The Effects of Intermittent Fasting on Human and Animal Health

7/26/2019 The Effects of Intermittent Fasting on Human and Animal Health

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The effects of intermittent fasting on human and animal

healtha systematic reviewThesis January 2012, University of Lund by Bojan KostevskiCenter for Primary Health Care Research, Lund University, CRC, SE-205 02 MALM, Sweden

Supervised by: Bengt Zller, Staffan LindebergExamination: Daniel ArvidssonKeywords: intermittent fasting, calorie restriction, obesity, aging, cardiovascular health, glucosemetabolism, 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.

IntroductionCalorie restriction and intermittent fasting

Almost a century has passed since Osborne and colleagues in 1917 observed that reducing calorieintake in rats increased the animals life span (1). In 1935, McCay et al. were first to describe that

calorie restriction deliberately reducing calories without causing malnutrition prolongs meanand maximal lifespan in rats compared with rats fed ad libitum (2). Numerous subsequent studieshave confirmed that a calorie restriction of 30 to 60 percent of ad libitum intake increases the lifespan by similar amounts in a range of organisms including yeast, roundworms and rodents, whilesimultaneously decreasing or delaying the occurrence of age related diseases such as numerouscancers (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 Alzheimers, Parkinsons and Huntingtons disease (5).Accordingly, overeating is considered a risk factor for the majority of the conditions mentionedabove, further supporting the hypothesis that calorie restriction can be beneficial (6,7). To furtherexplore 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 restrictionin rhesus monkeys (8). The incidence of diabetes, cancer, cardiovascular disease and brain atrophy


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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 with50% of the control fed animals. The data obtained to date suggest that calorie restriction slows agingin primates and improves health.Calorie restriction in humans is associated with weight loss, reduced inflammation and improvedmarkers 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, adherenceto 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 periodsof over-eating where subjects are fed ad libitum. Alternate-day fasting, one model of intermittentfasting has been widely used in animal calorie restriction research because it has shown to result inreduced food intake over time and decrease body weight in rats (15). In human trials, intermittentfasting has been shown to be equally effective as daily calorie restriction for causing weight loss inobese subjects (16).

While alternate-day fasting leads to calorie restriction over a two-day period in many rodentspecies, in some strains of mice, the animals managed to compensate for the calorie deficit createdon fast days by increasing their intake on feast days twofold and thus keeping the total calorie intakeover a two day period at the same level as in mice fed an ad libitumdiet (17). These mice managed tomaintain constant body weight but, interestingly, still acquired some of the health benefits as ratson daily calorie restriction. This lead to the hypothesis that by implementing periods of fasting, onecould improve health without deliberately reducing calorie intake. My objective was to reviewrelevant intervention studies on the effects of intermittent fasting on energy balance, cardiovascularrisk factors, glucose metabolism, neurodegenerative pathology, tumor physiology and life span.Significance: The study will be important for the understanding of excess caloric intake and themanagement 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 effectsof intermittent fasting on excess body weight, energy balance, aging physiology, cardiovascular riskfactors, glucose metabolism, tumor physiology and neurodegenerative pathology. For each of theMeSH terms, the search process was restricted by use of non-MeSH terms such as intermittentfasting, periodic fast, alternate-day fasting and other relevant terms. All terms used are listed inTable 1. Furthermore, relevant review articles on calorie restriction and intermittent fasting werereviewed for additional relevant studies to include in the review. Studies were included in the reviewif short term fasting was the primary intervention and studied any of the above mentionedoutcomes. Studies that purposely restricted calories in the intermittent fasting group were excluded.

Animal trials

Energy intake and body compositionA total of 36 studies were found. When an alternate-day fasting diet is implemented, overall calorierestriction and weight reduction occurs in most rodent species, indicating that the restriction on thefasting day isnt 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 calorierestriction in rodent species (15). This however is not a universal finding and numerous studies havereported no alterations in energy intake and body weight (17,35-39). In general, studies using


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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 similarfood 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 theanimal 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 fastingresearch. In this model, the animals are not completely fasted every other day, but allowed a smallenergy intake of 15-25% of the daily intake consumed by ad libitumfed animals. Modified alternate-day fasting could allow for better maintenance of body weight than true alternate-day fastingprotocols (a complete every other day fast) (30,38). The complete compensation and increasedenergy intake does not appear to be dependent on the calorie density of the food, since neither ahigh-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 bechanges in lean mass to fat mass ratio or altered fat distribution which of course would not bereflected in the animals 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 ofadipose tissue from visceral to subcutaneous depots without altering body weight overall (39).

Cardiovascular healthFour rodent studies that examined the effect of alternate-day fasting on cardiovascular disease wereincluded. In general, rats maintained on an alternate-day fasting regimen lose bodyweight anddisplay reduced blood pressure and heart rate, and improved insulin sensitivity, compared to ratsfed ad libitum (28,29,42). Reduced blood pressure was also demonstrated in diabetic rats, proposingthat 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-dayfasting diet, reduced infarction size, improved cardiac function, and increased survival wasobserved, compared to rats fed ad libitum (24,33,43). More interestingly, the effects on infarctionsize, survival rates and cardiac function can be observed even if the dietary intervention isinduced afterthe ischemic event, by increasing the expression of angiogenic factors and increased

vascularization of the damaged myocardium, proposing a novel non-pharmacological therapy forsubjects with chronic heart failure (43).

A possible contributing factor for the cardio protective effects of intermittent fasting is increasedlevels of adiponectin, a hormone that exhibits both anti-athrogenic and insulin sensitizing effectsand 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 inthe absence of calorie restriction and weight loss (39,46).

Glucose metabolismA total of seven studies were found. Increased insulin sensitivity, as indicated by decreased fastingconcentrations 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 onalternate-day fasting regimen who consume the same amount of food in a 48-hour period as micefed ad libitum,decreased glucose and insulin concentrations to a similar degree as did mice on dailycalorie restriction despite maintained energy intake and body weight (17). In another study, as littleas two 24 hour fasts per week, without calorie reduction overall, were sufficient to improve insulin


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sensitivity in mice (46). In diabetic rats, alternate-day fasting reduces blood pressure, normalizesHDL levels, protects against glomerular damage and prevents development of diabetes nephropathy(32). These findings suggest beneficial effects on glucose metabolism and improved markersassociated with obesity and the metabolic syndrome.

Brain pathologyA total of 17 studies were included. Numerous aspects of intermittent fasting and neuronal healthhave been examined in rodent species. Compared to rats fed ad libitum, alternate day fasted ratsshowed protection of age-related changes in dendritic spine number and morphology (20). Otherrodent experiments have showed increased neurogenesis in brains of rats maintained on analternate-day fasting diet, as evident by increased number of newly generated neural cells in thehippocampus (21). These results suggest that intermittent fasting could hinder morphologicalneuronal 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 andenhancement of learning abilities and other cognitive functions (47).Intermittent fasting potentially exhibits desirable effects in manifest neuronal diseases. Ratsmaintained on alternate-day fasting diets show reduced brain damage and mortality rate in rodent

models of stroke (19,31). After a period of 24 months on alternate-day fasting, a neuroprotectiveeffect against induced hippocampal excitotoxic damage was observed (25). Epileptic seizures inanimals 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

Alzheimers (25,48) and Parkinsons (18) disease. Furthermore, in an animal model of Huntingtons

disease, prolonged survival, reduced disease-associated weight loss and improved motor functionwas 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 damagehas 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 ondaily, 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 byimproved nerve morphology and performance compared to mice fed ad libitum (37). Furthermore,alternate-day fasting leads to increased functional recovery after experimentally induced spinal cordinjuries in rats, independently if the alternate-day fasting regimen is implemented prior or after thespinal cord is injured (27,50). If this effect is demonstrated in humans, intermittent fasting couldpotentially serve as a non-pharmacological therapeutic alternative in the rehabilitation process insubjects with spinal cord injuries. The effect in mice was greater with alternate-day fastingcompared to daily calorie restriction, suggesting that increased time span in the fasted state hasadditive effects other than those attributed to calorie restriction alone (27).The beneficial effect does however not appear universal to all neurologic disorders. No desirableeffect 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 cancerTo study the potential anti-carcinogenic effect of intermittent fasting, three different aspects oftumorgenesis have been studied: circulating markers of insulin-like growth factor-1 (IGF-1), cellproliferation 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 cancertypes. Furthermore, high circulating levels of insulin and IGF-1 in combination are often seen in


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subjects with obesity, insulin resistance and type 2 diabetes, patient categories that are also morelikely to be affected by cancers (52). Rats on alternate-day fasting diets showed decreased levels ofIGF-1 and proliferation rates of T-cells and prostate cells (30). Cell proliferation rates areconsidered a central element in the development of cancers (53). Decreased cell proliferation haspreviously 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 Tand liver cells, despite no weight change (41). In a third study, true but not modified alternate-dayfasting 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 hourfasts/week without overall calorie restriction showed increased levels of IGF-1 and no effects ontumor size or survival in rats with prostate cancer (46). One might suspect that two 24 hour fastsper 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 decreasesin bodyweight and decreased IGF-1 (17). The authors suggested a difference in the way intermittentfasting and calorie restriction influence the growth hormone -IGF-1 axis and insulin signalingpathways. The relevance of IGF-1 for tumor growth in intermittently fasted animals, with or withoutcalorie 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 lymphomascompared to 33% of mice in the control group fed ad libitum (36).There was no difference in foodintake or body weight between the two groups, suggesting that intermittent fasting has a protectiveeffect on lymphoma development in this mouse strain, and that the effect was independent of thetotal calorie intake. The effect of intermittent fasting on induced hepatocarcinogenesis has also beenexamined. When rats were put on a 48 hour fasting regimen once per week, they developed lesspreneoplastic 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 asubject 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 cancertypes.

Life spanTwo studies looked at survivalper 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 enhancementseems to be dependent on animal strain and age of initiation (40). Furthermore, in one study, onlyrats 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 asdecreased body weight, improved insulin sensitivity, improved cardiovascular health, decreasedtumor growth and improved neuronal health, or if intermittent fasting might have some distinctiveeffect 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 toincrease life span. Interestingly, the largest magnitude of life span expansion (25 percent increase inmean 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).


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Other effectsSome other interesting effects than the primary addressed in this review were observed in variousstudies. Many strains of laboratory rats develop spontaneous progressive kidney failure withdevelopment of proteinuria and glomerulosclerosis. Rats fed on alternate days showed preservedkidney 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 intermittentfasting is increased testicular mass and testosterone/estrogen ratio compared to control rats or ratson a calorie restriction diet (57). Analgesia, which may be attributed to negative modulation ofsynaptic transmission in nociceptive neurons in the dorsal horn of the spinal cord, has also beenreported 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 auseful new therapeutic approach for treating pain.

Human studies

The Ramadan fastFasting is one of the five pillars of Islam. During the holy month of Ramadan, Muslims restrainfrom fluid and food intake during daytime for the whole month. Worldwide, there are more thanone billion Muslims, of whom the majority fast annually (58). The holy month of Ramadan couldthus potentially be a good period to study prolonged short term intermittent fasting in humans on alarge scale. A total of 17 studies were found. Conclusions are however very hard to draw from thesestudies. Apart from the obvious difficulties with doing randomized controlled trials there is anumber 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 ofcontrol 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 weightloss (62). Therefore, no objective conclusions could be made about this type of short termintermittent fasting and cardiovascular and metabolic risk factors, and further research of higherquality is warranted.In one observational study, young competitive soccer players were sent to a training camp 3 weeksprior to, and during, the Ramadan fast. The fasting participants were compared to the non-fastingparticipants and all food was delivered from the same kitchen, thus eliminating some of theconfounding 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 bloodglucose levels, hematocrit, cortisol levels, inflammation markers or physical performance. Inanother study, fasting healthy men and women were compared to a matched non-fasting group withregard 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 levelsand decreased inflammation proposing a beneficial effect in the fasted subjects.Thus, there are some data suggesting altered health markers during the month of Ramadan, butmore research is needed if any objective conclusions about this type of intermittent fasting and thefactors studied in this review ought to be drawn.


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Alternate-day fastingTo date, very few human intervention studies have tried to replicate the reported effects ofalternate-day fasting seen in rodent studies. Only six such studies were found, with somewhatdisappointing study designs (64-69). The sample size in these studies was rather small, rangingfrom eight to sixteen participants, and the study period was often very short. Only one trial includeda 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 modifiedalternate-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 cardiovascularhealth, such as decreased total cholesterol, decreased LDL and triglycerides, increased HDLconcentrations and decreased oxidative stress and systemic inflammation, suggesting that alternate-day fasting might be a novel strategy for decreasing body weight and improving cardiovascularhealth in the obese population (64,68).To examine the effects of alternate-day fasting on glucose metabolism, eight healthy men weremaintained 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 adiponectinlevels were observed (65). In another trial, the insulin sensitizing effect of true alternate-day fastingwas 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 fastingdiet, 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 onalternate days. In this study, HDL levels were increased in women only, and triglycerides weredecreased in men but not women (67). Increased insulin sensitivity was suggested by decreasedinsulin levels with unaltered glucose levels. In this study, blood pressure was unaltered, but thestudy 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, suggestingthat 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 randomizedeight healthy men to a modified alternate-day fasting diet or a standard diet. No differences wereobserved in body weight, blood lipids, glucose metabolism or hormone levels, and there was adecrease in energy expenditure after the 2 week period in the alternate-day fasting group (69). Morecontrolled studies, with larger sample sizes and longer study durations are thus needed to bringclarification in this matter.No human trial has directly examined intermittent fasting and tumor physiology. A single two dayfast increases endogenous GH-production fivefold, reflecting the metabolic adaptation to fasting,including increased hepatic glucose production, lipolysis and nitrogen conservation (70). Howeverno 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-1and altered cancer growth observed in some rat studies. Whether a prolonged alternate-day fastingregimen can alter IGF-1 levels in humans remains an area for future research. Furthermore, nohuman trials to date have examined the effects of intermittent fasting on neuronal health or lifespan.

Mechanisms of calorie restriction and intermittent fasting


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The exact mechanism by which calorie restriction and intermittent fasting exhibits its effects onvarious organ systems remains unknown. The main hypothesis includes a stress preconditioningresponse 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 increasesthe organisms 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 ofneutrophilic factors and antioxidant enzymes, ketone body formation and altered metabolismenzyme production (5).

Potential adverse effects from fasting

Blood glucose levels, mood and cognitionA variety of questions often arises when discussing intermittent fasting and human health. It isoften believed that blood sugar levels will fall to pathological levels if prolonged fasts areimplemented. A characteristic decline in mood and energy levels before lunch among humans isoften attributed to a drop in blood sugar. However when actually testing blood sugar levels inhealthy subjects prone to this phenomena, no actual decline in blood sugar to pathologic levels wasseen during a 24 hour fast (72). In healthy human subjects, a 24 hour fast decreases liver glycogenstores no more than 57% and in absence of vigorous exercise does not lead to muscle glycogenconsumption, suggesting that liver glycogen stores are sufficient after a 24 hour fast to keep bloodglucose levels within normal range (73). Furthermore, a double-blind, placebo-controlled study oftwo 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).

HungerThe 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 onbody weight regulation and subjective feelings of hunger and satiety remains largely unknown. Thehunger response however seems to be highly adaptive in different meal patterns. Ghrelin, a gutderived hormone, is considered a meal-initiation signal. It increases during fasting and usuallypeaks in concentration before an anticipated meal, paired with increased feelings of hunger, anddecreases after feeding. Interestingly, the rise in ghrelin is independent of meal timing asdemonstrated by similar peaks before an anticipated meal in various meal frequencies, thussuggesting that subjective feelings of hunger and energy intake is highly dependent on theindividuals 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 interventionin human subjects. In obese patients, a 14 day total fast lead to strikingly decreased body weightsand decreased blood pressure, without causing increased hunger sensations. Thus a hungersuppressing effect of prolonged fasting was demonstrated (77). This anorexic effect might beattributed 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 onan intermittent fasting diet, by using a 100 mm visual analog scale (67). The subjects were fasted onalternate days and reported an increased feeling of hunger from 37 to 56 mm and decrease in feelingof fullness from 43 to 23 mm when the dietary intervention was initiated. The magnitude of hunger


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did however not change during the intervention period as repeated measurements were taken, andfeelings of fullness actually increased some over time. The duration of this study was only 22 daysand it is still purely speculative whether and adaptation to the new meal pattern would occur in alonger time span. In contrast, modified alternate-day fasting in obese asthmatic patients did notsignificantly increase the subjective perception of hunger from baseline during the eight week longintervention period (68).

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

Decreased metabolic rateIt is commonly believed that multiple small meals increase metabolism and lead to increased overallenergy expenditure. Following every meal there is an increase in expenditure due to the processingof the nutrients, commonly referred to Thermic Effect of Food (TEF) (78). A common belieftherefore is that increased meal frequency leads to increased TEF and increased overall energyexpenditure with multiple meals, and that intermittent fasting accordingly would decreasemetabolic 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 macronutrientcomposition (with the highest increase in energy expenditure observed with a high protein diet) andnot meal frequencyper 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 inhuman 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 decreasedtotal calorie intake and not fastingper se.

Increased stressIncreased 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 thatcortisol is one of the major hormones responsible for glucose utilization during fasting, the questionarises whether the increased stress in any way could be harmful to the human organism. Themolecular stress response in intermittently fasted subjects seems markedly different from the oneassociated with uncontrolled stress. In fasted rodents there is actually a down regulation ofglucocorticoid receptors in the brain, with maintained expression of mineralocorticoid receptors,suggesting that fasting might alter the brains 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-derivedneurotrophic factor (BDNF), a response quite the opposite of calorie restriction and intermittentfasting, where increased concentrations of BDNF have been observed in numerous studies (4). Inconclusion, the controlled stress response from intermittent fasting seems fundamentally differentfrom 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 forinitiating molecular resistance for larger stressors, and thus promote some of the beneficial effectsof intermittent fasting.

Loss of muscle massOne 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 proteolysisand flux of amino acids from skeletal muscle for hepaticde novo gluconeogenesis, to maintain healthy


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blood glucose concentrations. As discussed previously though, a 24 hour short term fast isinsufficient in duration to deplete liver glycogen stores in healthy subjects (73). Up to 40 hours oftotal 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 thesystematic search. No loss of fat free mass in the absence of weight loss was observed compared to acontrol 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 energysubstrate for various tissues, of which the brain is the most important, and thus decrease the needfor 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 theextent that markedly increased proteolysis and gluconeogenesis becomes necessary to maintainhealthy glucose concentrations. Still this notion needs to be clarified in future research of longerduration.

Conclusions

Alternate day fasting as a model for calorie

restrictionIntermittent fasting in the form of alternate day fasting in many instances reduces overall energyintake, with no obvious adverse effects, and thus becomes a model of calorie restriction in bothhuman and animal subjects. Secondary to reduced energy intake and weight loss, effects such asreduced risk factors for cardiovascular disease, and improved glucose metabolism have beendemonstrated 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 bothmyocardial and cerebral ischemic events. Other beneficial effects, such as slowing the neuronalaging process and increasing cognitive functions and memory, have been observed. In line withanimal studies on daily calorie restriction, alternate-day calorie restriction has shown beneficial

effects in neuronal disorders such as stroke, epilepsy and neurodegenerative disorders, includingAlzheimers, Parkinsons and Huntingtons disease. Additionally, calorie restriction can reducecancer risk and increase life span in rodent models on alternate-day fasting diets.

Intermittent fasting and health in the

absence of calorie restrictionSome effects occur even if the subject maintains body weight, suggesting that the reduced mealfrequency or prolonged time in the fasted state might have some additional effects regardless ofoverall calorie restriction and weight loss. In humans, modified alternate-day fasting diets might beeasier 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 beendemonstrated in both animals and humans. In line with these findings, adiponectin increases in ratsand humans on both true and modified alternate-day fasting diets in the absence of calorierestriction. Additionally, in mice, fat redistribution from visceral to subcutaneous stores has beenobserved despite unaltered overall body weight. If this effect proves to be true in human subjects itcould propose reduced disease risk despite unaltered body weight.

Animal data further indicate some beneficial effects of intermittent fasting diets even withoutcalorie restriction. Neuronal health improvements such as resistance to excitotoxic injury have been


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observed. Resistance to oxidative stress could be beneficial in the pathogenesis of epilepsy andvarious neurodegenerative diseases such as Alzheimers disease. Alternate-day fasting in animalsalso leads to improved recovery after induced spinal cord injuries and progressive demyelinatingdisease of the peripheral nervous system, in the absence of calorie restriction. Furthermore, inanimal studies, changes associated with retareded tumorgenesis, such as decreased cell proliferationrates 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 animalstudies have some validity in humans. We are in the very infancy of research on intermittent fastingin human subjects and future studies with larger sample sizes, longer durations and of better studydesign must be completed before any definite conclusions can be made regarding intermittentfasting and human health and the applicability to modern lifestyle.

AcknowledgementMy sincere gratitude to Staffan Lindeberg and Bengt Zller for helping me set up the systematicsearch, for all the intellectually stimulating discussions and for the guidance in writing this review.

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Table 1: Used search termsThe complete search term used was:(Hunger/physiology[mesh] OR Cholesterol/metabolism[mesh]

OR Blood Pressure/physiology[mesh] OR Body Composition/physiology[mesh] OR BloodGlucose/metabolism[mesh] OR Energy Metabolism/physiology[mesh] OR CardiovascularDiseases/prevention[mesh] OR Diabetes Mellitus, Type 2/prevention[mesh] ORNeoplasms/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] OReating/physiology[mesh] OR Ghrelin/blood[mesh] OR Ghrelin/metabolism[mesh] ORGlucagon/blood[mesh] OR Glucagon/metabolism[mesh] OR Insulin/blood[mesh] ORInsulin/metabolism[mesh] OR Insulin Resistance/physiology[mesh] OR Leptin/blood[mesh] ORLeptin/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 fastingOR Alternate-day fast OR Alternate day modified fasting OR Alternate day modified fast OREvery 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

Soeters et al, 2009 (69) 8, non-obese 20 h mod ADF

Varady et al, 2009 (64) 16, overweight 75% mod ADF

Johnson et al, 2007 (68) 10, overweight, asthmatic 80% mod ADF

Heilbronn et al, 2005a (67) 16, non-obese ADF


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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.- See more at: http://www.lift-heavy.com/intermittent-fasting/#sthash.BTAu1nHm.dpuf

Heilbronn et al, 2005b (66) 16, non-obese ADF

Halberg et al, 2005 (65) 8, non-obese 20 h mod ADF

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