The Effects of Intermittent Fasting On Human and Animal Health

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Posted on May 22, 2014 by Dr. Bojan — 58 Comments ↓
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Three years.
It has been three years since starting my study on Intermittent Fasting (IF) and its
proclaimed health effects.
I am finally ready to go public.

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A quick background story…
Why IF? Because for almost a decade I’d been interested in the subject. Can we Username
really lose weight, improve health and even live longer by staring at an empty plate
every now and then? It was against everything I’ve learned, in the gym, in bars, even
in med school. Password
Seemingly, there was a lot of confirming evidence to be found online, showing

amazing body transformations and improved health for many individuals. I spoke Remember Me
with many of those people. – Wow, to hear the stories was such an inspiration. But Log In
from a scientific standpoint the stories were highly biased and not doing much to
further improve our knowledge. You think anyone ever changed their feeding Forgot Password?
frequency and kept all other things equal? Of course not. How than can we know
what Really improved their life? IF or the fact that they also changed their training
routine, stopped smoking and started to walk to work? Or a combination?
I wanted to see what we knew at this point. How much was the subject really
studied and what did the evidence say?
I finished the work in about one year and the result was awesome. The audience
loved it.
I got my MD and felt on top of the world.
But where do I go next? First, the idea was publication in a scientific magazine. For
many reasons, taking time from becoming a good clinician being the most
important, but far from single one, I eventually decided not to go that route.
Ambivalentia led me to sit on it for way too long, sharing it only with personal
friends and people I respect…but not much more. I just could not decide what I
wanted to do with it. Since finishing it I’ve had several offers from various
‘important’ people wanting to use my paper. The problem was always integrity. This
is my baby. I’m not interested in other people making a quick buck on something
that was my life for over a year and giving me a piece of the cake.
Finally, after some recent online pressure – I decided to give it away for free – right
here. There is no use in it sitting on my dropbox-account.
Please show your appreciation for the enormous work that this required from me, a
hyperactive person that normally can’t sit for more than 10 minutes. And the fact
that you are getting it for free, on a sliver plate, without having to spend 300 nights,
bent over scientific papers, pulling your hair out.
Share it with your friends – the social media buttons are on your left. If you like it,
please drop a comment below, let me know. Don’t be anonymous.
If you want to know more about IF I’d recommend you to buy Brad Pilons book Eat-
Stop-Eat. The book, in my opinion, is not perfect, and I don’t agree with all the
conclusion drawn in there – but it is by far the most complete recourse available for
purchase out there with practical implications for anyone interested in the IF
lifestyle, and it has helped many people get leaner and healthier with a relaxed
mindset.
Without hesitation the best online recourse on the topic is my dear friend Martin
Berkhan’s Leangains.com . Martin is the original popularizer of the IF method and
has researched the subject extensively. He also helped me get the project started
with some pointers and connections. What’s more, he is a great dude and I made a
friend in the process, and that I am very grateful for. He is a guy I’d share my last
beer with. Martin, I know you’re reading this so thanks, bud.
Now, grab a (big) cup or coffee and enjoy the read.
Your friend,
Bojan
The effects of intermittent fasting on
human and animal health –
a systematic review
Thesis January 2012, University of Lund by Bojan Kostevski
Center for Primary Health Care Research, Lund University, CRC, SE-205 02
MALMÖ, Sweden
Supervised by: Bengt Zöller, Staffan Lindeberg
Examination: Daniel Arvidsson
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 1236 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 lowquality 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.
Alternateday 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.
Acknowledgement
My sincere gratitude to Staffan Lindeberg and Bengt Zöller for helping me set up
the systematic search, for all the intellectually stimulating discussions and for the
guidance in writing this review.
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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 Protocol Trial Body Glucose Cardiovascular

(n) length weight metabolism health
Soeters et 8, non 20 h 2wk - -glucose, - -TG

al, 2009 obese mod crossover insulin
(69) ADF
Varady et 16, 75% 10wk ↓ Not studied ↓BP, ↓HR

al, 2009 overweight mod
(64) ADF ↓TCL, ↓LDL,
↓TG, – HDL
Johnson 10, 80% 8wk ↓ -glucose, - ↓TCL,↑HDL,

et al, overweight, mod insulin ↓TG,
2007 (68) asthmatic ADF
-LDL
Heilbronn 16, non ADF 22d ↓ -glucose, -BP

et al, obese ↓insulin
2005a ↑HDL(women),
(67) ↓TG (men)
Heilbronn 16, non ADF 22d ↓ ↑insulin Not studied
et al, obese sensitivity
2005b (men), -
(66) insulin
sensitivity
(women)
Halberg et 8, non 20 h 15d - ↓glucose, - Not studied

al, 2005 obese mod insulin,
(65) ADF
↑insulin
sensitivity
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.
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58 comments on “The Effects of Intermittent Fasting on Human and Animal Health”
Michel says:
May 22, 2014 at 7:39 am
Very interesting stuff, I love that even though some of the references were a bit
over my head (the latin names for some illnessess and the implications of these,
etc) most of it was completely comprehensible eventhough it was made for
medical purposes.
You are one helluva writer Bojan, thanks for sharing this.
Reply
Erika Garza says:
June 6, 2014 at 5:22 pm
Thanks for sharing! Congrats on your MD status.
Reply
Jason ross says:
May 22, 2014 at 11:05 am
Wow…that is a lot of work. Thanks for sharing. Been IF for 2 days a week for a
year.
Reply
Dr. Drew Dahlgren says:
May 22, 2014 at 6:23 pm
Great summary of some of the work that has been done to date. Some more
recent studies showing timing (i.e. dinner instead of breakfast) may be more
beneficial (Kahleova et al., 2014; Fernemark et al., 2013; see
http://caloriesproper.com/?p=4773 for nice summary). Keep up the nice work.
Reply
Steve says:
May 22, 2014 at 8:10 pm
Fantastic job! I’ve been doing leangains for almost 2 years and love it! Appreciate
you (and Berkhan) sharing your work with us!
Reply
Lee says:
May 23, 2014 at 12:29 am
Thanks for taking the time to write this up, Bojan. It was a very nice, in-depth
look at the studies surrounding IF and written in a way that can appeal to the
medical-savvy people, and the general public interested in health like myself.
Appreciate the hard work you’ve put into this, and let’s hope there’s some
proper, high quality studies done on IF in humans in the years to come!
Reply
Jeff says:
May 23, 2014 at 7:04 pm
There used to be a time when people were trained to write and communicate,
and from the above article this time has clearly passed.
Too long, too much jargon, entire paragraphs that don’t move the topic forward,
and worst of all-the important stuff (the “lead”) is so buried and muddled that it
was just confusing. I can see that you are using this article to try to bring people
in and eventually sell them something. The way you are approaching it wont
work-unless you really think people are going to read 10,000 words of science
crap instead of just closing your site and going elsewhere. Just sayin’the truth.
Reply
Notjeff says:
January 3, 2015 at 8:30 pm
Obviously, you’ve never read a peer-reviewed journal article before. While it

may seem like jargon to you, it is the preferred lexicon for scholarly
publications. Also, “just sayin'” is an absolutely douchey thing to say.
Reply
Adam says:
With all due respect Jeff, this is a thesis paper and by you saying that it’s too
long with too much jargon is a statement of your lack of education. This is
proper academia and if you can’t digest this then that is truly unfortunate.
Reply
Brenda Rose says:
May 24, 2014 at 11:23 am
This study confirms much of the anecdotal evidence that I had already heard
about the possible long-term effects of intermittent fasting. I’m delighted and
relieved to now know that although it may be an unconventional weight loss
method for many people, it isn’t harmful.
Reply
Jessica says:
May 24, 2014 at 11:39 am
Thanks! Amazing work.
Reply
John A Hill says:
May 24, 2014 at 4:13 pm
Interesting timing of this post as I was just talking with a co-worker about the
benefits of intermittent fasting and the general practice of fasting.
Although it has been a while (many years)since I have practiced fasting, it is a
ritual that I have studied and used its healthy benefits in the past. I have used
short fasts of less than 36 hours and longer fasts of 7 days for personal
research,purposes and practice.
After having lived several years in an unhealthy way, I have re-tooled my lifestyle
into a sustainable healthy way of living and have lost 55 pounds in the past year.
The subject of intermittent fasting came up as I believe that I will begin a regular
practice of IF as a part of this lifestyle.
I am looking forward the time when I can read your complete work as I have only
scanned it this morning.
Thanks for sharing your work with me.
John <
Reply
Chaya says:
May 27, 2014 at 1:45 pm
Thank you for sharing your research. The popular models of IF being 5:2 with
the 2 days being 500 calories a day and 18:6 (over a 24 hr period) have received a
lot if attention. Do you have any results on their benefits from your research?
Reply
Boris says:
May 30, 2014 at 5:46 am
I need to leave a quick comment just as I started reading The best and biggest
recource base for the IF is by far Martin Berkhan, and his website leangains.com,
not Brad Pilon, whose book is good, to be fair. Now back to the reading…
Reply
Boris says:
May 30, 2014 at 5:53 am
Oh god, sorry, I’ve posted that comment before reading the next sentence, ignore
that
Reply
Keegi says:
May 30, 2014 at 6:48 am
It is a great summary and I do appreciate your work on this. However, I wanted

to ask whether you came upon studies that researched IF’s effects on female
reproductive health? I’ve seen anecdotal articles in blogosphere where women
claim that IF has destroyed their hormone profiles and thus reproductive health
and this was the reason I went off IF at some point, just in case. Still, I’ve kept on
being curious about it, but haven’t found evidence in either direction about it.
Reply
Shane says:
May 30, 2014 at 9:28 am
Thanks for sharing this. I have been practicing IF (Leangains) for a bit over a
year now, and I’m also a type one Diabetic. I’m curious about the effects and
benefits of insulin sensitivity on a type one Diabetic with fasting? It seems like
most of the research in this area has been done on type two Diabetics. Has there
been any research and/or findings in regards to fasting and type one Diabetes?
Reply
Mark says:
May 30, 2014 at 9:41 am
Hello Boyan,
I’d like to know if you have some data on how Intermittent Fasting acts on libido.
Thanks in advance
Reply
Micke says:
May 30, 2014 at 11:49 am
Thank you for putting in the work that I don’t have the stamina for. Great work!
Reply
Steve says:
May 30, 2014 at 4:09 pm
Great article, also a big fan of Martin’s site and message. However, as someone
who has been an IFer for seven years, Ori Hofmekler (author of the Warrior
Diet) deserves lots of credit for the IF movement.
Ori may in fact be the first well-known proponent of IF and Warrior Diet should
be recognized as one of original mainstream publications advocating IF for
general health and physique improvements…
Reply
Andrew Smith says:
May 30, 2014 at 5:01 pm
Great article. I spend much of my time researching information on fasting from

peer reviewed journals through my university. I find the health benefits of IF,
especially autophagy, are profound but tend to be poorly understood. I have the
article you posted. You may also want to look at a review article “Effects of Diet
on Brain Plasticity in Animal and Human Studies: Mind the Gap” by Tytus
Murphy et al at King’s College London published May 12 2014. Cheers.
Reply
the ulbator head honcho says:
May 30, 2014 at 5:53 pm
Thank you for sharing, quite extensive work I must say.
It would be interesting to understand how fasting affects our hormone profile,

and as lads primarily testosterone (you do mention testosterone/estrogen ratios)
and growth hormone. Perhaps there is not enough research, perhaps I would just
need a more “layman-like” explanation. What do you know about this topic?
Again, thank you for sharing.
Reply
Scott says:
May 30, 2014 at 7:59 pm
Lots of writing but I was conflicted.. You talked in the beginning about this being
your baby.. and how you didn’t even care to share it for a while because of the
pride of piecing it together.. but then after reading it, it’s just a collection of all
previously released studied and ideas. You made it sound like you had stumbled
on some gold nuggets of previously unknown information. By the time the end
finally arrives, there’s nothing new at all and even the idea of IF being superior is
still in question.
Nice resource of information overall but I still fail to understand why so many
people regard IF as some unique idea or think of it as a new way to solve an old
problem. I tried it for a full year before realizing that my results were identical to
when I ate 6 meals a day for a decade. Is it staving off disease in me a little longer
and giving me a future benefit in that respect? Possibly but not conclusively.
In the end.. it’s still all just calories in/out and and IF is just a fancy term for not
eating all damn day. It matters little and this just seems to justify that. I’ll
continue to be blown away by people who so firmly believe eating all their food in
an 8 hour window is greatly affecting their body composition. It ain’t. Eat 6
meals if you like or eat 1 or 2. It matters not.
All that said.. great work putting this much information together. I can see great
benefit in people linking to the article as a place to find many important studies
on fasting.
Reply
Jim DiGiovanni says:
June 1, 2014 at 7:25 pm
I don’t understand how a 24-hour fast for a human (about a 70-90 year lifespan)
is comparable to a 24-hour fast for a lab mouse/rat which lives 2-3 years.
Wouldn’t a human need to fast for 30 days or more?
Reply
Andy Morgan says:
June 2, 2014 at 1:57 am
Most appreciate the hard work, and you choosing to publish this free for all to
read and benefit after the hours of work. Will put several links up to it.
You’re open to questions or sick of the subject by now?
Reply
Andreas Berge says:
June 4, 2014 at 2:20 pm
A great article and a good read, appreciate all the hard work put into it, thanks.
Reply
Andy Mc says:
June 6, 2014 at 4:55 pm
I’ve read everything on IF and this is decent. I did it when it was called
Animalbolics, that’s Pre Warrior Diet stuff.
I especially liked the differentiation between normal stress and the stress of
fasting because that’s basically the biggest argument against IF right now.
It is true that junk food can totally screw up any health benefits of IF and the
people that bash it did just that, or did unhealthy low carb or too low calorie or
had lots of stress in other areas of life.
IF can also backfire if done to extreme. I’ve seen some very smart people do an
extreme version of IF (like 1 meal a day for 6 months) and then bash it then go
back to 6 meals a day. I mean come on. On the other hand I don’t believe one 24
hour fast a week is enough either but it doesn’t matter what I believe, what
matters is you doing what you feel like doing.
You can skip breakfast, push lunch back a few hours and skip the late night snack
and you are automatically doing IF/8 Hour diet, the diet that Wolverine did for
his last 3 movies so there is something more to the equation than just IF.
IF is the only diet that allows me to eat white bread and pasta everyday and get
the same results I got when I ate MUCH more strict and have a normal life and
no one even knows I’m dieting at all when they see me eat. That’s NICE because I
can’t stand talking diets with “muggles.”
Reply
Anon says:
June 8, 2014 at 5:28 pm
Thank you for all the work of putting it together! If you don’t mind, couple of
quick questions.
From perspective of
1. Mood and energy
2. Long-term health and longevity
3. Physical and mental performance
All other things being equal, according to current data, should someone training
two or three times a week fast once a week for the whole day or daily for about
14-16 hours?
Also, assuming the three days workout regimen (Mon, Wed, Fri) or two days
workout regimen (Mon and Fri) what would be the best day to fast to get most of
the benefits and sacrifice as little anabolism as possible? Thanks a lot!
Reply
Greg says:
June 11, 2014 at 4:57 pm
Thank you for sharing it! Is there any scientific evidence to support the answer to
this question?
What of the following types of fasting should one do if he or she is not interested
in weight loss (but rather muscle gain), but is very interested in all other health
benefits fasting might provide and specifically in the benefit below (related to
glomerulosclerosis) as this one can be life-saving(!)?
1. Intermittent fasting daily

1.1 No food food for 16 hours a day
1.2 No protein and no carbs for 16 hours a day, but some fat for breakfast
2. Alternate day fasting

2.1 No calories on a given day – one day a week
2.2 No calories on a given day – two days a week
2.3 No calories on a given day – every other day — this seems to be the method
of the discussed rat study (below)
2.4 Limited calories on a given day (max 800) – one day a week
2.5 Limited calories on a given day (max 800) – two days a week
2.6 Limited calories on a given day (max 800) – every other day
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.
Gehrig JJ, Ross J, Jamison RL. Effect of long-term, alternate day feeding on
renal function in aging conscious rats. Kidney international. 1988;34(5):620-
630.
Is there anything else to keep read and keep in mind?
Thank you again!
Reply
Homero says:
June 18, 2014 at 1:47 pm
Incredible article! Although scientific in its approach, quite accessible to the rest
of us to understand and assimilate.
Congratulations on your MD!

Reply
Lucy says:
June 23, 2014 at 10:00 pm
I try most days, to push back my eating widow – not for reasons of IF, but
usually because I just can’t be bothered to eat… Or I’m lazy. Or busy. And i don’t
know i want because really I don’t fancy anything.
I can usually go to somewhere between 2 -4 pm. But should I push it too long – I
often do! – I start to get shakey, nauseaus, and feeling terrible…
It’s interesting that you mentioned blood glucose levels, because that’s what I’ve
long thought it was. But if it’s not!? What is causing it?!
My husband goes even longer than I do, but he never has the same shaky
feelings.
It’s been much better for me since giving up most sugar and adopting a paleo
style diet. But yeah, if I go too long, it’s awful…
Reply
Judith Petersen says:
September 16, 2014 at 10:39 am
The symptoms you describe are associated with detoxing. You say the better
your diet the less you experience them. This is key. The quality of your food
matters, as the more toxins your body has to eliminate the more symptoms
you will feel during your food-free periods. You should be able to push
through these symptoms and stretch the length of time without food.
Reply
Carrie says:
July 10, 2014 at 5:37 pm
Great research! I certainly appreciate a scientific paper on weight loss versus the
advertisement-laced, fad based articles. As a woman, I am curious about the
physiological/hormonal differences between males and females and does IF
effect genders differently? I noticed when mentioning research you state
“humans” or “rodents” but do not specify whether males or females, or a
combination of both, were used. (Unless, I didn’t read carefully enough, if so, I
apologize.) I have read articles that state while research shows benefits for male
subjects (rodent and human alike), that longer periods of fasting were
detrimental for females. I’ve also heard there isn’t enough research on females to
draw a conclusion.
If anyone has insight on this topic, I’d be very appreciative to hear it.
Reply
Cristi Vlad says:
July 14, 2014 at 2:43 pm
I would say that besides the fact that ketones spare lean tissue, there’s also the
effect of growth hormone that prevents the loss of muscle under IF routine. what
do you think?
this is even more interesting in subjects (like me) who do not lose muscle on 48+
hours IF under very low carb ketogenic diets where glycogen storage is
significantly reduced.
thoughts?
Reply
nomi says:
July 14, 2014 at 9:21 pm
Very informative article. I started practicing Martin’s leangains style intermittent

fasting about 6 months ago and its my life style now. Already lost 28 lbs and
broke all my personal best in the major lifts.
Thank you for sharing your hard work.
Reply
Holger Maiväli says:
July 19, 2014 at 7:19 pm
Such great work that you are sharing with us!
A phenomenal read. Gave you a little shout-out on my site:
http://www.hungerfitness.com/the-effects-of-intermittent-fasting-on-human-
and-animal-health/
Keep up the great work!
Reply
Jake Sacino says:
July 30, 2014 at 3:29 pm
Great read Bojan, thank you for posting it online. I especially liked the section
regarding the Ramadan fast. And congratulations on your MD!
Reply
stef says:
August 11, 2014 at 9:25 pm
thank you! very good very interesting, muchas gracias! a great start for a
promising topic in future nutrition!
Reply
Ben Brock says:
August 9, 2014 at 9:12 pm
Great work. I personally feel that IF has changed my life, and taught me what it
really means to be hungry as opposed to just “time to eat.” After being exposed to
LeanGains several years ago I begain doing a 16hr daily fast, just by skipping
breakfast and avoiding late night snacking. It’s had minimal impact on my
lifestyle, and adjusting to the no breakfast, no snacking ways were easy, because
after only a few days of that I no longer felt hungry during the fasting period.
While I’m still not as lean as I’d like to be, I began IF right about the same time I
got out of the Army, and my activity levels decreased tremendously, yet thanks to
IF I’ve gotten somewhat leaner and significantly decreased my food intake with
minimal effort. I’ve also managed to gain plenty of muscle on IF through macro-
cycling as described by Martin. I’m terribly undisciplined and my motivation ebs
and flows throughout the year, but despite all that IF has been a very positive
thing in my life. Oh, my blood work looks incredible as well, with my total
cholesterol in the 180s despite very high HDL and my triglycerides in the mid
50s. Plus my blood pressure has decreased over the years from 200/120 at its
peak, to currently sitting at 125/75 with no medication. Thanks guys. Your
research changes lives. – Ben
Reply
Anne Helene says:
August 11, 2014 at 7:07 am
This was incredibly well written, fascinating and informative. Perhaps my news
feed has been littered with illiterate ‘gym junkie’ material causing quite a
negative perception of ‘fitness freaks’, yet I always kept an eye out in hope that I
would one day satiate my craving for a rare breed of fitness intellectual. That day
has finally come, it seems my fear of disappointment was just stopping me from
looking a little harder. What’s more, you did it for free! I sincerely hope you are
being fairly compensated for this gem that I will be keeping in my
‘understanding humanity’ arsenal alongside V.S Ramachandran, Dawkins and
the Lancet Journal. Thank you, can’t wait to read more.
Reply
sam says:
August 22, 2014 at 4:58 am
Brilliant article. I met a trainer who has a giant of a sculpted body. He told me
something about slingshot training which was based on eating and fasting cycles.
He said the body releases growth hormones when we fast. I didn’t quite
understand the concept then. Now it makes heck of a sense.
Also, while fasting during Ramadan is mandatory, it is encouraged among

Muslims to fast every Monday and Thursday. Very few people do it however.
Like most good things in life.
“O ye who believe! Fasting is prescribed to you as it was prescribed to those

before you, that ye may (learn) self-restraint. And that you fast, it is better for
you if only you know” – The Cow-verse 183- 184
Reply
Elaina Love says:
September 7, 2014 at 7:31 pm
Thank you so much for sharing. I have been studying fasting for years on my own
body as well as teaching it to others. I love the idea of IF because it is more
doable than prolonged fasts and doesn’t interfere with ones work life/energy
levels in general.
Great research! I hope you write a book some day
Reply
Matty B says:
Great stuff, though a PDF would be nice.
Reply
Pablo says:
Thanks for sharing the stuff, Bojan!!
I really appreciate not having to immerse myself in a stack of papers to

understand some of the real science beyond IF.
I don’t think IF is a shortcut to perfect health and body, specially if you are fed
up with crap when not fasting, but it really seems a useful tool to promote
optimal health.
I’ve read some biologist claiming that nature provides us with the perfect fasting
environment: darkness. Just studies in rodents by now.
Reply
Thomas says:
October 12, 2014 at 1:29 am
Muscle loss.
With increased ketones due to short period fasting and Preventing the loss of
non fat mass.
Can you advise a optimal period in hours of fasting followed by hours not
fasting?
Also on none fasting days. recommend calorie intake whether it is normal or
surplus?
Would a ketogenic diet play some role in pre and post fast to minimise shock to
the body and bring ketone levels up before a total nutritional cut off?
And any thoughts on carb loading or cheat days relating to IF?
Reply
Fiona Aleksoska says:
October 28, 2014 at 4:04 pm
Why have you not had your work published in a peer reviewed journal? I find
that highly suspicious.
Reply
Dimitris says:
November 4, 2014 at 12:20 am
All that sounds great… but for a sec. please consider that.
30-40 years ago people working heavy duty jobs like building constructions,
agricultural works, livestock operations for 7/365 days, 12 or 14 hours per day
carrying heavy weight loads or working in the sun, and finally during the brake
they ate little bread, onions, tomatoes and a few olives, or a cup of soup and
that’s it for the day. (I am from Greece and from family of building constructors).
Those people were strong, lean, with stamina, poor, happy and optimistic.
Now we are sick all the time, unsatisfied and with all my respect to the author
work, with all that scientific data, – we forgetting that not only the quran
reinforce fasting but the christianity too, vigorously i must say, – actually we
exploring the proven results of fasting mechanism, without the way to reinforce
the fundamental mentality of how to decide to live frugal.
Reply
Alisa says:
December 20, 2014 at 3:45 pm
Just a thought for further research: Islam isn’t the only religion that practices
their own brand of IF. The Church of Jesus Christ of Latter-Day Saints (aka
Mormons) generally fast once a month. I’m not sure if that’s exactly the type of
IF you’re looking to study, but it might also have health benefits.
Reply
Notjeff says:
Are the terms “Intermittent Fasting” and “Alternate Day Fasting”
interchangeable? If so, why not settle on one unified term? If not, why are they
used interchangeably throughout the article?
Reply
Anwar says:
Dr Kostevski,
Thank you for sharing your work. Intermittent fasting seems to be a generally
safe and effective regime; your year-long efforts help reveal the scientific
underpinnings.
I also read dietdoctor.com edited by another Swedish doctor, Dr Andreas

Eenfeldt.
Looks like we should look to Swedish doctors for leadership…!
Kind regards,
Anwar
Reply
Teresa Murphy says:
January 10, 2015 at 11:32 pm
I was a half-assed pescatarian for many years. I went full vegan in March 2013.
I’m a 5’8″ 57-year-old female. I’ve been moderately overweight (“you carry it
well”) my whole life. Going vegan was hard, especially the beginning. Not
anymore, though. I crave “real” raw fresh green foods these days. Weird. 2 years
ago I was 185. In March I was around 175. Today, I’m 143 working towards 135
so that I can bounce around between 135 and 139. 139 is apparently, roughly the
“ideal” weight for my stats. I’ve always known that I can’t eat at night. My
partner gets home late, loves to cook and thinks nothing of eating a gigantic
steak and full meal at 11pm. It was a tough change for me. Now, I limit my food
to window of time. Mid-to-late morning thru till around 6pm at the very latest. I
try to quit any big meal (and my meals aren’t that big anymore anyway) by 4pm.
The better I hang during those hours AND the closer I stick to RAW VEGAN, the
faster the weight just MELTS away. I’m not perfect and have some social times
where, while still eating vegan of course, I eat too late or too much. It seems to
me like I almost need those occasional times to re-jumpstart the downward
trend. I swim for 20 minutes a day. I think dropping your body temp for a while
also is good for kick-starting your body energy. I love to dance and dance around
our condo all the time. I work from home. I realized that I was doing some kind
of intermittent fasting and it sure seems to line up with my experience. I am ON
FIRE with ENERGY —— ALL THE TIME!!!!!! I feel euphoric often. I feel so dang
healthy I want to shout it from the rooftops! I haven’t had any cold or flu this
season yet. Don’t expect to.
Now, I eat for nutrition. I listen to my body more. I feel like a different person. I
feel clean and wonderful inside! I know I’ve lost some muscle mass. I’m about to
start a weight-focused routine focusing on my gluts and general core strength.
Looking forward to reshaping what’s left into the “new me!”
Anyway, just thought I’d share on the off chance it inspires anyone else!
Thank you for the awesome info.
Reply
Teresa Murphy says:
January 10, 2015 at 11:36 pm
Sorry, I meant so say I went Vegan in March 2014. My weight loss has been
about a 10-month journey.
Reply
Missy says:
January 12, 2015 at 1:28 am
Amen! Thanks for sharing your work with us!!
I am just now diving into IF, thanks to Dr Mercola occasionally promoting it.
I haven’t combed all though your website yet. Is there a spot where I can get
more basic how to details on the types of IF…and also figure our which is best
more weight loss. I am not obese…just modern day over weight. I’ll do some
more peaking around.
Thanks!
Reply
Trinity says:
February 2, 2015 at 9:58 pm
Wow, absolutely amazing. Mind blown, thank you so incredibly much. I’ve been
doing IM for about 3 weeks now, every day, based on a friend who recommended
it and I’ve been loving it. I’ve been drinking lemon water and matcha green tea
throughout my fasting period though, and I’m wondering if you think these will
limit the benefits I get in terms of HGH / Testosterone. What’s your opinion on
this? Can I still take lemon water & matcha green tea? (some people say matcha
has no calories, some say it’s 3 calories per gram. I only take about 3 grams. And
one small lime, which has about 5mL of juice). Would really appreciate your
opinion on this =) Thank you SO much! Shared!
Reply
James McIlroy says:
This is excellent. Thank you very much.
Congratulations on acquiring your MD. I will hopefully be following in your

footsteps when I graduate in 2017.
James
Reply
steve says:
took some effort putting all this info into one place, appreciated
Reply
Sebastian says:
March 7, 2015 at 6:43 am
Thank you for the Great work you have done! Its a appreciated as much as I
appreciat my kids!
Reply
Karen says:
March 13, 2015 at 6:00 pm
Thank you so much for sharing your research and information. It is refreshing to
know that someone is giving the information to anyone that wants to access it for
free. I have been so disappointed by all the teaser ads out there that link me to a
lengthy video ending up with the “secret” cure not being revealed unless you buy
their expensive product.
Reply
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I am finally ready to go public.

Seemingly, there was a lot of confirming evidence to be found online, showing

I got my MD and felt on top of the world.

Now, grab a (big) cup or coffee and enjoy the read.

Supervised by: Bengt Zöller, Staffan Lindeberg

Examination: Daniel Arvidsson

Keywords: intermittent fasting, calorie restriction, obesity, aging, cardiovascular

Calorie restriction in humans is associated with weight loss, reduced inflammation

To improve compliance in human subjects, a model in which calories are

While alternate-day fasting leads to calorie restriction over a two-day period in

Modified alternate-day fasting is one alternative model sometimes used in the

Furthermore, when myocardial infarction was induced in rats maintained on an

When mice with progressive demyelinating disorders of the peripheral nervous

Consequently, studies to date indicate that intermittent fasting hampers cell

It is merely speculative if the effect on longevity is secondary to the above described

To examine the effects of alternate-day fasting on glucose metabolism, eight healthy

Reference Subjects Protocol Trial Body Glucose Cardiovascular

Soeters et 8, non­ 20 h 2wk - -glucose, - -TG

Varady et 16, 75% 10wk ↓ Not studied ↓BP, ↓HR

Johnson 10, 80% 8wk ↓ -glucose, - ↓TCL,↑HDL,

Heilbronn 16, non­ ADF 22d ↓ -glucose, -BP

Halberg et 8, non­ 20 h 15d - ↓glucose, - Not studied

Abbreviations: ADF, alternate-day fasting; mod ADF, modified alternate day

Thanks for sharing! Congrats on your MD status.

Obviously, you’ve never read a peer-reviewed journal article before. While it

Thanks! Amazing work.

It is a great summary and I do appreciate your work on this. However, I wanted

Great article. I spend much of my time researching information on fasting from

Thank you for sharing, quite extensive work I must say.

It would be interesting to understand how fasting affects our hormone profile,

Again, thank you for sharing.

You’re open to questions or sick of the subject by now?

1. Intermittent fasting daily

2. Alternate day fasting

Many strains of laboratory rats develop spontaneous progressive kidney failure

Is there anything else to keep read and keep in mind?

Thank you again!

Congratulations on your MD!

Very informative article. I started practicing Martin’s leangains style intermittent

Such great work that you are sharing with us!

A phenomenal read. Gave you a little shout-out on my site:

Keep up the great work!

Also, while fasting during Ramadan is mandatory, it is encouraged among

“O ye who believe! Fasting is prescribed to you as it was prescribed to those

Great stuff, though a PDF would be nice.

Thanks for sharing the stuff, Bojan!!

I really appreciate not having to immerse myself in a stack of papers to

I also read dietdoctor.com edited by another Swedish doctor, Dr Andreas

Looks like we should look to Swedish doctors for leadership…!

Thank you for the awesome info.

Amen! Thanks for sharing your work with us!!

This is excellent. Thank you very much.

Congratulations on acquiring your MD. I will hopefully be following in your

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Soeters et 8, non 20 h 2wk - -glucose, - -TG

Heilbronn 16, non ADF 22d ↓ -glucose, -BP

Halberg et 8, non 20 h 15d - ↓glucose, - Not studied