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.
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.11,12ge 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,24poly(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
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 span29suggesting 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.32Differences 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
Physical and Cognitive Effects of Intermittent Fasting
In animals and humans, physical function is improved with intermittent fasting. For example, despite having similar body weight, mice maintained on alternate-day fasting have better running endurance than mice that have unlimited access to food. Balance and coordination are also improved in animals on daily time-restricted feeding or alternate-day fasting regimens.35Young men who fast daily for 16 hours lose fat while maintaining muscle mass during 2 months of resistance training.36
Studies in animals show that intermittent fasting enhances cognition in multiple domains, including spatial memory, associative memory, and working memory37; alternate-day fasting and daily caloric restriction reverse the adverse effects of obesity, diabetes, and neuroinflammation on spatial learning and memory (see Section S4).
In a clinical trial, older adults on a short-term regimen of caloric restriction had improved verbal memory.38 In a study involving overweight adults with mild cognitive impairment, 12 months of caloric restriction led to improvements in verbal memory, executive function, and global cognition.39More recently, a large, multicenter, randomized clinical trial showed that 2 years of daily caloric restriction led to a significant improvement in working memory.40 There is certainly a need to undertake further studies of intermittent fasting and cognition in older people, particularly given the absence of any pharmacologic therapies that influence brain aging and progression of neurodegenerative diseases.12
Clinical Applications
In this section, we briefly review examples of findings from studies of intermittent fasting in preclinical animal models of disease and in patients with various diseases.
OBESITY AND DIABETES MELLITUS
In animal models, intermittent feeding improves insulin sensitivity, prevents obesity caused by a high-fat diet, and ameliorates diabetic retinopathy.41 On the island of Okinawa, the traditional population typically maintains a regimen of intermittent fasting and has low rates of obesity and diabetes mellitus, as well as extreme longevity.42 Okinawans typically consume a low-calorie diet from energy-poor but nutrient-rich sources, particularly Okinawan sweet potatoes, other vegetables, and legumes.42 Likewise, members of the Calorie Restriction Society, who follow the CRON (Calorie Restriction with Optimal Nutrition) diet,43-45 have low rates of diabetes mellitus, with low levels of insulin-like growth factor 1, growth hormone, and markers of inflammation and oxidative stress.4,20,33,43
A multicenter study showed that daily caloric restriction improves many cardiometabolic risk factors in nonobese humans.46-50 Furthermore, six short-term studies involving overweight or obese adults have shown that intermittent fasting is as effective for weight loss as standard diets.51 Two recent studies showed that daily caloric restriction or 4:3 intermittent fasting (24-hour fasting three times a week) reversed insulin resistance in patients with prediabetes or type 2 diabetes.52,53 However, in a 12-month study comparing alternate-day fasting, daily caloric restriction, and a control diet, participants in both intervention groups lost weight but did not have any improvements in insulin sensitivity, lipid levels, or blood pressure, as compared with participants in the control group.54
CARDIOVASCULAR DISEASE
Intermittent fasting improves multiple indicators of cardiovascular health in animals and humans, including blood pressure; resting heart rate; levels of high-density and low-density lipoprotein (HDL and LDL) cholesterol, triglycerides, glucose, and insulin; and insulin resistance.41,43,47,55 In addition, intermittent fasting reduces markers of systemic inflammation and oxidative stress that are associated with atherosclerosis.17,27,36,56 Analyses of electrocardiographic recordings show that intermittent fasting increases heart-rate variability by enhancing parasympathetic tone in rats57 and humans.58 The CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) study showed that a 12% reduction in daily calorie intake for a period of 2 years improves many cardiovascular risk factors in nonobese persons.46-50 Varady et al. reported that alternate-day fasting was effective for weight loss and cardioprotection in normal-weight and overweight adults.59 Improvements in cardiovascular health indicators typically become evident within 2 to 4 weeks after the start of alternate-day fasting and then dissipate over a period of several weeks after resumption of a normal diet.57
CANCER
More than a century ago, Moreschi and Rous described the beneficial effect of fasting and caloric restriction on tumors in animals. Since then, numerous studies in animals have shown that daily caloric restriction or alternate-day fasting reduces the occurrence of spontaneous tumors during normal aging in rodents and suppresses the growth of many types of induced tumors while increasing their sensitivity to chemotherapy and irradiation.7-9,60 Similarly, intermittent fasting is thought to impair energy metabolism in cancer cells, inhibiting their growth and rendering them susceptible to clinical treatments.61-63 The underlying mechanisms involve a reduction of signaling through the insulin and growth hormone receptors and an enhancement of the forkhead box O (FOXO) and nuclear factor erythroid 2–related factor 2 (NRF2) transcription factors. Genetic deletion of NRF2 or FOXO1 obliterates the protective effects of intermittent fasting against induced carcinogenesis while preserving extension of the life span,64,65 and deletion of FOXO3 preserves the anticancer protection but diminishes the longevity effect.66Activation of these transcription factors and downstream targets by means of intermittent fasting may provide protection against cancer while bolstering the stress resistance of normal cells (Figure 1).
Clinical trials of intermittent fasting in patients with cancer have been completed or are in progress. Most of the initial trials have focused on compliance, side effects, and characterization of biomarkers. For example, a trial of daily caloric restriction in men with prostate cancer showed excellent adherence (95%) and no adverse events.67 Several case studies involving patients with glioblastoma suggest that intermittent fasting can suppress tumor growth and extend survival.9,68 Ongoing trials listed on ClinicalTrials.gov focus on intermittent fasting in patients with breast, ovarian, prostate, endometrial, and colorectal cancers and glioblastoma (see Supplementary Table S1). Specific intermittent-fasting regimens vary among studies, but all involve imposition of intermittent fasting during chemotherapy. No studies have yet determined whether intermittent fasting affects cancer recurrence in humans.9
NEURODEGENERATIVE DISORDERS
Epidemiologic data suggest that excessive energy intake, particularly in midlife, increases the risks of stroke, Alzheimer’s disease, and Parkinson’s disease.69 There is strong preclinical evidence that alternate-day fasting can delay the onset and progression of the disease processes in animal models of Alzheimer’s disease and Parkinson’s disease.5,12 Intermittent fasting increases neuronal stress resistance through multiple mechanisms, including bolstering mitochondrial function and stimulating autophagy, neurotrophic-factor production, antioxidant defenses, and DNA repair.12,70 Moreover, intermittent fasting enhances GABAergic inhibitory neurotransmission (i.e., γ-aminobutyric acid–related inhibitory neurotransmission), which can prevent seizures and excitotoxicity.71 Data from controlled trials of intermittent fasting in persons at risk for or affected by a neurodegenerative disorder are lacking. Ideally, an intervention would be initiated early in the disease process and continued long enough to detect a disease-modifying effect of the intervention (e.g., a 1-year study).
ASTHMA, MULTIPLE SCLEROSIS, AND ARTHRITIS
Weight loss reduces the symptoms of asthma in obese patients.72 In one study, patients who adhered to the alternate-day fasting regimen had an elevated serum level of ketone bodies on energy-restriction days and lost weight over a 2-month period, during which asthma symptoms and airway resistance were mitigated.17 A reduction in symptoms was associated with significant reductions in serum levels of markers of inflammation and oxidative stress.17 Multiple sclerosis is an autoimmune disorder characterized by axon demyelination and neuronal degeneration in the central nervous system. Alternate-day fasting and periodic cycles of 3 consecutive days of energy restriction reduce autoimmune demyelination and improve the functional outcome in a mouse model of multiple sclerosis (experimentally induced autoimmune encephalomyelitis).73,74 Two recent pilot studies showed that patients with multiple sclerosis who adhere to intermittent-fasting regimens have reduced symptoms in as short a period as 2 months.73,75 Because it reduces inflammation,17 intermittent fasting would also be expected to be beneficial in rheumatoid arthritis, and indeed, there is evidence supporting its use in patients with arthritis.76
SURGICAL AND ISCHEMIC TISSUE INJURY
Intermittent-fasting regimens reduce tissue damage and improve functional outcomes of traumatic and ischemic tissue injury in animal models. Preoperative fasting reduces tissue damage and inflammation and improves the outcomes of surgical procedures.77 In animal models of vascular surgical injury, 3 days of fasting reduced ischemia–reperfusion injury in the liver and kidneys and, before the injury, resulted in a reduction in trauma-induced carotid-artery intimal hyperplasia.78 A randomized, multicenter study showed that 2 weeks of preoperative daily energy restriction improves outcomes in patients undergoing gastric-bypass surgery.79 Such findings suggest that preoperative intermittent fasting can be a safe and effective method of improving surgical outcomes.
Several studies have shown beneficial effects of intermittent fasting in animal models of traumatic head or spinal cord injury. Intermittent fasting after injury was also effective in ameliorating cognitive deficits in a mouse model of traumatic brain injury.80 When initiated either before or after cervical or thoracic spinal cord injury, intermittent fasting reduces tissue damage and improves functional outcomes in rats. Emerging evidence suggests that intermittent fasting may enhance athletic performance and may prove to be a practical approach for reducing the morbidity and mortality associated with traumatic brain and spinal cord injuries in athletes. (See the section above on the physical effects of intermittent fasting.) Studies in animals have shown that intermittent fasting can protect the brain, heart, liver, and kidneys against ischemic injury. However, the potential therapeutic benefits of intermittent fasting in patients with stroke or myocardial infarction remain to be tested.
Conclusions
Preclinical studies and clinical trials have shown that intermittent fasting has broad-spectrum benefits for many health conditions, such as obesity, diabetes mellitus, cardiovascular disease, cancers, and neurologic disorders. Animal models show that intermittent fasting improves health throughout the life span, whereas clinical studies have mainly involved relatively short-term interventions, over a period of months. It remains to be determined whether people can maintain intermittent fasting for years and potentially accrue the benefits seen in animal models. Furthermore, clinical studies have focused mainly on overweight young and middle-age adults, and we cannot generalize to other age groups the benefits and safety of intermittent fasting that have been observed in these studies.
Although we do not fully understand the specific mechanisms, the beneficial effects of intermittent fasting involve metabolic switching and cellular stress resistance. However, some people are unable or unwilling to adhere to an intermittent-fasting regimen. By further understanding the processes that link intermittent fasting with broad health benefits, we may be able to develop targeted pharmacologic therapies that mimic the effects of intermittent fasting without the need to substantially alter feeding habits.