D IE T A N D H E AL TH

REVIEW Caloric restriction

Early observations linking reduced food intake

A time to fast
to improvements on health and survival are now
a century old. Rous discovered that limiting food
intake had an impact on cancer development
Andrea Di Francesco, Clara Di Germanio, Michel Bernier, Rafael de Cabo* (11), and Osborne et al. reported growth retar-
dation and life-span extension by a reduction
Nutrient composition and caloric intake have traditionally been used to devise optimized in food intake (12). McCay and colleagues later
diets for various phases of life. Adjustment of meal size and frequency have emerged published a seminal paper showing that rats
as powerful tools to ameliorate and postpone the onset of disease and delay aging, fed a limited amount of food lived much longer
whereas periods of fasting, with or without reduced energy intake, can have profound than their ad libitum (AL)–fed littermates (13).
health benefits. The underlying physiological processes involve periodic shifts of metabolic Nearly a century after these initial studies, the
fuel sources, promotion of repair mechanisms, and the optimization of energy utilization positive impact of CR on health span and life
for cellular and organismal health. Future research endeavors should be directed to the span has been documented in many model or-
integration of a balanced nutritious diet with controlled meal size and patterns and ganisms that include unicellular yeast, nematode
periods of fasting to develop better strategies to prevent, postpone, and treat the worms, fruitflies, mice, and primates, suggesting
socioeconomical burden of chronic diseases associated with aging. a strong evolutionary conservation of common
mechanisms connecting food intake to longev-

T
ity (4). CR interventions oppose several age-
he worldwide increase in life expectancy sights into its molecular mechanisms of action associated pathophysiological changes, including

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has not been paralleled by an equivalent (4). However, chronic CR has been reported to reduction of metabolic rate and oxidative dam-
increase in healthy aging. Developed and exert adverse effects for a number of mouse age (14), enhanced cellular turnover and protein
developing countries are facing social and strains (5) and could push humans to what one homeostasis, and improvement of age-related
economic challenges caused by dispropor- may consider a near anorexic state (6), underlying metabolic disorders that include central obesity,
tional increases in their elderly populations and some cautionary negative outcomes pointed out insulin resistance, dyslipidemia, and hypertension.
the accompanying burden of chronic diseases (1). by the eating-disorders field as well (7–9). Studies seeking to unravel the link between me-
Geriatricians and gerontologists have contributed An emerging area of research is the investi- tabolism and aging have demonstrated that CR
greatly to our understanding of the consequences gation of the independent consequences of var- induces profound metabolic and molecular
and processes that underlie aging from clinical, iations in meal size (through the control of energy changes in components of the nutrient-sensing
social, mental, physical, and biological perspec- intake) and meal frequency (by controlling the and stress-responsive pathways, such as growth
tives. The primary goal of aging research is to time of feeding and fasting) on the incidence or hormone, insulin and insulin-like growth factor
improve the health of older persons and to de- amelioration of multiple age-related diseases, (IGF) signaling, mechanistic target of rapamycin
sign and test interventions that may prevent or including cardiovascular disease, diabetes, cancer, (mTOR), adenosine 5′-monophosphate–activated
delay age-related diseases. Besides socioeconomic and dementia (2, 10). These studies are starting to protein kinase (AMPK), forkhead box protein O
status, energy, environmental quality, and genet- reveal that health-span and life-span extension (FOXO), sirtuins, and nuclear factor erythroid
ics are the most powerful determinants of health can be achieved by interventions that do not re- 2–related factor 2 (NRF2) (15, 16) (Fig. 2). The
and longevity. Although environmental quality quire an overall reduction in caloric intake. Ma- identification of longevity-regulatory pathways
and genetics are not under our direct control, jor challenges for the future include the design of led to studies of pharmacological interventions
energy intake is. The consumption of food pro- well-controlled and randomized clinical trials with U.S. Food and Drug Administration–approved
vides energy and nutrients necessary to sustain to test whether these observations can be trans- drugs (for example, rapalogs and metformin) and
life and allows growth, repair, and reproduction. lated to humans, determination of the impor- other naturally occurring compounds (such as
Proper nutrition can influence health and survival tance of individual genetic variant medicine, and resveratrol and spermidine) that mimic changes
and delay or, in some cases, prevent the onset and implementation of health care policies in which observed in CR without the requirement of changes
progression of chronic diseases. However, both new eating regimens can be integrated into clin- in food intake (17, 18). We focus on the most rel-
hypo- and hypernutrition have the potential to ical practice. We discuss four experimental strat- evant molecular and metabolic alterations elicited
increase the risk of chronic disease and pre- egies aimed at altering energy intake or the by dietary interventions that involve a reduction
mature death. Furthermore, manipulation of a duration of fasting and feeding periods that re- in caloric intake and fasting periods.
nutritionally balanced diet, whether by altering sult in improved aspects of health in mammals. Numerous strides have been made to under-
caloric intake or meal timing, can lead to a delay These are (i) classical CR, in which daily caloric stand how the number of calories, diet compo-
of the onset and progression of diseases and to intake is typically decreased by 15 to 40%; (ii) time- sition, and timing of the intervention can be
a healthier and longer life in most organisms restricted feeding (TRF), which limits daily intake manipulated to effectively extend longevity and
(2–4). In general, both prolonged reduction in of food to a 4- to 12-hour window; (iii) intermittent to translate these observations into feeding par-
daily caloric intake and periodic fasting cycles or periodic full or partial fasting, that is a periodic, adigms that can be applied to humans, with the
have the power to delay the onset of disease and full- or multiday decrease in food intake; and goal of delaying the onset of age-associated con-
increase longevity. Data from experimental studies (iv) fasting-mimicking diets (FMDs) that use a ditions and promoting healthy aging. CR without
in short-lived species and emerging clinical and strategy to maintain a physiological fasting-like malnutrition can be accomplished by chronically
epidemiological observations indicate that die- state by reducing caloric intake and modifying reducing energy intake by 15 to 40% from AL
tary interventions are valuable strategies that diet composition but not necessarily fasting conditions, while maintaining adequate intake
can be applied to promote healthy aging. In mod- (Fig. 1). We also summarize the metabolic and of vitamins and minerals. In rodents, under cer-
el organisms, caloric restriction (CR) provides cellular responses triggered by these feeding reg- tain circumstances, CR can extend life span by
beneficial effects on health and survival, and imens and their impact on physiology, focusing up to 50% (19). Traditionally, diet composition
there is an extensive literature that provides in- on studies in rodents, monkeys, and humans. and genetic background have been thought to
Finally, we discuss how these studies may pro- have a marginal impact on life-span extension
vide a basis for future investigations on the role elicited by CR. More recently, studies in mice
Translational Gerontology Branch, National Institute
on Aging, National Institutes of Health, Baltimore,
of various dietary interventions in the prevention and nonhuman primates have revealed that the
MD 21224, USA. of diseases and promotion of health throughout effect of CR on life-span extension is not uni-
*Corresponding author. Email: decabora@grc.nia.nih.gov the life span. versal (20). Indeed, certain mouse recombinant

Di Francesco et al., Science 362, 770–775 (2018) 16 November 2018 1 of 6

 Median
Feeding
Description Macronutrient balance Feeding time life-span Effects on health
regimen
Fat Protein Carbohydrate Fasting Feeding increase
6
Caloric restriction Daily reduction by 15 to 40% 30% Prevention of obesity,
(CR) of caloric intake without 24 12 Yes diabetes, oxidative stress,
55%
malnutrition hypertension, cancer,
15% cardiovascular disease
Standard 18

60%
Time-restricted Daily food consumption 30% Defense against type II
feeding (TRF) restriced to 4- to 12-hour No data diabetes, hepatic steatosis,
window or 10% hypercholesterolemia
Standard Obesogenic

IF: Alternation of 24-hour fasting

or very low calories (25% of Protection against obesity,
Intermittent or
oxidative stress,
periodic fasting energy needs) with a 24-hour ad Yes
cardiovascular disease,
(IF or PF) libitum eating period
hypertension, neurodegen-
PF: 1 to 2 days fasting or very low eration, diabetes
Standard

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calories followed by a 5-day ad
libitum eating period (5:2)

Fasting-mimicking Reduced caloric intake (~30% of 40% Protection from cancer

diet (FMD) energy needs) for five consecutive 50% and diabetes, improved
days before returning to normal Yes risk factors associated
eating cycles of FMD once a month with multiple age-related
or every 3 to 4 months per year 10% diseases
FMD Standard

Fig. 1. Experimental approaches used to improve fitness and promote health span. Description of different feeding regimens, their macronutrient
balance, and feeding time during a 24-hour period. The feeding time represented in the day-night diagrams refers to eating time in humans and
nonhuman primates. Mice undergoing a CR regimen tend to finish their food allotment quickly, self-imposing a continuous form of TRF. In human studies,
people voluntarily reduce their food intake and mostly adhere to a three-meals-per-day schedule. Mean life-span extension is documented for all the
treatments in the species depicted in the box, whereas maximum life span is only achieved after CR and IF or PF.

inbred strains show either little increase or del- striction Society (CRONies) who self-impose CR current “obesogenic” social environment makes
eterious effects on life span after CR (5). Analysis (31) have shown the occurrence of many of the it difficult for individuals to adhere to strict
of body composition revealed that the best out- same physiological, metabolic, and molecular ben- dietary regimens and lifestyle modifications for
comes on survival were obtained in mice that efits typically associated with long-lived animals long periods of time. Thus, there is interest in
preserved their fat stores during the second year on CR. These studies support the observation alternative feeding regimens that may recapit-
of life, suggesting the necessity of a minimum that long-term CR preserves a more youthful ulate at least some of the beneficial effects of CR
level of adiposity for the full benefit of CR (21, 22). functionality by improving several markers of by controlling feeding-fasting patterns with little
In CR regimens, sex, age, and genetic background health, including decreases in body weight, meta- or no reduction in caloric intake.
contribute to outcomes regarding health and sur- bolic rate, and oxidative damage (14); lower in-
vival in mice (22), and this may also be true for cidence of cardiovascular disease (31) and cancer; Time-restricted feeding
long-lived organisms, including humans. Data and decreased activity of the insulin-Akt-FOXO Recent evidence indicates that the benefits of
from two independent nonhuman primate studies, signaling pathway (32, 33) (Fig. 2). CR may not be entirely related to a reduction
one at the National Institute on Aging (NIA) Although these findings clearly indicate that in calories. In many experimental models of
and the other at the University of Wisconsin– a reduction of caloric intake could be an ef- CR, the reduction in energy intake encourages
Madison (UW), challenged the association be- fective intervention to improve health and pre- the animals to consume their entire daily food al-
tween life-span extension and health span by vent disease during aging in humans, there are lowance in a very short interval, thus promot-
reporting similar improvements in health but several obstacles that halt the transition from ing a longer fasting period than when consuming
contrasting survival benefits in response to CR experimental studies into standard medical prac- standard or hypercaloric diets AL (37). Although
(23, 24). Possible explanations for the divergent tice: (i) the lack of clinical data supporting con- (nocturnal) rodents with free access to food eat
outcomes emanating from these two studies have sistent effects of CR in older populations and predominantly at night, they also tend to feed
revealed important differences in genetic back- the incomplete understanding of the age-specific during the day, which correlates with gains in
ground, onset of the intervention, feeding prac- effects of these interventions (4, 10); (ii) safety body weight (37). These observations raise the
tices, and diet composition (25). concerns related to lack of reserve capacity upon question of whether the timing of food con-
In humans, short-term trials such as the multi- exposure to infection (34), injury, or surgery sumption (either feeding duration or circadian
center CALERIE (Comprehensive Assessment of (35) and about bone thinning that could lead timing) is a determinant of metabolic health,
Long-Term Effects of Reducing Intake of Energy) to the development of osteoporosis in older in- independent of total caloric intake and quality
study (26–29), the observational studies of cente- dividuals (36); (iii) the difficulty of compliance of calories. Thus, it is possible that triggering
narians residing in Okinawa who have been ex- to extreme restriction; and (iv) the interindividual the fasting response on a daily basis or at spe-
posed to CR for most of their lives (30), and variability in body mass, especially lean mass, cific times is in itself beneficial. This would ex-
observations of the members of the Calorie Re- which strongly correlates with frailty (23). The plain why dietary dilution, a form of CR in which

Di Francesco et al., Science 362, 770–775 (2018) 16 November 2018 2 of 6

 D IE T A N D H E AL TH

mice eat all day to compensate for the low without reduction in caloric intake (Fig. 1). Al- reduction in body weight, increase in energy
density of energy in their diet, does not result though data on the effects of TRF on longevity expenditure, improved glycemic control and
in life-span extension (38, 39). Hence, chronic CR are not yet available, studies in rodents have lower insulin levels, decrease in hepatic fat and
may improve health, at least in part, through an shown that TRF can confer protection against hyperlipidemia, and attenuated inflammatory
extended period of fasting. several detrimental metabolic consequences of outcomes, even when food intake or body weight
TRF refers to daily limitations in the timing a typical western diet (high fat and high carbo- or both are matched to the control group (40–43).
of food intake, spanning from 4 to 12 hours, hydrates, particularly refined sugars) through The molecular mechanisms responsible for the
effects of altered meal patterns on metabolic
health appears to be related, at least in part, to
Me the synchronization between the time of fasting-
tab feeding and the circadian rhythm (3) (Fig. 3).
oli
ce ch The circadian clock provides a conserved mech-
en Growth anism that allows organisms to anticipate and
i

om
sil
Re

respond to environmental changes. This per-

eo
Mitochondrial

sta
Autophagy petual rhythm leads to the timely expression of
function

sis
IIS clock-controlled genes, especially those encom-
PGC-1α mTOR passing enzymes and regulatory molecules that
mediate physiological and metabolic functions.
_ NAD+ Insulin/
+ Protein A strong relation exists between the circadian
AMPK NADH IGF-1 synthesis clock and metabolism, as they share some com-
Energy S6K

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Amino mon regulators. Indeed, TRF can restore cycling
balance AMP Feeding
ATP Acids of metabolic regulators, such as nicotinamide
Akt phosphoribosyltransferase (NAMPT), cAMP re-
FOXO HSC sponse element–binding protein, mTOR, AMPK,
Fatty PKA renewal or the insulin signaling pathway, all of which
Glucose Fasting acids take part in the life-span and health-span ben-
AcCoA/ efits of CR (40) (Fig. 3).
Genomic Ketones The NIA and UW CR monkey studies showed
stability Sirtuins CoA
NRF2 that the genetic background, age of onset of the
Inflammation intervention, and diet composition per se were
Tis

BDNF HDACs not sufficient to explain the differences observed

n
su

tio

in longevity under both control diet and CR.

er

nc

Stress Upon completion of the studies, the two research

ep

fu

resistance
air

al

Chromatin teams came to realize the notable differences in

m

s
modification ni the feeding regimen (25), whereby UW monkeys
rga
Neurogenesis O were fed in the morning and the food was re-
moved in the afternoon when another small
treat, such as a piece of fruit, was offered. This
Fig. 2. Fasting time and energy restriction share biological responses implicated in metabolite- protocol caused the animals to eat during the
controlled longevity pathways. Reduction of calories by continuous energy restriction or prolonged day and fast overnight. By contrast, NIA animals
fasting periods trigger metabolic adaptations characterized by increased amounts of circulating were fed twice daily, without removal of the sec-
ketones, whereas circulating fatty acids, amino acids, glucose, and insulin are maintained at ond meal, thus virtually excluding the possibility
low concentrations. Adaptive cellular responses involve alterations in the ratios of adenosine of an overnight fast. To further shed light on the
monophosphate (AMP) to adenosine triphosphate (ATP), of oxidized nicotinamide adenine interaction between diet composition and eating
dinucleotide (NAD+) to the reduced form NADH, and of acetyl-CoA to CoA. After a few hours of patterns in a genetically homogeneous animal
fasting, increased AMP to ATP ratios activate AMPK, which triggers repair and inhibits anabolic model, we recently compared the survival of mice
processes. Acetyl-CoA and NAD+ serve as cofactors for epigenetic modifiers such as histone fed the same diets used in the two nonhuman
acetyltransferases and NAD+-dependent deacetylases, the sirtuins, thus linking nutrition, energy primate studies (NIA and UW) under AL, 30%
metabolism, and post-translational modifications of histone proteins. Sirtuins deacetylate FOXOs CR, or a daily single meal feeding (MF) to match
and peroxisome proliferator-activated receptor g coactivator 1a (PGC-1a), factors respectively the calories consumed by the AL animals. Al-
involved in stress resistance and mitochondrial biogenesis. Production of ketone bodies such as though both CR and MF mice showed increased
b-hydroxybutyrate from fatty-acid catabolism may operate as endogenous histone deacetylase life span compared with the AL groups, the ef-
(HDAC) inhibitors and may contribute to epigenetic control of gene expression, DNA repair, and fect was independent of the diet composition.
genome stability. Ketogenesis also promotes synaptic plasticity and neurogenesis by increasing the Both the CR and MF mice self-imposed a TRF
expression of brain-derived neurotrophic factor (BDNF). Periodic cycles of fasting have systemic paradigm, and the life-span and health-span
anti-inflammatory effects and increase progenitor stem cells. Down-regulation of the insulin–IGF- extension seen in those groups appeared to be
1 signaling (IIS) pathway and reduction of circulating amino acids repress the activity of mTOR and directly proportional to the time spent fasting
its downstream effector, the ribosomal protein S6 kinase beta-1 (S6K). This mechanism inhibits (44). Similar behavior was reported in mice
global protein synthesis and promotes recycling of macromolecules by stimulation of autophagy. CR under CR, which voluntarily adopted a TRF par-
promotes the expression and activity of NRF2, which induces a number of antioxidative and adigm, as measured by an automated system
carcinogen-detoxifying enzymes. Collectively, the organism responds to a low-energy challenge by that recorded time of food availability and
minimizing anabolic processes (synthesis, growth, and reproduction), favoring maintenance systems, consumption (37).
and enhancing stress resistance, tissue repair, and recycling of damaged molecules. Improvement in Outcomes from TRF trials in humans also ap-
resilience, metabolic homeostasis, tissue repair, and organismal function can act as direct modifiers of the pear to depend on the distribution of meals dur-
four domains of the aging phenotype: body composition (1); balance between energy availability and ing the day and the duration of fasting (45–49).
energy demand (27); signaling networks that maintain homeostasis (81); and neurodegeneration (4). Each Limiting food intake to the middle of the day
of these domains can be assessed readily by routine clinical tests. decreased body weight or body fat, fasting glucose

Di Francesco et al., Science 362, 770–775 (2018) 16 November 2018 3 of 6

and insulin levels, insulin resistance, hyperlip- fasting is a natural phenomenon to which both benefits. However, in our present-day civiliza-
idemia, and inflammation and produced mild humans and lower organisms were regularly ex- tion, hunger and food-seeking behavior result
caloric restriction and weight loss, without calorie posed. Although many animals in the wild still in instant gratification and alterations in eating
counting (46, 47, 50, 51). Similarly, metabolic encounter prolonged periods of time with little patterns characterized by the consumption of
markers were improved in a group of people or no food, humans have rapidly transitioned into high-energy meals as soon as the urge arises,
eating an isocaloric diet with a bigger breakfast a sedentary lifestyle accompanied by a continuous thus negating the putative benefits that periods
and a smaller dinner (52, 53), and type 2 diabetic and abundant supply of food. In a bygone era, the without food provide. This behavior might be a
patients under hypocaloric diet obtained better postabsorptive, or fasting, state triggered hunger major contributor to the emergence of the obesity
metabolic outcome by eating most of their daily and food-seeking behavior that took hours, some- epidemic and obesity-related morbidities (2).
allotment in the first half of the day rather than times days, to satisfy. Mechanisms to survive such In rodents, IF extends life span (60) and pro-
divided into six meals throughout the day (54). periods of fasting are believed to have pleiotropic tects against obesity, cardiovascular disease,
On the contrary, restricting food intake to the
late afternoon or evening either produced mostly
null results or worsened glucose levels after eat- Metabolic rate
ing, b cell responsiveness, blood pressure, and Fasting Dark Gluconeogenesis
Ad libitum
lipid levels (45, 48, 49). A strictly controlled Feeding Light Lipolysis 1.2
Caloric restriction
feeding trial tested prediabetic subjects that 1.1
1.0
were allowed to eat their meals in either a 6-hour Insulin secretion

RER
0.9
time window in the morning (before 3 p.m.) or Adipogenesis
0.8
a 12-hour time window for 5 weeks. Early TRF Hunger 0.7

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ameliorated the metabolic markers of diabetes 0.6
without a significant reduction of body weight BMAL1 Nampt 1.2 Free access to food
(55). Individuals on a hypocaloric, three-meal- Catabolism Time restricted
Energy intake Clock 1.1
per-day diet lost more weight when the major-
Diet composition 1.0
Anabolism

RER
ity of the food was consumed in the morning, as 0.9
Length of fasting
opposed to the evening (51). However, no signif- 0.8
icant changes in glycemia, insulin sensitivity, or 0.7
SIRT1 0.6
respiratory exchange ratio (RER, defined as the
ratio between the amount of carbon dioxide pro-
AMP 1.2 Feeding days
duced and oxygen used during breathing) were Plasma membrane NAMPT Fasting days
redox system 1.1
observed when obese, insulin-resistant men were NAD(P)+ ATP 1.0

RER
exposed to a hypocaloric diet with food provided 0.9
in the morning (56). In the context of cancer, two NAD+
0.8
studies found that a fasting period of more than NAD(P)H 0.7
13 hours resulted in lower risk of breast cancer 0.6
recurrence than that in subjects who fasted less
NRF2 AMPK mTOR PGC-1α SIRTs FOXOs 1.2 Standard diet
than 13 hours (57, 58). The discrepancies remain
1.1 FMD
to be explained, but collectively, given the pre- 1.0

RER
sent body of knowledge, these studies indicate Stress Protein synthesis Autophagy Mitochondrial Inflammation Cell 0.9
that both the amount of time spent eating during resistance and translation biogenesis survival 0.8
each day and the time at which food is consumed 0.7
relative to the circadian rhythm are critically Health and survival 0.6
important to the effects of diet on health and
longevity. Fig. 3. Integration of the circadian rhythms and feeding-fasting cycles with metabolism.
(Left) The transcriptional activators BMAL1 and CLOCK are at the core of a cell-autonomous
Intermittent and periodic fasting molecular circuit that governs circadian rhythms. Fasting increases hunger, the extent of which
An increasingly popular alternative to both con- depends on the overall energy intake, diet composition, and length of fasting. The internal circadian
tinuous CR and TRF is intermittent fasting (IF), clock also increases hunger independent of food intake and other behaviors. Intermittent energy
an eating pattern in which no or few calories restriction increases concentrations of the plasma membrane redox system enzymes, NADH-
are consumed for periods of time that range cytochrome b5 reductase and NAD(P)H-quinone oxidoreductase, contributing to oscillations in the
from one to several days, followed by AL feeding NAD(P)H [reduced form of NAD(P)+] to NAD(P)+ (nicotinamide adenine dinucleotide phosphate)
on the remaining days (10) (Fig. 1). One example ratio (82). The circadian rhythmicity of CLOCK and BMAL1 expression regulates the transcription of
of IF is the 24-hour water fast without solid food NAMPT, a key regulatory enzyme involved in the generation of NAD+, a metabolite required
followed by a normal feeding period of 24 hours. for the deacetylase activity of SIRT1. Active SIRT1 influences metabolism through its effects on
This alternate-day fasting differs somewhat from catabolic and anabolic reactions and mediates BMAL1 deacetylation, which inhibits the circadian
the alternate-day modified fasting in which clock machinery. During the active phase (yellow boxes), increased production of ATP
participants consume very few calories one day sustains anabolic pathways. During the resting phase (green boxes), a shift toward AMP gears
(e.g., 25% of usual intake) followed by a day with- metabolism toward catabolic processes. These intermediate energy carriers activate downstream
out restrictions. transcription factors, kinases, and deacetylases like NRF2, AMPK, PGC-1a, sirtuins, and FOXOs,
Both CR and fasting promote stress resist- whose activation influences health and survival. (Right) At the organismal level, fasting or
ance in model organisms ranging from uni- feeding states are paralleled by changes in the metabolic rate. AL–fed animals set their RERs at
cellular yeast to mammals, presumably by shifting around 0.9, showing an intermediate preference between fat and carbohydrate metabolism.
energy from growth and reproduction to mainte- Both CR and TRF regimens increase the amplitude of RER oscillations, characterized by
nance, recycling, and repair in order to increase higher RER (utilization of carbohydrates) during feeding and lower RER (utilization of lipids)
cellular protection and survival (Fig. 2). There is during fasting. Under prolonged fasting, lipids are the only source of energy, as opposed
an abundance of data that supports this hy- to feeding time. The FMD diet results in lower RER with a slight peak after the meal. The RER
pothesis (59). From an evolutionary perspective, traces are idealized and may be close to what is seen in nocturnal rodents.

Di Francesco et al., Science 362, 770–775 (2018) 16 November 2018 4 of 6

 D IE T A N D H E AL TH

Total intake Exposure to food the compliance rate was reduced to 82% with
(CR, FMD) (TRF, IF, PF) the restriction achieved averaging −12%, which
was half the targeted reduction (28). The suc-
cess of the long-term CRONies study in which
Energy consumption individuals of the CR group ate nearly half of
the calories compared to the AL subjects (1112 to
Blood Brain
Hunger response 1958 kcal/day compared with 1976 to 3537 kcal/day)
Ketone bodies
Adiponectin levels Neurotropic factors relied upon the strong motivation of its partic-
Cortisol and ghrelin levels NPY levels ipants (31). There are side effects associated with
Glucose, insulin, IGF-1, and leptin levels Cognitive function prolonged periods of daily fasting (>15 hours) for
Triglycerides and LDL levels Stress resistance human health. Studies associating such extended
Inflammatory markers and CRP Inflammation fasting periods and skipping breakfast with mor-
Oxidative stress tality and disease in humans have been reported
Liver Cardiovascular system (74, 75), although most long-lived populations
Ketone bodies production Resting heart rate from around the globe do practice 12- to 13-hour
Insulin sensitivity Blood pressure TRF with little to no adverse effects (5).
Glycogen production To make fasting acceptable to most people, Longo
Pancreas
Liver size and colleagues conceived a low-carbohydrate,
Insulin production
high-fat diet that enhances compliance by avoid-
Intestine Adipose tissue ing complete deprivation of food. The diet coined
Ketone bodies production

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Lipolysis as FMD (Fig. 1) has low calories and provides for
Adiponectin production plant-based soups, herbal tea, energy bars, nut-
Insulin sensitivity based snacks, and supplements to be gradually
Skeletal muscle
Leptin production implemented in a 5-day cycle each month for
Insulin sensitivity Fat mass
Structure and function 3 months (76). For the first day, the caloric amount
Inflammation
is about 1090 kcal (10% protein, 56% fat, and 34%
Fig. 4. Systemic effects of caloric restriction or intermittent fasting. The balance between carbohydrate) and, for days 2 to 5, only 725 kcal
reduction in total food intake and timing contributes to differences in energy consumption, leading to are provided (9% protein, 44% fat, and 47% car-
changes in circulating factors and organ function. The height of each arrow does not reflect the bohydrate) (76). A similar diet was also designed
intensity level but instead highlights a grouping. Down arrows indicate decreased levels, and up for laboratory mice, whereby animals were al-
arrows indicate increased levels. lowed to consume 50% of the AL food supplied
as a vegetable-based powder mixed with hydro-
gel on day 1 and reduced to 10% of AL on days 2
hypertension, diabetes, and neurodegenerative extended periods of food shortage. Production through 4. The main goal of the FMD is to
diseases (2). It also retards the growth of tumors of ketone bodies (b-hydroxybutyrate and aceto- maintain low circulating concentrations of IGF-1,
(61) and sensitizes a range of cancer cell types to acetate) by the liver and gut epithelial cells (68) insulin, and glucose, while increasing plasma
chemotherapy (62). Additional benefits of IF during b-oxidation of fatty acids to acetyl–coenzyme concentrations of IGF-binding protein 1 and
include improvement in insulin sensitivity, in- A (CoA) or conversion of ketogenic amino acids ketone bodies. Rejuvenating effects of FMD
dependently of both total food intake and weight or both, are released into the bloodstream to were initially reported through an increased
loss (63), and enhancement in brain function as provide metabolic fuel to various organs (Fig. 4). number of progenitor stem cells (77). The FMD
evidenced by better performance on behavioral Several short-term human clinical trials have regimen also leads to improvement of markers
tests that assess motor responses to sensory shown that alternate-day fasting can deliver ben- of diseases and metabolic dysfunction, lowers
stimuli (64). The behavioral responses to IF are efits similar to CR in terms of weight loss and cancer incidence, and extends health span in
associated with increased synaptic plasticity and cardiometabolic health, including reduction in rodents, but without affecting maximum lon-
increased production of new neurons from neu- body weight and improved lipid profiles, lower gevity (76, 78). More recently, FMD has been
ral stem cells (2). Similar results were achieved blood pressure, and increased insulin sensitivity proposed to exert a therapeutic, antidiabetic
when animals were fed a ketogenic diet (65) that (69–71). In cancer patients, fasting selectively effect by fostering regeneration of pancreatic
is composed almost exclusively of fat. In mice, a protects normal cells, but not cancerous cells, b cells and restoring insulin secretion and glucose
ketogenic diet improved health span and delayed against toxicity related to chemotherapeutic homeostasis in mice through the regulation of
age-associated neurological decline, without an agents, and fasting for up to 5 days followed by protein kinase A (PKA) and mTOR pathways
effect on longevity (66, 67). In the study of Verdin a normal diet appear to be a safe, feasible, and (77). Furthermore, this dietary intervention im-
and colleagues, feeding a ketogenic diet to mice effective strategy in reducing common side effects proves the control of autoimmune disease—for
caused weight gain without life-span extension associated with chemotherapy (72). Nevertheless, example, multiple sclerosis—through regulation
when compared to the controls, but a cyclic ke- the challenges of implementing alternate-day of the immune system (79). Despite the positive
togenic diet reduced midlife mortality, whereas fasting or similar interventions are real and can results on health span, FMD did not increase
in the second study, mice consuming a ketogenic be a major burden by causing difficulties rem- maximum longevity in mice, and, when admin-
diet isocaloric to that of the control group had iniscent to those encountered by individuals on istered to very old animals, it may have been
increased life span despite having similar body chronic CR. detrimental (76).
weight (66, 67). The benefits of fasting may be
mediated by a highly conserved stress-response Fasting-mimicking diets Conclusions
or nutrient-sensing pathway, whereby organis- Implementing a long-term calorie restriction Pharmacological interventions with proven ef-
mal metabolism switches from storage to mobi- or complete fasting can be challenging in hu- fectiveness are often accompanied by a range
lization, in part, by increasing autophagy and mans, and compliance tends to decrease with of unwanted side effects. Many elderly people
recycling at the cellular level. The ensuing pro- time. In a human study, the withdrawal rates of take multiple medications, which can cause ad-
duction and utilization of fatty acid–derived ke- CR and periodic fasting (PF) participants from a verse geriatric outcomes linked to increases in
tones serve to preserve the brain and muscle 12-month study were about 40 and 30%, respec- morbidity and mortality (80). Dietary interventions
function and allow the organism to withstand tively (73). In the 2-year CALERIE clinical trial, that are accompanied by long fasting periods

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A time to fast
Andrea Di Francesco, Clara Di Germanio, Michel Bernier and Rafael de Cabo

Science 362 (6416), 770-775.

DOI: 10.1126/science.aau2095

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