The effects of intermittent fasting on human and animal health –

a systematic review

Bojan Kostevski

Center for Primary Health Care Research, Lund University, CRC, SE-205 02 MALMÖ, Sweden

University of Lund, 2011

Keywords: intermittent fasting, calorie restriction, obesity, aging, cardiovascular health, glucose metabolism, cancer, neurodegenerative disease.

Abstract

An increasing number of animal studies have shown altered markers for health in subjects exposed to intermittent fasting, i.e. regularly and repeatedly abstaining from eating during 12-36 hours per period. It has been hypothesized that the reported beneficial health effects from caloric restriction on excess body weight, cardiovascular risk factors, glucose metabolism, tumor physiology, neurodegenerative pathology and life span can be mimicked by alternating periods of short term fasting with periods of refeeding, without deliberately altering the total caloric intake. Therefore, a systematic review of available intervention studies on intermittent fasting and animal and human health was performed. In rodents, intermittent fasting exhibits beneficial effects including decreased body weight, improved cardiovascular health and glucose regulation, enhanced neuronal health, decreased cancer risk and increased life span – some of the effects independent of the effects attributed to calorie restriction alone. The human studies performed to date are generally of low-quality design. Beneficial effects such as weight loss, reduced risk for cardiovascular disease and improved insulin sensitivity have been observed, but conflicting data exists. The potential health promoting effects of intermittent fasting in humans and applicability to modern lifestyle are discussed.

Introduction

Calorie restriction and intermittent fasting

Almost a century has passed since Osborne and colleagues in 1917 observed that reducing calorie intake in rats increased the animal’s life span (1). In 1935, McCay et al. were first to describe that calorie restriction – deliberately reducing calories without causing malnutrition – prolongs mean and maximal lifespan in rats compared with rats fed ad libitum (2). Numerous subsequent studies have confirmed that a calorie restriction of 30 to 60 percent of ad libitum intake increases the life span by similar amounts in a range of organisms including yeast, roundworms and rodents, while simultaneously decreasing or delaying the occurrence of age related diseases such as numerous cancers (including lymphomas, breast and prostate cancers), hypertension, stroke, diabetes, nephropathy, autoimmune disorders and other risks factors for cardiovascular disease (3,4). Furthermore, it is suggested that calorie restriction can display beneficial effects in rodent models of various neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease (5). Accordingly, overeating is considered a risk factor for the majority of the conditions mentioned above, further supporting the hypothesis that calorie restriction can be beneficial (6,7). To further explore the relevance of these findings in rodents on primate health, a study was initiated at the Wisconsin National Primate Research Center (WNPRC) in 1989, studying a 30% calorie restriction in rhesus monkeys (8). The incidence of diabetes, cancer, cardiovascular disease and brain atrophy was reduced in animals on the calorie restricted diet compared with monkeys on the control diet. Twenty years into the study, 80% of the calorie restricted animals were still alive, compared with 50% of the control fed animals. The data obtained to date suggest that calorie restriction slows aging in primates and improves health.

Calorie restriction in humans is associated with weight loss, reduced inflammation and improved markers for cardiovascular and metabolic health in obese{Formatting Citation} (9,10) as well as non-obese (11,12) subjects, proposing a novel therapy for increasing life span. However, adherence to the recommended calorie reduced/low fat diet remains an issue for some people in the long term (13,14).

To improve compliance in human subjects, a model in which calories are periodically restricted has been proposed. Intermittent fasting is a paradigm where periods of fasting are cycled with periods of over-eating where subjects are fed ad libitum. Alternate-day fasting, one model of intermittent fasting has been widely used in animal calorie restriction research because it has shown to result in reduced food intake over time and decrease body weight in rats (15). In human trials, intermittent fasting has been shown to be equally effective as daily calorie restriction for causing weight loss in obese subjects (16).

While alternate-day fasting leads to calorie restriction over a two-day period in many rodent species, in some strains of mice, the animals managed to compensate for the calorie deficit created on fast days by increasing their intake on feast days twofold and thus keeping the total calorie intake over a two day period at the same level as in mice fed an ad libitum diet (17). These mice managed to maintain constant body weight but, interestingly, still acquired some of the health benefits as rats on daily calorie restriction. This lead to the hypothesis that by implementing periods of fasting, one could improve health without deliberately reducing calorie intake. My objective was to review relevant intervention studies on the effects of intermittent fasting on energy balance, cardiovascular risk factors, glucose metabolism, neurodegenerative pathology, tumor physiology and life span.

Significance: The study will be important for the understanding of excess caloric intake and the management of obesity, and identify ways to alter cardiovascular, metabolic and neuronal health.

Methods

A systematic review of intervention studies in mammals, including humans was performed. PubMed between 1973 and 2011 was searched by use of relevant MeSH terms related to the effects of intermittent fasting on excess body weight, energy balance, aging physiology, cardiovascular risk factors, glucose metabolism, tumor physiology and neurodegenerative pathology. For each of the MeSH terms, the search process was restricted by use of non-MeSH terms such as “intermittent fasting”, “periodic fast”, “alternate-day fasting” and other relevant terms. All terms used are listed in Table 1. Furthermore, relevant review articles on calorie restriction and intermittent fasting were reviewed for additional relevant studies to include in the review. Studies were included in the review if short term fasting was the primary intervention and studied any of the above mentioned outcomes. Studies that purposely restricted calories in the intermittent fasting group were excluded.

Animal trials

Energy intake and body composition

A total of 36 studies were found. When an alternate-day fasting diet is implemented, overall calorie restriction and weight reduction occurs in most rodent species, indicating that the restriction on the fasting day isn’t compensated fully on feasting days when food is offered ad libitum (18-34). Consequently, alternate-day fasting is a widely used model for studying the effects of calorie restriction in rodent species (15). This however is not a universal finding and numerous studies have reported no alterations in energy intake and body weight (17,35-39). In general, studies using Sprague-Dawley and Wistar rats show decreased energy intake and reduced body weights (15,25). However, C57BL/6 mice maintained on the same alternate-day fasting regimen consume similar food quantities in a 48-hour time period and maintain body weights similar to that of mice fed ad libitum (17). The effect of intermittent fasting on body weight thus seems largely dependent on the animal genotype but could also be affected by the age of initiation, with optimal age varying in the various rodent strains (40).

Modified alternate-day fasting is one alternative model sometimes used in the intermittent fasting research. In this model, the animals are not completely fasted every other day, but allowed a small energy intake of 15-25% of the daily intake consumed by ad libitum fed animals. Modified alternate-day fasting could allow for better maintenance of body weight than true alternate-day fasting protocols (a complete every other day fast) (30,38). The complete compensation and increased energy intake does not appear to be dependent on the calorie density of the food, since neither a high-fat or low-fat 85% modified alternate-day fasting diet alters body weight compared to ad libitum feeding over a four week period (41).

Total body weight however does not reflect alterations in body composition, and there could be changes in lean mass to fat mass ratio or altered fat distribution which of course would not be reflected in the animal’s body weight alone. Alterations in fat distribution were demonstrated in one study in which mice on both true and modified alternate-day fasting diets showed a redistribution of adipose tissue from visceral to subcutaneous depots without altering body weight overall (39).

Cardiovascular health

Four rodent studies that examined the effect of alternate-day fasting on cardiovascular disease were included. In general, rats maintained on an alternate-day fasting regimen lose bodyweight and display reduced blood pressure and heart rate, and improved insulin sensitivity, compared to rats fed ad libitum (28,29,42). Reduced blood pressure was also demonstrated in diabetic rats, proposing that alternate-day fasting can have a preventive effect on the progression of diabetes nephropathy (32).This data is suggesting that intermittent fasting may reduce the risk of cardiovascular disease.

Furthermore, when myocardial infarction was induced in rats maintained on an alternate-day fasting diet, reduced infarction size, improved cardiac function, and increased survival was observed, compared to rats fed ad libitum (24,33,43). More interestingly, the effects on infarction size, survival rates and cardiac function can be observed even if the dietary intervention is induced after the ischemic event, by increasing the expression of angiogenic factors and increased vascularization of the damaged myocardium, proposing a novel non-pharmacological therapy for subjects with chronic heart failure (43).

A possible contributing factor for the cardio protective effects of intermittent fasting is increased levels of adiponectin, a hormone that exhibits both anti-athrogenic and insulin sensitizing effects and has been shown to protect cardiac myocytes against ischemic injury (44,45). Interestingly, alternate-day fasting demonstrates increased adiponectin levels in numerous rodent studies, even in the absence of calorie restriction and weight loss (39,46).

Glucose metabolism

A total of seven studies were found. Increased insulin sensitivity, as indicated by decreased fasting concentrations of glucose and insulin, has been demonstrated in rodents on alternate-day fasts both with (19,28,33) and without (17) decreased calorie intake. Anson et al. showed that mice on alternate-day fasting regimen who consume the same amount of food in a 48-hour period as mice fed ad libitum, decreased glucose and insulin concentrations to a similar degree as did mice on daily calorie restriction despite maintained energy intake and body weight (17). In another study, as little as two 24 hour fasts per week, without calorie reduction overall, were sufficient to improve insulin sensitivity in mice (46). In diabetic rats, alternate-day fasting reduces blood pressure, normalizes HDL levels, protects against glomerular damage and prevents development of diabetes nephropathy (32). These findings suggest beneficial effects on glucose metabolism and improved markers associated with obesity and the metabolic syndrome.

Brain pathology

A total of 17 studies were included. Numerous aspects of intermittent fasting and neuronal health have been examined in rodent species. Compared to rats fed ad libitum, alternate day fasted rats showed protection of age-related changes in dendritic spine number and morphology (20). Other rodent experiments have showed increased neurogenesis in brains of rats maintained on an alternate-day fasting diet, as evident by increased number of newly generated neural cells in the hippocampus (21). These results suggest that intermittent fasting could hinder morphological neuronal changes seen with normal aging and could thus slow down the neuronal aging process. Other observed effects in mice include increased synaptic plasticity in the hippocampus and enhancement of learning abilities and other cognitive functions (47).

Intermittent fasting potentially exhibits desirable effects in manifest neuronal diseases. Rats maintained on alternate-day fasting diets show reduced brain damage and mortality rate in rodent models of stroke (19,31). After a period of 2–4 months on alternate-day fasting, a neuroprotective effect against induced hippocampal excitotoxic damage was observed (25). Epileptic seizures in animals maintained on an alternate-day fasting diet lead to decreased brain damage (22,26,34). Beneficial effects have been demonstrated in animal models of neurodegenerative diseases such as Alzheimer’s (25,48) and Parkinson’s (18) disease. Furthermore, in an animal model of Huntington’s disease, prolonged survival, reduced disease-associated weight loss and improved motor function was observed in animals on an alternate-day fasting diet compared to animals fed ad libitum (49). Interestingly, the protective effect of intermittent fasting against induced excitotoxic brain damage has been demonstrated in mice despite no reduction in calorie intake or weight loss. Furthermore, mice on alternate-day fasting diets showed greater resistance to excitotoxic injury than mice on daily, controlled calorie restriction (17).

When mice with progressive demyelinating disorders of the peripheral nervous system were put on an alternate-day fasting diet regime, hampered disease progression was observed as indicated by improved nerve morphology and performance compared to mice fed ad libitum (37). Furthermore, alternate-day fasting leads to increased functional recovery after experimentally induced spinal cord injuries in rats, independently if the alternate-day fasting regimen is implemented prior or after the spinal cord is injured (27,50). If this effect is demonstrated in humans, intermittent fasting could potentially serve as a non-pharmacological therapeutic alternative in the rehabilitation process in subjects with spinal cord injuries. The effect in mice was greater with alternate-day fasting compared to daily calorie restriction, suggesting that increased time span in the fasted state has additive effects other than those attributed to calorie restriction alone (27).

The beneficial effect does however not appear universal to all neurologic disorders. No desirable effect was observed in an animal model of amyotrophic lateral sclerosis (ALS), indicating that intermittent fasting has no beneficial effect on the development of this motor neuron disease (51).

Cell proliferation and cancer

To study the potential anti-carcinogenic effect of intermittent fasting, three different aspects of tumorgenesis have been studied: circulating markers of insulin-like growth factor-1 (IGF-1), cell proliferation rates, and direct effect of intermittent fasting on carcinogenesis in animal models. Seven studies were included.

Subjects with elevated IGF-1 levels have been reported to exhibit increased risk of several cancer types. Furthermore, high circulating levels of insulin and IGF-1 in combination are often seen in subjects with obesity, insulin resistance and type 2 diabetes, patient categories that are also more likely to be affected by cancers (52). Rats on alternate-day fasting diets showed decreased levels of IGF-1 and proliferation rates of T-cells and prostate cells (30). Cell proliferation rates are considered a central element in the development of cancers (53). Decreased cell proliferation has previously been demonstrated with reduced feeding frequency alone, despite matched calorie intake (54). Mice put on a 85% modified alternate-day fast (eating 15% of ad libitum daily energy intake on fasting days) reduced IGF-1 levels and decreased proliferation rates of epidermal, prostate, splenic T and liver cells, despite no weight change (41). In a third study, true but not modified alternate-day fasting decreased IGF-1 levels in mice. Cell proliferation rates were however reduced in both groups, even in the absence of weight loss (38).

There is however some conflicting data in regard to intermittent fasting and IGF-1. Two 24 hour fasts/week without overall calorie restriction showed increased levels of IGF-1 and no effects on tumor size or survival in rats with prostate cancer (46). One might suspect that two 24 hour fasts per week would be insufficient to exhibit the anti-carcinogenic effects. However, Anson et al. displayed increased levels of IGF-1 in mice on alternate-day fasting diets with maintained body weight compared to controls, in contrast to mice on daily calorie restriction who showed decreases in bodyweight and decreased IGF-1 (17). The authors suggested a difference in the way intermittent fasting and calorie restriction influence the growth hormone -IGF-1 axis and insulin signaling pathways. The relevance of IGF-1 for tumor growth in intermittently fasted animals, with or without calorie restriction remains thus a subject for further clarification.

Recent research has also examined intermittent fasting and its direct effect on tumor development. OF1 is a strain of mice that spontaneously develops age related lymphomas at a high rate. In a 16 week trial, none of the mice of this particular strain fed on alternate days developed lymphomas compared to 33% of mice in the control group fed ad libitum (36). There was no difference in food intake or body weight between the two groups, suggesting that intermittent fasting has a protective effect on lymphoma development in this mouse strain, and that the effect was independent of the total calorie intake. The effect of intermittent fasting on induced hepatocarcinogenesis has also been examined. When rats were put on a 48 hour fasting regimen once per week, they developed less preneoplastic lesions compared to rats fed ad libitum over a 48 week period (55). The effects of shorter, more frequent fasts, such as alternate-day fasting on hepatocarcinogenesis remains a subject for future research.

Consequently, studies to date indicate that intermittent fasting hampers cell proliferation rates in a variety of cell types, and that it could potentially protect against direct development of some cancer types.

Life span

Two studies looked at survival per se. They propose that animals on alternate-day fasting diets increase life span compared to those fed ad libitum (15,40). The magnitude of life span enhancement seems to be dependent on animal strain and age of initiation (40). Furthermore, in one study, only rats on alternate-day fasting diets survived to 30 months of age compared to a mean lifespan of 22-24 months for rats fed ad libitum (20).

It is merely speculative if the effect on longevity is secondary to the above described effects such as decreased body weight, improved insulin sensitivity, improved cardiovascular health, decreased tumor growth and improved neuronal health, or if intermittent fasting might have some distinctive effect on the aging process. No study to date has specifically studied the effect of intermittent fasting without calorie restriction on lifespan, although the effects that have been described are expected to increase life span. Interestingly, the largest magnitude of life span expansion (25 percent increase in mean life span) is seen in C57BL/6J mice, the same strain that in many of the studies on alternate-day fasting maintain a constant total energy intake and body weight (40).

Other effects

Some other interesting effects than the primary addressed in this review were observed in various studies. Many strains of laboratory rats develop spontaneous progressive kidney failure with development of proteinuria and glomerulosclerosis. Rats fed on alternate days showed preserved kidney function as demonstrated by preserved glomerular filtration rate and renal plasma flow, compared to rats fed ad libitum (56). Another surprising finding in rats maintained on intermittent fasting is increased testicular mass and testosterone/estrogen ratio compared to control rats or rats on a calorie restriction diet (57). Analgesia, which may be attributed to negative modulation of synaptic transmission in nociceptive neurons in the dorsal horn of the spinal cord, has also been reported in rats maintained on an alternate-day fasting diet (35). This finding opens up the question whether intermittent fasting alone or in combination with a pharmacological agent could serve as a useful new therapeutic approach for treating pain.

Human studies

The Ramadan fast

Fasting is one of the five pillars of Islam. During the holy month of Ramadan, Muslims restrain from fluid and food intake during daytime for the whole month. Worldwide, there are more than one billion Muslims, of whom the majority fast annually (58). The holy month of Ramadan could thus potentially be a good period to study prolonged short term intermittent fasting in humans on a large scale. A total of 17 studies were found. Conclusions are however very hard to draw from these studies. Apart from the obvious difficulties with doing randomized controlled trials there is a number of confounding factors (59,60). Such confounding variables include:

Altered food choices and macronutrient distribution during the fasting month

Dehydration and the difficulties with reliable lab tests

Changes in activity patterns

Reduced sleep due to nighttime eating and socializing

Differences in fasting length and hydration status in different geographical locations and time of year

Furthermore, the studies were generally of poor study design with few participants and lack of control group. As a result the studies are highly inconclusive with the effects on body weight and blood lipids with some studies showing unchanged body weight (59,61) while others show weight loss (62). Therefore, no objective conclusions could be made about this type of short term intermittent fasting and cardiovascular and metabolic risk factors, and further research of higher quality is warranted.

In one observational study, young competitive soccer players were sent to a training camp 3 week’s prior to, and during, the Ramadan fast. The fasting participants were compared to the non-fasting participants and all food was delivered from the same kitchen, thus eliminating some of the confounding factors above (60,63). Apart from a small difference in body weight (0,7 kg) that could be explained by hydration status between the two groups, no differences were observed in blood glucose levels, hematocrit, cortisol levels, inflammation markers or physical performance. In another study, fasting healthy men and women were compared to a matched non-fasting group with regard to inflammation markers and blood lipid status (61). No differences were observed in body weight, total cholesterol, triglycerides or LDL levels. There was however an increase in HDL levels and decreased inflammation – proposing a beneficial effect in the fasted subjects.

Thus, there are some data suggesting altered health markers during the month of Ramadan, but more research is needed if any objective conclusions about this type of intermittent fasting and the factors studied in this review ought to be drawn.

Alternate-day fasting

To date, very few human intervention studies have tried to replicate the reported effects of alternate-day fasting seen in rodent studies. Only six such studies were found, with somewhat disappointing study designs (64-69). The sample size in these studies was rather small, ranging from eight to sixteen participants, and the study period was often very short. Only one trial included a control group. The results are summarized in Table 2.

In both true alternate-day fasting trials, a decreased body weight was observed (66,67). In modified alternate-day fasting trials, maintained bodyweight was observed in lean (65,69) but not obese (64,68) subjects. In obese subjects, a modified 8-10 week alternate-day fasting regimen resulted in weight loss, reduced blood pressure and heart rate, and improved markers for cardiovascular health, such as decreased total cholesterol, decreased LDL and triglycerides, increased HDL concentrations and decreased oxidative stress and systemic inflammation, suggesting that alternate-day fasting might be a novel strategy for decreasing body weight and improving cardiovascular health in the obese population (64,68).

To examine the effects of alternate-day fasting on glucose metabolism, eight healthy men were maintained on a 20h modified alternate-day fast for two weeks. Despite unaltered body weight and habitual physical activity, insulin dependent glucose uptake increased, and increased adiponectin levels were observed (65). In another trial, the insulin sensitizing effect of true alternate-day fasting was observed through reduced insulin response to a standardized meal in men, but not women – suggesting a potential sex difference in the effect of alternate-day fasting on glucose metabolism (66). Although not demonstrated in all human studies (68,69), these results indicate that alternate-day fasting might mimic the insulin sensitizing effects observed in rodents on alternate-day fasting diet, and that the effect might be due to increased adiponectin levels.

Sex differences were also observed in another study where healthy men and women were fasted on alternate days. In this study, HDL levels were increased in women only, and triglycerides were decreased in men but not women (67). Increased insulin sensitivity was suggested by decreased insulin levels with unaltered glucose levels. In this study, blood pressure was unaltered, but the study duration was merely 22 days. In contrast, one trial showed decreased blood pressure and resting heart rates in subjects on modified alternate-day fasting regimens for 10 weeks, suggesting that longer intervention periods might be needed for this effect to occur (64). There is, however, conflicting data from another study that utilized a two week crossover study design and randomized eight healthy men to a modified alternate-day fasting diet or a standard diet. No differences were observed in body weight, blood lipids, glucose metabolism or hormone levels, and there was a decrease in energy expenditure after the 2 week period in the alternate-day fasting group (69). More controlled studies, with larger sample sizes and longer study durations are thus needed to bring clarification in this matter.

No human trial has directly examined intermittent fasting and tumor physiology. A single two day fast increases endogenous GH-production fivefold, reflecting the metabolic adaptation to fasting, including increased hepatic glucose production, lipolysis and nitrogen conservation (70). However no significant changes in IGF-1 are seen after a single fast period in human subjects, suggesting that repeated fasts and longer intervention periods might be necessary to mimic the changes in IGF-1 and altered cancer growth observed in some rat studies. Whether a prolonged alternate-day fasting regimen can alter IGF-1 levels in humans remains an area for future research. Furthermore, no human trials to date have examined the effects of intermittent fasting on neuronal health or life span.

Mechanisms of calorie restriction and intermittent fasting

The exact mechanism by which calorie restriction and intermittent fasting exhibits its effects on various organ systems remains unknown. The main hypothesis includes a stress preconditioning response mechanism, in which it is believed that periods of nutrient deprivation displays a beneficial mild stress that results in molecular adaptive changes in various tissues, which increases the organism’s resistance to bigger stressors such as excitotoxic and oxidative injury, including ischemia (33,71). Alternating periods of anabolism and catabolism during intermittent fasting might further increase the cellular stress resistance. Other displayed effects are increased production of neutrophilic factors and antioxidant enzymes, ketone body formation and altered metabolism enzyme production (5).

Potential adverse effects from fasting

Blood glucose levels, mood and cognition

A variety of questions often arises when discussing intermittent fasting and human health. It is often believed that blood sugar levels will fall to pathological levels if prolonged fasts are implemented. A characteristic decline in mood and energy levels before lunch among humans is often attributed to a drop in blood sugar. However when actually testing blood sugar levels in healthy subjects prone to this phenomena, no actual decline in blood sugar to pathologic levels was seen during a 24 hour fast (72). In healthy human subjects, a 24 hour fast decreases liver glycogen stores no more than 57% and in absence of vigorous exercise does not lead to muscle glycogen consumption, suggesting that liver glycogen stores are sufficient after a 24 hour fast to keep blood glucose levels within normal range (73). Furthermore, a double-blind, placebo-controlled study of two days of calorie deprivation showed no adverse effect on cognitive performance, activity, sleep, and mood, when the subjects were unaware of the calorie content of the treatments (74).

Hunger

The homeostasis of body weight regulation and hunger signaling is composed of complex circuits of both central signals including orexin, neuropeptide Y, melanin concentrating hormone and alpha-melanocyte, and peripheral signals from the gut and adipose tissue, such as ghrelin, peptide YY and leptin (75). The interplay between these and other endocrine signaling systems and its effect on body weight regulation and subjective feelings of hunger and satiety remains largely unknown. The hunger response however seems to be highly adaptive in different meal patterns. Ghrelin, a gut derived hormone, is considered a meal-initiation signal. It increases during fasting and usually peaks in concentration before an anticipated meal, paired with increased feelings of hunger, and decreases after feeding. Interestingly, the rise in ghrelin is independent of meal timing as demonstrated by similar peaks before an anticipated meal in various meal frequencies, thus suggesting that subjective feelings of hunger and energy intake is highly dependent on the individual’s preferred meal pattern (76).

Increases in subjective feelings of hunger might be the single most important factor to consider when discussing the applicability of intermittent fasting as a therapeutic or preventive intervention in human subjects. In obese patients, a 14 day total fast lead to strikingly decreased body weights and decreased blood pressure, without causing increased hunger sensations. Thus a hunger suppressing effect of prolonged fasting was demonstrated (77). This anorexic effect might be attributed to the evolutionary purpose of seeking for nutrients in absence of food. The experiment, dating back to 1962, was effective and well tolerated.

Only one study has directly examined the feelings of hunger and fullness in non-obese subjects on an intermittent fasting diet, by using a 100 mm visual analog scale (67). The subjects were fasted on alternate days and reported an increased feeling of hunger from 37 to 56 mm and decrease in feeling of fullness from 43 to 23 mm when the dietary intervention was initiated. The magnitude of hunger did however not change during the intervention period as repeated measurements were taken, and feelings of fullness actually increased some over time. The duration of this study was only 22 days and it is still purely speculative whether and adaptation to the new meal pattern would occur in a longer time span. In contrast, modified alternate-day fasting in obese asthmatic patients did not significantly increase the subjective perception of hunger from baseline during the eight week long intervention period (68).

Whether repeated bouts of short term fasting can alter hunger hormone signaling or demonstrate the same anorexic effect as the long term fast described above is highly speculative and an interesting area for future research.

Decreased metabolic rate

It is commonly believed that multiple small meals increase metabolism and lead to increased overall energy expenditure. Following every meal there is an increase in expenditure due to the processing of the nutrients, commonly referred to Thermic Effect of Food (TEF) (78). A common belief therefore is that increased meal frequency leads to increased TEF and increased overall energy expenditure with multiple meals, and that intermittent fasting accordingly would decrease metabolic rate and lead to increased fat accumulation and possibly obesity. According to current research though, TEF is proportional to the calorie content and vary with macronutrient composition (with the highest increase in energy expenditure observed with a high protein diet) and not meal frequency per se, as demonstrated by the equal TEF in different meal patterns under iso-caloric conditions (79,80). Furthermore, one study examined alterations in resting metabolic rate in human subjects on alternate-day fasting diets, and found no changes after a 22 day period (67). According to these findings, any potential decreases in metabolic rate would be due to decreased total calorie intake and not fasting per se.

Increased stress

Increased levels of both ACTH and corticosteroids can be noted in rodents maintained on alternate-day fasting diets compared with rats fed ad libitum (28,29,42). Apart from the obvious notion that cortisol is one of the major hormones responsible for glucose utilization during fasting, the question arises whether the increased stress in any way could be harmful to the human organism. The molecular stress response in intermittently fasted subjects seems markedly different from the one associated with uncontrolled stress. In fasted rodents there is actually a down regulation of glucocorticoid receptors in the brain, with maintained expression of mineralocorticoid receptors, suggesting that fasting might alter the brain’s responsiveness to glucocorticoids (81). In contrast, in uncontrolled stress, down regulation of the mineral corticoid receptor has been noted. Furthermore, deleterious stress responses are associated with a decrease in the expression of brain-derived neurotrophic factor (BDNF), a response quite the opposite of calorie restriction and intermittent fasting, where increased concentrations of BDNF have been observed in numerous studies (4). In conclusion, the controlled stress response from intermittent fasting seems fundamentally different from the one by uncontrolled physiological and psychological stress. Conversely, In line with the mechanisms described above, the increased stress might be one of the necessary factors for initiating molecular resistance for larger stressors, and thus promote some of the beneficial effects of intermittent fasting.

Loss of muscle mass

One potential serious side effect of intermittent fasting would be loss of muscle mass. Theoretically, food deprivation would result in depleted hepatic glycogen stores, leading to increased proteolysis and flux of amino acids from skeletal muscle for hepatic de novo gluconeogenesis, to maintain healthy blood glucose concentrations. As discussed previously though, a 24 hour short term fast is insufficient in duration to deplete liver glycogen stores in healthy subjects (73). Up to 40 hours of total fasting does not stimulate catabolic processes and lead to skeletal muscle atrophy (82). Modified alternate-day fasting and loss of lean body mass was investigated in only one study in the systematic search. No loss of fat free mass in the absence of weight loss was observed compared to a control group fed a standardized diet (69). Furthermore, an increase in ketone body concentrations has been observed in subjects on alternate-day fasting diets in both human and animal studies (17,68). Ketone bodies spare skeletal muscle from breakdown by providing non-glucose energy substrate for various tissues, of which the brain is the most important, and thus decrease the need for protein-derived substrates for gluconeogenetic conversion to maintain glucose homeostasis (83). Available data thus suggests that short term fasting does not deplete hepatic glycogen stores to the extent that markedly increased proteolysis and gluconeogenesis becomes necessary to maintain healthy glucose concentrations. Still this notion needs to be clarified in future research of longer duration.

Conclusions

Alternate day fasting as a model for calorie restriction

Intermittent fasting in the form of alternate day fasting in many instances reduces overall energy intake, with no obvious adverse effects, and thus becomes a model of calorie restriction in both human and animal subjects. Secondary to reduced energy intake and weight loss, effects such as reduced risk factors for cardiovascular disease, and improved glucose metabolism have been demonstrated in both animal and human subjects on true and modified alternate-day fasting diets.

In rats, protection against ischemic injury and improved survival has been demonstrated in both myocardial and cerebral ischemic events. Other beneficial effects, such as slowing the neuronal aging process and increasing cognitive functions and memory, have been observed. In line with animal studies on daily calorie restriction, alternate-day calorie restriction has shown beneficial effects in neuronal disorders such as stroke, epilepsy and neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Huntington’s disease. Additionally, calorie restriction can reduce cancer risk and increase life span in rodent models on alternate-day fasting diets.

Intermittent fasting and health in the absence of calorie restriction

Some effects occur even if the subject maintains body weight, suggesting that the reduced meal frequency or prolonged time in the fasted state might have some additional effects regardless of overall calorie restriction and weight loss. In humans, modified alternate-day fasting diets might be easier to adhere to and they seemingly lead to less pronounced weight loss than true alternate-day fasting. Without causing weight loss, effects such as improved fasting insulin have been demonstrated in both animals and humans. In line with these findings, adiponectin increases in rats and humans on both true and modified alternate-day fasting diets in the absence of calorie restriction. Additionally, in mice, fat redistribution from visceral to subcutaneous stores has been observed despite unaltered overall body weight. If this effect proves to be true in human subjects it could propose reduced disease risk despite unaltered body weight.

Animal data further indicate some beneficial effects of intermittent fasting diets even without calorie restriction. Neuronal health improvements such as resistance to excitotoxic injury have been observed. Resistance to oxidative stress could be beneficial in the pathogenesis of epilepsy and various neurodegenerative diseases such as Alzheimer’s disease. Alternate-day fasting in animals also leads to improved recovery after induced spinal cord injuries and progressive demyelinating disease of the peripheral nervous system, in the absence of calorie restriction. Furthermore, in animal studies, changes associated with retareded tumorgenesis, such as decreased cell proliferation rates in various cell lines and decreased incidence of lymphoma, have been observed. Whether these observations are valid in human subjects as well remains an interesting area for future research.

Future research is warranted to test whether the health promoting effects described in animal studies have some validity in humans. We are in the very infancy of research on intermittent fasting in human subjects and future studies with larger sample sizes, longer durations and of better study design must be completed before any definite conclusions can be made regarding intermittent fasting and human health and the applicability to modern lifestyle.

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Table 1: Used search terms

The complete search term used was: (Hunger/physiology[mesh] OR Cholesterol/metabolism[mesh] OR Blood Pressure/physiology[mesh] OR Body Composition/physiology[mesh] OR Blood Glucose/metabolism[mesh] OR Energy Metabolism/physiology[mesh] OR Cardiovascular Diseases/prevention[mesh] OR Diabetes Mellitus, Type 2/prevention[mesh] OR Neoplasms/prevention[mesh] OR Caloric restriction[mesh] OR Caloric restriction/methods[mesh] OR Fasting[mesh] OR Fasting/physiology[mesh] OR Fasting/blood[mesh] OR Feeding behavior[mesh] OR Obesity[mesh] OR Energy intake[mesh] OR diet/methods[mesh] OR eating/physiology[mesh] OR Ghrelin/blood[mesh] OR Ghrelin/metabolism[mesh] OR Glucagon/blood[mesh] OR Glucagon/metabolism[mesh] OR Insulin/blood[mesh] OR Insulin/metabolism[mesh] OR Insulin Resistance/physiology[mesh] OR Leptin/blood[mesh] OR Leptin/metabolism[mesh]) AND (Short term fasting” OR “Short term fast” OR “Intermittent fasting” OR “”Intermittent fast” OR “Periodic fasting” OR “Periodic fast” OR “Alternate-day fasting” OR “Alternate-day fast” OR “Alternate day modified fasting” OR “Alternate day modified fast” OR “Every other day feeding” OR “Reduced meal frequency” OR Nibbling gorging OR Hormesis OR “Omitting breakfast” OR “Omit breakfast” OR “Skipping breakfast” OR ramadan OR fasting refeeding OR Alternate day caloric restriction).

Table 2: Alternate day fasting and body weight, glucose metabolism and cardiovascular health in humans

Reference Subjects (n) Protocol Trial length Body weight Glucose metabolism Cardiovascular health Soeters et al, 2009 (69) 8, non-obese 20 h mod ADF 2wk crossover – -glucose, -insulin -TG Varady et al, 2009 (64) 16, overweight 75% mod ADF 10wk ↓ Not studied ↓BP, ↓HR ↓TCL, ↓LDL, ↓TG, – HDL Johnson et al, 2007 (68) 10, overweight, asthmatic 80% mod ADF 8wk ↓ -glucose, -insulin ↓TCL,↑HDL, ↓TG, -LDL Heilbronn et al, 2005a (67) 16, non-obese ADF 22d ↓ -glucose, ↓insulin -BP ↑HDL(women), ↓TG (men) Heilbronn et al, 2005b (66) 16, non-obese ADF 22d ↓ ↑insulin sensitivity (men), -insulin sensitivity (women) Not studied Halberg et al, 2005 (65) 8, non-obese 20 h mod ADF 15d – ↓glucose, -insulin, ↑insulin sensitivity Not studied

Abbreviations: ADF, alternate-day fasting; mod ADF, modified alternate day fasting; BP, blood pressure; HR, heart rate; TCL, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglyceride. -, unaltered; ↑, increase; ↓, decrease.