses to fasting and feeding are conserved across taxa.10 Cells throughout the bodies and brains of animals maintained on intermittent-fasting regimens show improved function and robust resistance to a broad range of potentially damaging insults, including those involving metabolic, oxidative, ionic, traumatic, and proteotoxic stress.12 Intermittent fasting stimulates autophagy and mitophagy while inhibiting the mTOR (mammalian target of rapamycin) protein-synthesis pathway. These responses enable cells to remove oxidatively damaged proteins and mitochondria and recycle undamaged molecular constituents while temporarily reducing global protein synthesis to conserve energy and molecular resources (Figure 3). These pathways are untapped or suppressed in persons who overeat and are sedentary.12
Effects of Intermittent Fasting on Health and Aging
Until recently, studies of caloric restriction and intermittent fasting focused on aging and the life span. After nearly a century of research on caloric restriction in animals, the overall conclusion was that reduced food intake robustly increases the life span.
In one of the earliest studies of intermittent fasting, Goodrick and colleagues reported that the average life span of rats is increased by up to 80% when they are maintained on a regimen of alternate-day feeding, started when they are young adults. However, the magnitude of the effects of caloric restriction on the health span and life span varies and can be influenced by sex, diet, age, and genetic factors.7 A meta-analysis of data available from 1934 to 2012 showed that caloric restriction increases the median life span by 14 to 45% in rats but by only 4 to 27% in mice.28 A study of 41 recombinant inbred strains of mice showed wide variation, ranging from a substantially extended life span to a shortened life span, depending on the strain and sex.29,30 However, the study used only one caloric-restriction regimen (40% restriction) and did not evaluate health indicators, causes of death, or underlying mechanisms. There was an inverse relationship between adiposity reduction and life span29 suggesting that animals with a shortened life span had a greater reduction in adiposity and transitioned more rapidly to starvation when subjected to such severe caloric restriction, whereas animals with an extended life span had the least reduction in fat.
The discrepant results of two landmark studies in monkeys challenged the link between health-span extension and life-span extension with caloric restriction. One of the studies, at the University of Wisconsin, showed a positive effect of caloric restriction on both health and survival,31 whereas the other study, at the National Institute on Aging, showed no significant reduction in mortality, despite clear improvements in overall health.32 Differences in the daily caloric intake, onset of the intervention, diet composition, feeding protocols, sex, and genetic background may explain the differential effects of caloric restriction on life span in the two studies.7
In humans, intermittent-fasting interventions ameliorate obesity, insulin resistance, dyslipidemia, hypertension, and inflammation.33 Intermittent fasting seems to confer health benefits to a greater extent than can be attributed just to a reduction in caloric intake. In one trial, 16 healthy participants assigned to a regimen of alternate-day fasting for 22 days lost 2.5% of their initial weight and 4% of fat mass, with a 57% decrease in fasting insulin levels.34 In two other trials, overweight women (approximately 100 women in each trial) were assigned to either a 5:2 intermittent-fasting regimen or a 25% reduction in daily caloric intake. The women in the two groups lost the same amount of weight during the 6-month period, but those in the group assigned to 5:2 intermittent fasting had a greater increase in insulin sensitivity and a larger reduction in waist circumference.20,27
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Edited by Engadin, 27 December 2019 - 08:59 PM.
