Health Benefits of Fasting and Caloric Restriction

Abstract

Purpose of review:
Obesity and obesity-related diseases, largely resulting from urbanization and behavioral changes, are now of global importance. Energy restriction, though, is associated with health improvements and increased longevity. We review some important mechanisms related to calorie limitation aimed at controlling of metabolic diseases, particularly diabetes.

Recent findings:
Calorie restriction triggers a complex series of intricate events, including activation of cellular stress response elements, improved autophagy, modification of apoptosis, and alteration in hormonal balance. Intermittent fasting is not only more acceptable to patients, but it also prevents some of the adverse effects of chronic calorie restriction, especially malnutrition. There are many somatic and potentially psychologic benefits of fasting or intermittent calorie restriction. However, some behavioral modifications related to abstinence of binge eating following a fasting period are crucial in maintaining the desired favorable outcomes.

Full text

LIFESTYLE MANAGEMENT TO REDUCE DIABETES/CARDIOVASCULAR RISK (B CONWAY AND H KEENAN, SECTION EDITORS)
Health Benefits of Fasting and Caloric Restriction
Saeid Golbidi
1
&Andreas Daiber
2
&Bato Korac
3
&Huige Li
4
&M. Faadiel Essop
5
&
Ismail Laher
1
#Springer Science+Business Media, LLC 2017
Abstract
Purpose of Review Obesity and obesity-related diseases,
largely resulting from urbanization and behavioral changes,
are now of global importance. Energy restriction, though, is
associated with health improvements and increased longevity.
We review some important mechanisms related to calorie lim-
itation aimed at controlling of metabolic diseases, particularly
diabetes.
Recent Findings Calorie restriction triggers a complex series
of intricate events, including activation of cellular stress re-
sponse elements, improved autophagy, modification of apo-
ptosis, and alteration in hormonal balance. Intermittent fasting
is not only more acceptable to patients, but it also prevents
some of the adverse effects of chronic calorie restriction, es-
pecially malnutrition.
Summary There are many somatic and potentially psycholog-
ic benefits of fasting or intermittent calorie restriction.
However, some behavioral modifications related to abstinence
of binge eating following a fasting period are crucial in main-
taining the desired favorable outcomes.
Keywords Calorie restriction .Diabetes .Adipose tissue .
Oxidative stress
Introduction
It is abundantly clear that the obesity epidemic has affected
most countries in the Middle East more severely [1,2,3•,4,
5]. It is disconcerting that increases in the rates of obesity and
type 2 diabetes continue unabated in spite of great efforts at
sounding the alarm of the health costs—suggesting that the
many conferences, scientific articles, and public alerts have so
far had little impact in changing lifestyle choices. Another
approach is to harness the health and spiritual benefits of
obligatory and voluntary religious fasts, which are routinely
practiced in the Middle East, as an added means of producing
lasting lifestyle changes that will ultimately lead to improved
health outcomes. Fasting is an age-old practice that has been
prescribed in many religions and requires caloric restrictions
of various durations and formats [6,7]. Examples of religious
fasting regimens are shown in Table 1. We review the mech-
anisms by which periodic caloric restriction, through obliga-
toryandvoluntaryfasts,canleadtoimprovedhealth
outcomes.
Fasting by Muslims in the Middle East
Fasting during Ramadan displays some overlap with alternate-
day fasting as in both instances there are recurring periods of
fasting and feeding. However, alternate-day fasting involves
alternating 24-h periods of fasting and feasting while water
This article is part of the Topical Collection on Lifestyle Management to
Reduce Diabetes/Cardiovascular Risk
*Ismail Laher
ilaher@mail.ubc.ca
1
Faculty of Medicine, Department of Pharmacology and Therapeutics,
The University of British Columbia, 2176 Health Sciences Mall,
Vancouver V6T 1Z3, Canada
2
Center of Cardiology, Cardiology 1, Medical Center of the Johannes
Gutenberg University, Mainz, Germany
3
Department of Physiology, Institute for Biological Research “Sinisa
Stankovic”, University of Belgrade, Belgrade, Serbia
4
Department of Pharmacology, Medical Center of the Johannes
Gutenberg University, Mainz, Germany
5
Department of Physiological Sciences, Stellenbosch University,
Stellenbosch, South Africa
Curr Diab Rep (2017) 17:123
https://doi.org/10.1007/s11892-017-0951-7

intake is also allowed [6]. The data on the health benefits of
fasting remain inconclusive as some studies show lower,
higher, or no changes in nutrient intake during Ramadan [7].
Similar findings exist for BMI, blood metabolites profile (glu-
cose, lipids), and the onset of cardio-metabolic diseases [7].
Fasting times vary according to geographical location and
season. There are also cultural differences that likely impact
dietary intake and smoking patterns.
Unique cultural practices in the Middle East and North
Africa (MENA) region during Ramadan likely offset potential
benefits usually achieved by caloric restriction. A meta-
analysis reports that East Asian individuals displayed more
significant weight loss during Ramadan when compared to
West Asian populations [7]. Furthermore, others established
increased energy intake in Saudi Arabia when compared to
other countries [e.g., India] during Ramadan [8]. Thus, we
hypothesize that individuals within the MENA countries dis-
play unique cultural/behavioral patterns that pre-dispose them
to increased risk for the onset of cardio-metabolic diseases.
Although the major factor[s] driving this process remain un-
clear, we propose that altered circadian rhythms during
Ramadan may have a central role as the usual circadian
rhythm among fasting Muslims in this region is significantly
altered during Ramadan, with fasting individuals generally
remaining awake during the night while spending most of
the day sleeping [9,10].
Disturbances in circadian rhythms are linked with cardio-
metabolic diseases onset, as Ramadan fasting may affect the
timing of acute coronary event presentation [11] and moreover
that systemic cortisol levels are disrupted during Ramadan in a
Saudi Arabian cohort, with high levels during the evenings
compared to mornings [12]. Of note, such changes in cortisol
levels are typically associated with the metabolic syndrome,
e.g., hypercortisolemia is linked to insulin resistance due to
impaired insulin secretion and increased hepatic glucose out-
put [13,14]. Sleep deprivation also triggers a pro-
inflammatory milieu and micro/macro-vascular changes
linked to impaired vascular stimulation following a flow-
mediated dilation test. Altered adipokine levels also occur,
with increased circulating leptin and decreased adiponectin
in a Saudi Arabian cohort during Ramadan. Such an altered
adipokine signature is usually linked to insulin resistance. To
further compound the issue, there is excessive food intake
[“gorging”] during Ramadan nights in some of these countries
that will further fuel metabolic syndrome-like features such as
increased weight gain and insulin resistance [15]. In addition,
active/passive smoking is widespread in this region and fur-
ther fuels cardio-metabolic diseases [16,17]. For example,
Ramahi et al. [17] examined a Jordanian cohort and
established that indoor pollution (due to increased smoking
activity) increased to unsafe levels during Ramadan after
breaking of the fast. In light of these findings, we propose that
altered circadian rhythms during Ramadan trigger down-
stream effects that eventually contribute to the onset of
cardio-metabolic diseases (Fig. 1).
Intermittent Caloric Restriction [Fasting]
Calorie restriction (CR) is associated with health improve-
ment, increased longevity, and a reduction of morbidity and
mortality in animal studies [19–22]. Calorie control also ben-
efits cardiovascular status, weight reduction, insulin sensitiv-
ity, diabetes control, cognitive function, and cancer prevention
among its many effects in humans [23–26]. However, CR is
difficult to practice and increases the risk of malnutrition.
Intermittent fasting (IF) reduces the risk of malnutrition and
is easier to follow and is gaining popularity with health ex-
perts. We review some mechanistic insights for the health
benefits of IF.
Tissue Changes Following Energy Intake
Restriction: Putative Mechanisms
Stress-Activated Pathways
IF activates stress-induced pathways and increases transcrip-
tion of stress-induced proteins such as heat shock protein
Tabl e 1 Common fasts and their dietary restrictions in some religions
Religion Timing of fast Etiquette
Baha’i 19 days (2–10 March) No food/drinks from sunrise to
sunset
Buddhist Usually on full-moon days and
other holidays
No solid food; some liquids
allowed
Catholics Ash Wednesday and Good
Friday
No meat (and no meat on
Fridays during Lent). Small
meals allowed
Eastern
Orthodox
Fast periods include Lent,
Apostles’Fast, Dormition
Fast, Nativity Fast. Also
includes every Wednesday
and Friday
No meat, dairy products, eggs.
Fish prohibited on some
fast days
Hindu New moon days, some
festivals such as Shivaratri,
Saraswati Puja, and Durga
Puja
Can involve 24 h of full
abstinence from al foods
and liquids; commonly
practiced with abstinence
from solid food
Islam 28–30 days of Ramadan
(obligatory) and each
Monday and Thursday
(voluntary)
No food /water from sunrise to
sunset
Jewish Yom Kippur, the Day of
Atonement, and 6 other
days of “minor fasts”
No food/drinks from sunset to
sunset (and from sunrise to
sunset for “minor fasts”
Mormon First Sunday of each month No food/water for two
consecutive meals
123 Page 2 of 11 Curr Diab Rep (2017) 17:123

(HSP) 70 [27]. Increased HSPs are a generic cellular response
to harsh conditions including oxidative stress [28], hypoxia
[29], protein degradation [30], and energy depletion [31].
HSPs attach to unfolded or misfolded proteins and restore
normal configurations [32] and have anti-inflammatory and
anti-apoptotic properties [33]. Decreased levels of HSPs occur
in skeletal muscles of diabetic patients, possibly related to
insulin resistance [34–36]. This phenomenon may in part ex-
plain some of the metabolic benefits of IF, since elevations in
HSPs mitigate insulin resistance, glucose intolerance, and
diet- or obesity-induced hyperglycemia in animal studies [37].
Improved Autophagy
IF promotes cellular autophagy [38], a process by which
distorted molecules and impaired organelles are eliminat-
ed—thus providing cells with a limited supply of energy from
recycled materials. Cellular senescence is associated with re-
duced autophagy and accumulation of malfunctioning constit-
uents. CR attenuates the effects of aging on autophagy and
maintains cellular rejuvenation [39]. The role of sirtuin-1
(SIRT-1), a NAD
+
-dependent deacetylase, in the regulation
of autophagy has been shown in several cell lines (including
human cells). Caloric restriction stimulates sirtuin-1 activity
and enhances autophagy, while its pharmacological inhibition
is accompanied by decreased autophagy and accumulation of
biomarkers of aging [40].
Reduction of Advance Glycation End-Products [AGEs]
by Intermittent Fasting
Another putative mechanism for the beneficial effects of
fasting is reduced levels of AGEs that result from non-
enzymatic attachments of carbohydrate molecules to proteins,
lipids, or nucleic acids, mostly during normal metabolism but
also in the process of food cooking at high temperatures [41,
42]. Foods rich in AGEs include red meats, cheeses, and proc-
essed grains. There is increased production or reduced excre-
tion of AGEs in diabetes, where this can initiate several path-
ophysiologic processes [43]. Mice exposed to a diet low in
AGEs have extended mean and maximum life spans [44].
AGEs exert their functions through reaction with AGE recep-
tors, which are multiligand receptors that can also be activated
by other ligands with similar three-dimensional structures
[45]. Activation of AGE receptors on macrophages/
mesangial cells increases production of growth factors and
several pro-inflammatory cytokines, including nuclear factor
kappa B (NF-κB). Since AGE receptor signaling can override
cellular regulatory mechanisms, it perpetuates pro-
inflammatory cytokine production [46]. NF-κB and other pro-
inflammatory mediators in turn increase the expression of
AGE receptors [47] so that a short inflammatory circuit is
turned to a long-lasting process by a positive-feedback loop.
This provides a link between inflammation and oxidative
stress through a positive-feedback loop whereby ROS acti-
vates AGE/RAGE signaling [47] and RAGE stimulation in-
duces oxidative stress [48,49]. Serum AGEs levels can be
reduced by a low-calorie diet, which also reduces triglycer-
ides, waist circumference, and body mass index BMI [50,51].
In a study of ten patients with rheumatoid arthritis, 54 days of
IF significantly decreased urinary excretion of pentosidine (an
AGE) along with a reduction in severity of the rheumatologic
markers [52].
Hormonal Changes
CR and IF increase adiponectin levels in humans and labora-
tory animals [53,54]. This adipose-secreted protein is inverse-
ly related to body weight, adiposity, and insulin-resistance
[55]. Adiponectin modulates insulin activity [56] and also
reduces insullin levels and beta cell dysfunction [57,58].
Lower levels of adiponectin occur in patients with diabetes
[59]. Long-lived humans and animals have increased levels
of adiponectin [60–63]. For instance, Ames mice have
adiponectin levels that are three times higher than control mice
[64]. It is hypothesized that the propensity of adiponectin to
shift metabolism from glucose burning to fat burning reduces
oxidative stress and promotes longevity [38]. Dietary manip-
ulation of four strains of mice [obese-prone C57BL/6, genet-
ically obese ob/ob, obese-resistant A/J and peroxisome
proliferator-activated receptor-αgene knockout] strongly
Fig. 1 Disturbances in circadian rhythms related to sleep/awake cycles,
nutritional and smoking patterns may be a unifying factor that eventually
contributes to the onset of cardio-metabolic diseases. Such changes can
increase psycho-social stress and circulating cortisol levels, triggering
oxidative stress and inflammation (systemically and target organs).
Such events, with/without a genetic pre-disposition, can lead to a
“tipping point”being reached that will result in pathological outcomes
as indicated [18]
Curr Diab Rep (2017) 17:123 Page 3 of 11 123

suggests that it is the amount of calories, rather than the fat
content, that is the major determinant of adiponectin secretion
[65]. Adiponectin also mediates the cardiovascular benefits of
IF as shown in animal studies [66]; however, its prognostic
value in human disease has been questioned as higher levels of
adiponectin are associated with less favorable outcomes in
congestive heart failure [54](Fig.2).
Tissue and Metabolic Changes
Adipose Tissue
The complex role of adipose tissue (AT), white and brown
(WAT and BAT, respectively) in overall energetic homeosta-
sis, in both physiological and pathological conditions is intri-
cately linked with lipid (fatty acid, FA) metabolism in AT- and
non-AT (muscle, heart), where the liver acts as an integrative
metabolic organ (Figs. 3and 4).
There are three sources of FA: food intake, storage from
white adipose tissue (WAT), and de novo synthesis (mainly in
liver and also in AT). Together with other lipids, FA from
different sources (in the form of triacylglycerols, TAG) are
packaged in lipoprotein particles: chylomicrons in the intes-
tine and VLDL (very-low-density lipoproteins) in the liver
and through lymphatic or blood vessels move to capillary of
extrahepatic tissues [67,68].
All aspects of AT biology are connected with the develop-
ment of metabolic disorders, including metabolic syndrome,
obesity, cardiovascular diseases, type II diabetes, cancer, and
neurodegenerative disorders. This involves the following spe-
cific alterations: morphological and cellular (hypertrophy/hy-
perplasia/atrophy), metabolic (ratio of lipolysis/lipogenesis
and degree of re-esterification and releasing of adipocyte
FA, level of FFA in circulation, and balance of re-
esterification of FA between AT and liver), and physiological
and endocrine (production of adipocytokines with depot-
specific signature).
IF affects WAT cellularity at the level of the size of
adipocytes. Studies in humans show that enlarged sub-
cutaneous abdominal adipocyte size, but not obesity it-
self, predicts type II diabetes [69]. Increases in fat cell
size (“hypertrophic obesity”) play a more important role
in metabolic diseases than increases in fat cell number
(“hyperplastic obesity”)[70]. The authors suggest that
larger adipocytes have higher capacity for TAG synthe-
sis and lipolysis. Consequently, higher FA release from
WAT and flux of FFA in circulations contribute to met-
abolic diseases [70]. Another study [71] reports that
inguinal (subcutaneous depot) and epididymal (visceral
depot) fat cells were smaller in IF. The large reduction
in adipocyte size of both WAT depots correlates with
their increased insulin sensitivity, likely due to increases
in insulin receptor number [72]. Studies in animals and
humans demonstrate that IF and CR positively modulate
the secretory signatures of adipocyte cytokines by de-
creasing secretion of pro-inflammatory mediators and
the development of a pro-inflammatory phenotype in
WAT [73,74••].
Experiments by Ding et al. [75•] showed that fasting
for up to 24 h significantly reduced the body weight of
both male and female mice, with moderate reductions in
weight of subcutaneous visceral fat depots. Recent results
of Fabbiano et al. [76] show that long-term CR or IF
regimens stimulate browning of WAT. Indeed, induction
of “browning”in WAT or transplantation of BAT is con-
sidered by some to have a therapeutic potential [77].
Stimulation of “browning”in WAT by dietary means can
influence body weight and the potential success of anti-
obesity therapies. Hence, even though induction of
“browning”in WAT is logically contrary to the physiolog-
ical response to negative energy balance due to IF and
Hsp27 ↑
Autophagy
↑
Inflammaon
Cytokines ↓ AGE/RAGE ↓
Caloric restricon / intermient fasng
Decreased vascular dysfuncon, cardiovascular
risk and/or mortality
Lepn ↓
Ghrelin ↑
Insulin/IGF-1 ↓
BDNF ↑
Adiponecn
↑
AMPK ↑ ROS ↓ Nrf2 ↑
??
Fig. 2 Some of the mechanisms
involved in cardiovascular effects
of intermittent fasting
123 Page 4 of 11 Curr Diab Rep (2017) 17:123

CR, it should be kept in mind that different food constit-
uents and intermediary metabolites can induce browning
of WAT. For example, lactate and the ketone body β-
hydroxybutyrate [78] are strong “browning”inducers,
while the amino acid L-arginine improves all metabolic
aspects in WAT and BAT, and has the potential to induce
“browning”[79,80]. Similar effects are also produced by
exercise training where “browning”of WAT occurs in vis-
ceral and especially subcutaneous adipose depots [80].
Diabetes Mellitus
A popular method of IF involves 1 day of eating followed by a
day of fasting, while others suggest 20 h of fasting followed
by 4 h of eating time or 16 h of fasting followed by 8 h of
eating [81]. Several clinical trials have compared IF vs CR;
however, to our knowledge, there is no clinical study compar-
ing the various IF protocols with each other. For instance,
Adrienne et al. compared IF and CR in type II diabetic patients
Fig. 3 General overview of lipid
metabolic pathways in the body
with the accent to white adipose
tissue (WAT) biology (for
explanation see text). BAT, brown
adipose tissue; TAG,
triacylglycerols; FA, fatty acids;
FFA, free fatty acids; VLDL,
very-low-density lipoproteins;
LPL, lipoprotein lipase; HSL,
hormone sensitive lipase
Curr Diab Rep (2017) 17:123 Page 5 of 11 123

Fig. 4 The main depots of human adipose tissue (AT) types according to
their relative amounts,functional specificities and the clinical significance
are listed (a). Discrete functional-metabolic, endocrine and expanding
characteristics of human AT depots, primarily that of subcutaneous- and
the visceral depots, can influence metabolic health/risk. Thus, in contrast
to subcutaneous depots, visceral depots are less sensitive to insulin,
express higher levels of pro-inflammatory adipocytokines and grow
mostly by adipocyte hypertrophy. Accordingly, subjects with more
visceral AT can have a restricted (short term) capacity to buffer high
calorie (nutritional) overload, and ultimately develop a higher risk
insulin resistance and diabetes. Depots of AT in humans are
predominantly white fat which is able to store lipids and have limited
numbers of mitochondria. In contrast, brown and beige/bright adipocytes
contain significantly more mitochondria that are rich in uncoupling
protein-1 (UCP1), which regulates oxidative phosphorylation from ATP
synthesis and energy dissipating as heat. Some depots of AT in newborn
babies (interscapular), as well as inadults (deep neck,supraclavicular) are
brown fat (a, right), and bright UCP1 containing adipocytes can be found
within various AT depots, visceral and subcutaneous. Increases of the
relative amounts of brown adipose tissue, brown/bright adipocytes in
white AT, and the brown-like functional characteristics of white
adipocytes—browning (b), may have greater relevance in obesity and
diabetes type 2 treatment
123 Page 6 of 11 Curr Diab Rep (2017) 17:123

[82]. They found that even though CR is superior in terms of
weight reduction, CR and intermittent fasting had comparable
effects in visceral fat mass reduction, fasting insulin, and in-
sulin resistance. IF also improves metabolic parameters in
non-diabetic individuals [83]. Data related to adherence rates
were not reported in the study [83]. Intermittent fasting dimin-
ishes fat mass while preserving lean body mass, as opposed to
daily CR, which results in reduced fat and lean body mass
[74••,84].
Dietary modification is a critical factor in the management
of diabetes. In a 20-year longitudinal study of Rhesus mon-
keys, CR lowered age-related diseases including diabetes,
where 5 of 38 control animals developed diabetes and another
11 being pre-diabetic, while animals experiencing CR showed
no impairment of glucose homeostasis [85]. IF leads to similar
outcomes in both diabetic and pre-diabetic individuals, as a 1-
kg reduction of body weight is associated with 16% reduction
in diabetes risk [86]. A number of studies confirm the effec-
tiveness of IF in reducing risk factors for diabetes or its com-
plications. For instance, intermittent fasting reduces visceral
fat, an important site for producing TNF-αin diabetic patients
[87]. Reductions of visceral fat after 6 to 24 weeks of IF have
been reported in several studies [74••,88–91]. In almost all of
these investigations, reductions of visceral fat paralleled loss
of body weight. IF decreases fasting glucose and insulin levels
in non-obese [92], overweight/obese [90,91], and diabetic
individuals [93] with simultaneous improvements in insulin
sensitivity.
Several mechanisms have been proposed to explain the
modifying effects of CR on glucose metabolism. First, re-
duced energy intake reduces pancreatic cell apoptosis, as
shown in diabetic rats where caloric restriction attenuates beta
cell apoptosis [94]. Improved insulin sensitivity increases the
expression of SIRT-1 [94]. It is likely that SIRT-1 adjusts
hepatic gluconeogenic/glycolytic pathways in response to
CR. SIRT-1 increases hepatic glucose output by affecting
PPARγco-activator alpha [PGC]-1α[95]. Overexpression
of SIRT-1 in mice increases metabolic rate and reduces
weight, blood cholesterol, adipokines, fasting blood sugar,
and insulin levels [96]. In other words, SIRT-1 activity pro-
motes the beneficial effects of CR. The life extending effects
of CR is lost in SIRT1 deficient mice [97]. Six months of CR
in overweight adolescents also increased expression of SIRT-1
and other genes whose protein products are essential for mi-
tochondrial function [98].
The aggravating effects of oxidative stress in the pathogen-
esis of diabetes and its complications [99] include impeding
the ability of endothelial cells to combat glucotoxicity associ-
ated with an array of the cardiovascular consequences of
diabetes [100]. Hyperglycemia triggers several pathways
that lead to the mitochondrial and non-mitochondrial pro-
duction of reactive oxygen species [ROS] that participates
in the pathogenesis of diabetes-induced vascular damage
[101]. Increased levels ROS inhibit the activity of
glyceraldehyde-3-phosphate dehydrogenase [GAPDH] and
lead to increased concentrations of glyceraldehyde-3-
phosphate [GA3P] and other upstream glycolytic interme-
diates. Levels of methylglyoxal, which are elevated by
GA3P, lead to [i] increased production of AGE and [ii]
activation of protein kinase C (PKC), which has a number
of effects including reduced activity of endothelial nitric
oxide synthase [eNOS], production of ROS by the phago-
cyte NADPH oxidase isoform, over-activity of the coagu-
lation system, increased expression of some growth fac-
tors, and stimulation of NF-κB all of which promote an
inflammatory state. Non-mitochondrial origins of ROS in-
clude NAD[P]H oxidase, xanthine oxidase, uncoupled
eNOS, lipoxygenase, cyclooxygenase, cytochrome P450
enzymes, and other hemoproteins [102].
CR boosts the activity of endogenous antioxidant systems.
In a study of 46 overweight [BMI 25–29.9] individuals,
6 months of CR increased plasma glutathione peroxidase ac-
tivity and reduced plasma protein carbonyl levels, which were
associated with non-significant decreases in plasma 8-epi-
prostaglandin F2αlevels [103]. The antioxidant effects of
CR manifest several days after initiation of the diet, as shown
in a study of 40 overweight/obese women [BMI 32 ± 5.8]
where F2-isoprostane concentrations were reduced after 5 days
of a 25% CR diet [104].
Many epidemiologic studies indicate an association
between reduced food intake and lower cardiovascular
diseases [105,106]. As mentioned before, CR reduces
oxidative stress in endothelial cells, a phenomenon that
is associated with increased expression of eNOS. SIRT-1
acetylates lysine residues to enhance eNOS activity
[107]. Greater bioavailability of eNOS-derived nitric ox-
ide (NO), associated with decreased ROS, reduces blood
pressure in both animal and human studies following
CR [108,109]. Apart from its vasodilating effects, NO
also reduces oxidative stress and has anti-inflammatory
properties [110]. Furthermore, the anti-proliferative ef-
fects of NO in vascular smooth muscle coupled with
its inhibitory action on platelet aggregation and inflam-
matory cell adhesion play a significant role in preven-
tion of atherosclerosis [105]. Several cytokines [e.g., IL-
6, IL-1β,IL-17A,TNF-α] are positively correlated with
cardiovascular outcome [111] and CR suppresses in-
flammatory pathways.
In light of the fact that the majority of parameters that are
changed by caloric restriction and IF [e.g., nuclear factor ery-
throid 2-related factor 2 (Nrf2) activation, decreased oxidative
stress, lower leptin levels, activation of AMP-activated protein
kinase (AMPK), higher adiponectin levels, suppressed AGE/
RAGE signaling and inflammation] is associated with de-
creased cardiovascular risk and mortality, it is not surprising
that CR/IF is highly beneficial for the aging heart and
Curr Diab Rep (2017) 17:123 Page 7 of 11 123

vasculature [112]. This evidence is supported by a systematic
review of three randomized controlled clinical trials of fasting
in humans reporting improvements in weight and other risk-
related outcomes as well as two observational clinical out-
come studies of fasting in humans showing an association
with a lower prevalence of coronary artery disease or new
onset of diabetes [113].
Conclusion
This brief overview summarizes some of the mecha-
nisms that are activated by intermittent fasting. The ben-
efits of fasting are described in some detail based on
findings from experimental animal studies, and epidemi-
ologic studies that confirm beneficial outcomes in hu-
man populations. Despite the many efforts to increase
awareness of the obesity/diabetes epidemic that appears
to be affecting the Middle East to a greater extent than
other regions, the prevalence of cardio-metabolic dis-
eases continues unabated [1,2,3•,5]. A solution, at
least in part, may be found in religious edicts in the
Middle East where people of various religious persua-
sions fast regularly. In spite of the well-known health
benefits of intermittent caloric restriction, the prevalence
of obesity continues to escalate, with seemingly little
efforts for limiting overall energy intake. Fasting or pe-
riodic calorie restriction also prevents unwanted effects
of chronic energy restriction such as malnutrition.
Intermittent fasting, by acting as acute intermittent
stressor, activates stress-response pathways that lead to
improvement in well-being. Finding optimal methods of
fasting, in terms of the intensity of calorie restriction
and duration is proposed as a method to alleviate many
metabolic diseases. The requirement of many religions
in the Middle East to fast, either as obligatory fasts or
optional fasts, not only fulfills religious obligations but
has the added benefit of stemming the rising tide of
obesityintheregion.
Compliance with Ethical Standards
Conflict of Interest Saeid Golbidi, Andreas Daiber, Bato Korac, Huige
Li, M. Faadiel Essop, and Ismail Laher declare that they have no conflict
of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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