PRACTICE APPLICATIONS Topics of Professional Interest Intermittent Fasting and Human Metabolic Health P ERIODS OF VOLUNTARY ABS- tinence from food and drink (ie, intermittent fasting) has been practiced since earliest antiquity by peoples around the globe. Books on ethnology and religion describe a remarkable variety of fasting forms and practices. 1 Renewed interest in fasting regimens is evidenced by a plethora of popular press publications and diet recommendations. For example, in 2013, Mosley and Spencer 2 published a best-selling book titled The Fast Diet, which touts the benefits of restricting energy intake severely for 2 days a week while eating normally the rest of the week. Dozens of books promote various fasting dietary patterns and the web of- fers hundreds of fasting-related sites. However, scienti fic evidence for the health benefits of intermittent fasting in human beings is often extrapolated from animal studies, based on observa- tional data on religious fasting (particu- larly Ramadan), or derived from experimental studies with modest sam- ple sizes. Our overall objective is to provide an overview of intermittent fasting regimens (Figure 1) and summarize the evidence on the health benefits of intermittent fasting with a focus on human intervention studies. Because much of the data on intermittent fasting are from research in animal models, we briefly summarize key rodent studies and reviews. Health outcomes of interest are changes in weight and metabolic parameters associated with type 2 diabetes, car- diovascular disease, and cancer. We also present an overview of the major mechanisms hypothesized to link fasting regimens with human health; that is, circadian biology; the gastrointestinal microbiota; and modifiable lifestyle behaviors such as diet, activity, and sleep. Finally, we present conclusions regarding the evidence base for intermittent fasting as an intervention for improving hu- man health and propose a research agenda. We provide a uniquely broad syn- thesis of the scientific evidence linking intermittent fasting with human health and a framework for future research on this topic. METHODS As noted above, we present a brief background of the considerable literature on intermittent fasting in an- imal models to provide context to the translational research that has been completed in human beings. For human studies, we focus on findings from in- terventions that examined alternate- day fasting, modified fasting regimens, and time-restricted feeding (Figure 1). A Medline search in PubMed was per- formed using the terms intermittent fasting, fasting, time-restricted feeding, and food timing. In addition, we culled relevant articles from the reference list of research articles as well as reviews of fasting regimens. 3,4 Inclusion criteria for human studies were randomized controlled trials and nonrandomized trials; adult male or female participants; and end points of changes in body weight or biomarkers of risk of diabetes, cardiovascular disease, or cancer. This is not a formal review or a meta-analysis. These studies cannot be combined because they are markedly dissimilar with regard to the intervention, the comparison group (or lack thereof), sample composition, study design, and intervention duration. Intermittent fasting performed as a religious practice (eg, Ramadan) is reviewed separately and with less detail because these eating patterns are not motivated by health reasons and have generally been studied using observational study designs. INTERMITTENT FASTING: HUMAN INTERVENTION TRIALS This summary emphasizes findings from intervention trials (see the Table) that provide evidence for evaluating the influence of intermittent fasting on human health. Alternate Day Fasting Alternate-day fasting involves fasting days in which no energy-containing foods or beverages are consumed alternating with days where foods and beverages are consumed ad libitum. In 2007, Varady and Hellerstein 3 This article was written by Ruth E. Patterson, PhD, professor, associate director, Population Sciences, and program leader, Cancer Prevention; Gail A. Laughlin, PhD, associate pro- fessor of epidemiology; Andrea Z. LaCroix, PhD, professor and chief of epidemiology; Sheri J. Hartman, PhD, assistant professor; Loki Natarajan, PhD, professor; Carolyn M. Senger, MD, associate physician; María Elena Martínez, PhD, professor and program leader, Reducing Cancer Dis- parities; and Adriana Villaseñor, PhD, postdoctoral fellow, all at Moores UCSD Cancer Center and Department of Family Medicine and Public Health, University of California, San Diego, La Jolla; Dorothy D. Sears, PhD, associate professor of medicine, Moores UCSD Cancer Center and Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla; Catherine R. Marinac, doctoral candidate, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, and Graduate School of Public Health, San Diego State University, San Diego, CA; and Linda C. Gallo, PhD, professor, Department of Psychology, San Diego State University, San Diego, CA. http://dx.doi.org/10.1016/j.jand.2015.02.018 Available online 6 April 2015 To take the Continuing Professional Education quiz for this article, log in to www.eatrightPRO. org, go to the My Account section of the My Academy Toolbar, click the “Access Quiz” link, click “Journal Article Quiz” on the next page, and then click the “Additional Journal CPE quizzes” button to view a list of available quizzes. ª 2015 by the Academy of Nutrition and Dietetics. JOURNAL OF THE ACADEMY OF NUTRITION AND DIETETICS 1203
Transcript
This article was written by Ruth E.Patterson, PhD, professor, associatedirector, Population Sciences, andprogram leader, Cancer Prevention;Gail A. Laughlin, PhD, associate pro-fessor of epidemiology; Andrea Z.LaCroix, PhD, professor and chief ofepidemiology; Sheri J. Hartman, PhD,assistant professor; Loki Natarajan,PhD, professor; Carolyn M. Senger,MD, associate physician; MaríaElena Martínez, PhD, professor andprogram leader, Reducing Cancer Dis-parities; and Adriana Villaseñor, PhD,postdoctoral fellow, all at MooresUCSD Cancer Center and Departmentof Family Medicine and Public Health,University of California, San Diego, LaJolla; Dorothy D. Sears, PhD,associate professor of medicine,Moores UCSD Cancer Center andDepartment of Medicine, Division ofEndocrinology and Metabolism,University of California, San Diego, LaJolla; Catherine R. Marinac, doctoralcandidate, Moores UCSD CancerCenter, University of California, SanDiego, La Jolla, and Graduate Schoolof Public Health, San Diego StateUniversity, San Diego, CA; and LindaC. Gallo, PhD, professor, Departmentof Psychology, San Diego StateUniversity, San Diego, CA.
http://dx.doi.org/10.1016/j.jand.2015.02.018Available online 6 April 2015
To take the Continuing Professional Educationquiz for this article, log in to www.eatrightPRO.org, go to the My Account section of the MyAcademy Toolbar, click the “Access Quiz” link,click “Journal Article Quiz” on the next page,and then click the “Additional Journal CPEquizzes” button to view a list of availablequizzes.
ª 2015 by the Academy of Nutrition and Dietetics. JO
PRACTICE APPLICATIONS
Topics of Professional Interest
Intermittent Fasting and HumanMetabolic Health
PERIODS OF VOLUNTARY ABS-tinence from food and drink(ie, intermittent fasting) hasbeen practiced since earliest
antiquity by peoples around the globe.Books on ethnology and religiondescribe a remarkable variety of fastingforms and practices.1 Renewed interestin fasting regimens is evidenced by aplethora of popular press publications
anddiet recommendations. For example,in 2013, Mosley and Spencer2 publisheda best-selling book titled The Fast Diet,which touts the benefits of restrictingenergy intake severely for 2 days aweekwhile eating normally the rest of theweek. Dozens of books promote variousfasting dietary patterns and the web of-fers hundreds of fasting-related sites.However, scientific evidence for thehealth benefits of intermittent fastingin human beings is often extrapolatedfrom animal studies, based on observa-tional data on religious fasting (particu-larly Ramadan) , or derived fromexperimental studies with modest sam-ple sizes.Our overall objective is to provide
an overview of intermittent fastingregimens (Figure 1) and summarizethe evidence on the health benefits ofintermittent fasting with a focus onhuman intervention studies. Becausemuch of the data on intermittentfasting are from research in animalmodels, we briefly summarize keyrodent studies and reviews. Healthoutcomes of interest are changes inweight and metabolic parametersassociated with type 2 diabetes, car-diovascular disease, and cancer. Wealso present an overview of themajor mechanisms hypothesized tolink fasting regimens with humanhealth; that is, circadian biology;the gastrointestinal microbiota; andmodifiable lifestyle behaviors such asdiet, activity, and sleep. Finally, wepresent conclusions regarding theevidence base for intermittent fastingas an intervention for improving hu-man health and propose a researchagenda.We provide a uniquely broad syn-
thesis of the scientific evidence linkingintermittent fasting with human healthand a framework for future research onthis topic.
METHODSAs noted above, we present a briefbackground of the considerable
URNAL OF THE ACADE
literature on intermittent fasting in an-imal models to provide context to thetranslational research that has beencompleted in human beings. For humanstudies, we focus on findings from in-terventions that examined alternate-day fasting, modified fasting regimens,and time-restricted feeding (Figure 1). AMedline search in PubMed was per-formed using the terms intermittentfasting, fasting, time-restricted feeding,and food timing. In addition, we culledrelevant articles from the referencelist of researcharticles aswell as reviewsof fasting regimens.3,4 Inclusion criteriafor human studies were randomizedcontrolled trials and nonrandomizedtrials; adultmale or female participants;and end points of changes in bodyweight or biomarkers of risk of diabetes,cardiovascular disease, or cancer. This isnot a formal review or a meta-analysis.These studies cannot be combinedbecause they are markedly dissimilarwith regard to the intervention, thecomparison group (or lack thereof),sample composition, study design, andintervention duration. Intermittentfasting performed as a religious practice(eg, Ramadan) is reviewed separatelyand with less detail because theseeating patterns are not motivated byhealth reasons and have generally beenstudied using observational studydesigns.
INTERMITTENT FASTING:HUMAN INTERVENTION TRIALSThis summary emphasizes findingsfrom intervention trials (see the Table)that provide evidence for evaluatingthe influence of intermittent fasting onhuman health.
Alternate Day FastingAlternate-day fasting involves fastingdays in which no energy-containingfoods or beverages are consumedalternating with days where foods andbeverages are consumed ad libitum.In 2007, Varady and Hellerstein3
These regimens involve alternating fasting days (no energy-containing foods or beveragesconsumed) with eating days (foods and beverages consumed ad libitum).
Modified fasting regimens Modified regimens allow for the consumption of 20% to 25% of energy needs on scheduledfasting days. This regimen is the basis for the popular 5:2 diet, which involves severe energyrestriction for 2 nonconsecutive days a week and ad libitum eating the other 5 days.
Time-restricted feeding These protocols allow individuals to consume ad libitum energy intake within specificwindows, which induces fasting periods on a routine basis. Studies of <3 meals per dayare indirect examinations of prolonged daily or nightly fasting periods.
Religious fasting A wide variety of fasting regimens are undertaken for religious or spiritual purposes.
Ramadan fasting A fast from dawn to sunset during the holy months of Ramadan. The most common dietarypractice is to consume 1 large meal after sunset and 1 lighter meal before dawn. Therefore,the feast and fast periods of Ramadan are approximately 12 h in length.
Other religious fasts Latter-day Saints followers routinely abstain from food and drink for extended periods oftime. Some Seventh-day Adventists consume their last of 2 daily meals in the afternoon,resulting in an extended nighttime fasting interval that may be biologically important.
Figure 1. Types of intermittent fasting regimens that are hypothesized to influence health outcomes.
PRACTICE APPLICATIONS
reviewed alternate-day fasting studiesin animals and concluded that thisfasting regimen was as effective assimple calorie restriction in decreasingfasting insulin and glucose concen-trations. Alternate-day fasting inanimals also reduced total plasmacholesterol and triglyceride (TG) con-centrations, and had beneficial effectson cancer risk factors such as cellproliferation.To our knowledge, three intervention
studies have explored the metaboliceffects of alternate-day fasting (see theTable).5-7 Sample sizes were modestand ranged from 8 to 30 normal-weight adults. No information wasprovided about the physical activitylevels of these participants. Two ofthree studies reported significantweight loss, although we questionthe clinical relevance of weight loss in a1-day study.7 In the 22-day study ofalternate-day fasting, participantsexperienced a mean of 2.5% weightloss (P<0.001).6 All studies found asignificant decrease in at least oneglucoregulatory marker. One studyexamined lipid levels with mixed re-sults: improvements in high-densitylipoprotein (HDL) cholesterol and TG,but increased low-density lipoprotein(LDL) cholesterol. One of two studiesfound significant improvements in in-flammatory markers.Although limited, these data suggest
that alternate-day fasting regimenscan result in modest weight loss. Thesedata also show some positive effects
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on metabolic parameters, althoughthese studies enrolled normal-weightadults who were unlikely to showsubstantial improvements in metabolicrisk factors. However, Heilbronn andcolleagues6 noted that self-reportedhunger on fasting days was consider-able and did not decrease over time,suggesting that alternate-day fastingmay not be a feasible public healthintervention.
Modified Fasting RegimensModified fasting regimens generallyallow for the consumption of 20%to 25% of energy needs on regularlyscheduled fasting days. In thesestudies, the term fasting describes pe-riods of severely limited energy intakerather than no energy intake. Thisregimen is the basis for the popular 5:2diet, which involves energy restrictionfor 2 nonconsecutive days a week andusual eating the other 5 days.2
Varady and colleagues8-10 have in-vestigated the effects of modifiedalternate-day fasting in mice. In a trialcomparing 85% energy restriction onalternate fasting days to ad libitumchow, the energy-restricted conditionresulted in decreased visceral fat, lep-tin, and resistin and increases in adi-ponectin.11 Similar studies conductedby this research group also found thatthese fasting regimens in mice appearto reduce adipocyte size, cell prolifer-ation, and levels of insulin-like growthfactor-1.
TION AND DIETETICS
As shown in the Table, we identifiedeight trials of modified fasting in hu-man beings.12-19 Study sample sizesranged from 10 to 107 adults, all ofwhom were overweight or obese. Theduration of these fasting interventionsranged from 8 weeks to 6 months. Ofthe eight studies, only one institutedweekly exercise goals.12 Overall, six ofeight studies (75%) reported statisti-cally significant weight loss, whichranged from 3.2% in comparison to acontrol group16 over a 12-week periodto 8.0% in a one-arm trial over an 8-week period.13 Two of five studiesfound significant decreases in fastinginsulin, but none found reductionsin fasting glucose. Three of the eightstudies found significant improvementsin lipid levels. Two of five studies foundsignificant improvements in inflam-matory markers, including C-reactiveprotein, tumor necrosis factor-alpha(TNF-a), adiponectin, leptin, and brain-derived neutrotophic factor. Half ofthese studies assessed some aspect ofmood or other behavior-related sideeffects in response to the fasting re-gimen.13,15,18,19 In general, these studiesreported that a small number (generally<15%) of participants reported negativeside effects, such as feeling cold, irrita-ble, low energy, or hungry. However,there were mean improvements inmood, including reductions in tension,anger, and fatigue and increases in self-confidence and positive mood.
Three of the eight trials summarizedabove compared modified fasting
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regimens to simple energy restric-tion.12,15,18 As shown in the Table,the weight-loss regimens were either1,200 to 1,500 kcal12 or 25% energyrestriction per day.15,18 One of thesestudies instituted weekly exercisegoals.12 In only one case did the fastingregimen result in significantly moreweight loss than a standard weight lossdiet (4.1%).12 In two of these studies,there were significantly reduced in-sulin concentrations compared withenergy restriction, but no other differ-ences in biomarker concentrations. The12-week, controlled weight-loss trialfound that a modified fasting regimencombined with an exercise protocolproduced significantly superior weightloss results (6.5%) compared withfasting alone (3.2%) or exercise alone(1.1%).16
A number of reviews have comparedthe results of fasting regimens withcontinuous or daily energy restric-tion.20,21 The most recent of these re-views (conducted in 2014) found thatintermittent fasting regimens demon-strated 3% to 8% reductions in bodyweight after 3 to 24 weeks in com-parison to energy restriction, whichdemonstrated 4% to 14% reductionsin weight after 6 to 24 weeks.21 Theauthors also reported that these twoweight loss strategies yielded compa-rable reductions in visceral fat mass,fasting insulin, and insulin resistanceand no meaningful reductions in fast-ing glucose concentrations.Results from these intervention tri-
als of modified fasting regimens sug-gest that these eating patterns resultin weight loss, with modest and mixedeffects on glucoregulatory markers,lipid levels, and inflammatory mar-kers. However, there is little evidenceto suggest that modified alternate-day fasting produces superior weightloss or metabolic changes in compari-son to standard energy restrictionregimens.
Time-Restricted FeedingRothschild and colleagues4 recentlyreviewed the animal literature ontime-restricted feeding. Twelve studieswere identified with daily fasting in-tervals ranging from 12 to 20 hours,in numerous mouse models, withvariability in coordination with light/dark phases and composition of chow.Despite the heterogeneity of these
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studies, the authors concluded thatin mice, time-restricted feeding wasassociated with reductions in bodyweight, total cholesterol, TG, glucose,insulin, interleukin 6, and TNF-a aswell as improvements in insulin sen-sitivity. It is notable that these healthoutcomes occurred despite variable ef-fects of intermittent fasting on weightloss.Research in animals highlights the
potential importance of synchronizingintermittent fasting regimens withdaily circadian rhythms. Animals givenunlimited access to a high-fat dieteat frequently throughout the nightand the day, disrupting their normalnocturnal feeding cycle. These mice fedan ad libitum high-fat diet developobesity, diabetes, and metabolicsyndrome. However, it was unclearwhether these diseases result from thehigh-fat diets, disruption of circadianrhythms, or both. Compared with adlibitum feeding, mice whose feedingwas restricted to normal nocturnaleating times consumed equivalent en-ergy but were protected from obesity,hyperinsulinemia, hepatic steatosis,and inflammation.22
We were only able to identify twotrials in human beings that investi-gated the effects of time-restrictedfeeding interventions that extend theduration of nighttime fasting. Neithertrial prescribed or measured physicalactivity. Both of these crossover studiesfound significant reductions in weight.In the study among 29 normal-weightmen (2 weeks per study condition), aprescribed nighttime fasting interval of�11 hours resulted in a significantweight change difference between theintervention (e0.4 kg) and control(þ0.6 kg) conditions, which translatesinto 1.3% weight loss.23 No biomarkerswere assessed. Another crossover studycompared the effect of consuming oneafternoon meal per day for 8 weeksand reported 4.1% weight loss in com-parison to an isocaloric diet consumedas three meals per day.24,25 One mealper day was also associated with re-ductions in fasting glucose and im-provements in LDL and HDL cholesterollevels. Whereas self-reported hungerwas higher in the morning for thoseconsuming one meal per day, thisfasting regimen was considered ac-ceptable because there were no meanchanges in tension, depression, anger,vigor, fatigue, or confusion.
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Although clearly limited, resultsfrom these studies of time-restrictedfeeding are consistent with researchin animals indicating that incorpora-tion of regular fasting intervals andeating in accordance with normaldaily circadian rhythms (ie, daytimehours in human beings) may beimportant for maintaining optimalmetabolic function.
RELIGIOUS FASTING:OBSERVATIONAL RESEARCHMany religions incorporate fasting forboth spiritual and physical benefits.However, published research on thesefasting regimens is almost entirelyobservational. Therefore, we provideonly an overview of these fastingregimens.
Ramadan FastingOne of the five pillars of Islam is thathealthy adult Muslims must fast fromdawn to sunset during the holy monthof Ramadan. In addition, fluid intake,cigarette smoking, and medications areforbidden. Depending on the seasonand the geographic location of thecountry, day fasting can vary from 11to 22 hours. Islamic fasting duringRamadan does not require energy re-striction; however, as intake of foodand fluid becomes less frequent,changes in body weight may occur.
In 2012 a meta-analysis of 35 stud-ies examined weight change duringRamadan.26 Across these studies, par-ticipant age ranged from 18 to 58years; just more than half (52%) wereconducted in men and women, 34%were in men only, and 11% were inwomen only.26 The authors of this re-view26 found statistically significantweight loss in 21 (62%) of these studies.When pooled, the studies in this meta-analysis showed a 1.24-kg weightreduction (95% CI e1.60 to e0.88 kg)over the month of Ramadan fasting.Across 16 follow-up studies, meanweight regain was 0.72 kg (95% CI 0.32to 1.13 kg) in the 2 weeks followingRamadan.
A 2013 meta-analysis of 30 cohortstudies including healthy young menand women examined whetherRamadan fasting altered biomarkers inaddition to weight.27 The primaryfinding of this meta-analysis was thatafter Ramadan fasting, LDL cholesterol
MY OF NUTRITION AND DIETETICS 1205
Table. Human intervention studies testing the influence of intermittent fasting regimens on weight and metabolic biomarkers associated with risk of diabetes,cardiovascular disease, and cancer
Author (y)Samplesize (n)
Type ofparticipants
Intervention durationand type of fasting
Comparisongroup orcondition
Weightchange
Changes in FastingConcentrations of Biomarkers
Glucoregulatorymarkers Lipids
Inflammatorymarkers
Alternate-day fasting
Halberg andcolleagues (2005)5
8 Ma Healthy nonobese 15 d: Alternate-day fasting(20-h fasting intervals)
None NSb Yc GlucoseNS insulin
— [d AdiponectinY LeptinNS IL-6e
NS TNF-af
Heilbronn andcolleagues (2005)6
8 Fg
8 MNonobese adults 22 d: No caloric intake every
other day (36-h fasting intervals)None Y NS glucose
Y Insulin— —
Horne andcolleagues (2012)7
20 F10 M
Healthy adults 1 d: Water only(28-h fasting interval)
None Y Y GlucoseY Insulin
[ LDLh
[ HDLi
Y TGj
NS CRPk
NS adiponectin
Modified fastingregimens
Williams andcolleagues (1998)12
31 F23 M
Overweight orobese diabetics
20 wk: 1 d per week fast or 5-dconsecutive fasts every 5 wk(400-600 kcal on fasting days)l
1,200-1,500 kcalweight-loss diet
Y NS glucoseNS insulin
NS LDLNS HDLNS TG
—
Johnson andcolleagues (2007)13
8 F2 M
Overweight adultswith asthma
8 wk: <20% of usual intake onalternate days. Ad libitum dieton nonfasting days
None Y NS glucoseNS insulin
NS LDL[ HDLY TG
NS CRPNS leptinY TNF-aY BDNFm
Varady andcolleagues (2009)14
12 F8 M
Obese adults 8 wk: Weight-loss diet withalternate-day modified fasting(w25% of total energy needs)
None Y — YLDLNS HDLY TG
—
Harvie andcolleagues (2011)15
107 F Young, overweight,or obese adults
6 mo: 25% energyrestriction 2 d/wk
25% energyrestriction 7 d/wk
NS NS glucoseY Insulin
NS LDLNS HDLNS TG
NS CRPNS adiponectinNS leptinNS BDNF
Bhutani andcolleagues (2013)16
39 F2 M
Obese adults 12 wk: 25% of energy needsalternating with adlibitum intake
Control group Y NS glucoseNS insulin
NS LDLNS HDLNS TGs
NS CRP
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Table. Human intervention studies testing the influence of intermittent fasting regimens on weight and metabolic biomarkers associated with risk of diabetes,cardiovascular disease, and cancer (continued)
Author (y)Samplesize (n)
Type ofparticipants
Intervention durationand type of fasting
Comparisongroup orcondition
Weightchange
Changes in FastingConcentrations of Biomarkers
Glucoregulatorymarkers Lipids
Inflammatorymarkers
Eshghinia andcolleagues (2013)17
15 F Overweightor obese
6 wk: 25%-30% energy needs onSaturday, Monday, Wednesday;ad libitum other days
None Y — NS LDLNS HDLNS TG
—
Harvie andcolleagues (2013)18
37 F Overweight orobese women
12 wk: 25% energy restriction2 consecutive days per week
25% energyrestriction alldays of week
NS NS glucoseNS HbA1cn
Y insulin
NS LDLNS HDLNS TG
NS adiponectinNS leptinNS IL-6NS TNF-a
Varady andcolleagues (2013)19
22 F8 M
Normal tooverweight adults
12 wk: Weight-loss diet withalternate-day modified fasting(w25% of energy needs)
Control group Y — NS LDLNS HDLY TG
Y CRP[ AdiponectinY Leptin
Time-restricted feeding
Carlson andcolleagues (2007)24
Stote (2007)25
10 F5 M
Normal weight,middle-aged
8-wk period: 1 meal/d 8 wk of 3 meals/d(crossover design)
Y Y glucoseNS insulin
Y LDL[ HDL[ TG
NS leptinNS resistinNS adiponectinNS BDNF
LeCheminant andcolleagues (2013)23
29 M Normal weightyoung men
2 wk: Nightly fasting periodfrom 7 pm to 6 am (�11 h)
2 wk of usual nightlyfasting interval(crossover design)
Figure 2. Association of intermittent fasting with intestinal microbiota, circadian clock, and other lifestyle factors hypothesizedto result in metabolic regulation and downstream effects on obesity, type 2 diabetes (T2D), cancer, and cardiovascular disease(CVD).
PRACTICE APPLICATIONS
and fasting blood glucose levelswere decreased in both sex groupsand also in the entire group comparedwith levels before Ramadan.27 Inwomen only, HDL cholesterol levelswere significantly increased. In men,there was a significant decrease inweight, total cholesterol level, and TGlevel. Some studies have reportedthat Ramadan fasts are associatedwith significantly lower concentrationsof inflammatory markers such asC-reactive protein, interleukin-6, andTNF-a.28,29
Ramadan is the most common formof time-restricted feeding and resultsin transitory weight loss, with mixedevidence for improvements in meta-bolic markers. However, this feedingpattern is in biologic oppositionto human circadian rhythms (seebelow) and, therefore, unlikely to bepursued as a desirable weight lossintervention.
Other Religious FastsA study of 448 patients from hospitalsin Utah found that Church of the Latter-day Saints followers who reported
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routine fasting (29%) exhibited signifi-cantly lower weight and lower fastingglucose as well as lower prevalence ofdiabetes (odds ratio [OR] 0.41, 95% CI0.17 to 0.99) and coronary stenosis (OR0.42, 95% CI 0.21 to 0.84).30 Seventh-day Adventists emphasize a healthydiet and lifestyle as important expres-sions of their faith and live approxi-mately 7.3 years longer than otherwhite adults. This increase in life ex-pectancy has been primarily attributedto healthful lifestyles, including notsmoking, eating a plant-based diet, andregular exercise.31 Seventh-day Ad-ventists often consume their last of twodaily meals in the afternoon, whichresults in a long nighttime fastingperiod that may be biologically impor-tant. Although it is unknown whatproportion of Seventh-day Adventistsadhere to a 2 meals/day pattern, thismeal pattern is typically chronic, andsometimes lifelong, which would allowsufficient time to achieve stablechanges in physiology.25 However, therelationship of reduced meal frequencyand prolonged nightly fasting withhealth among Adventists has not beenstudied.32
TION AND DIETETICS
MECHANISTIC FACTORSLINKING INTERMITTENTFASTING WITH HEALTHFigure 2 illustrates how factors hy-pothesized to link intermittent fastingwith health outcomes are related.Briefly, intermittent fasting regimensare hypothesized to influence meta-bolic regulation via effects on circadianbiology, the gastrointestinal micro-biota, and modifiable lifestyle behav-iors. Negative perturbations in thesesystems can produce a hostile meta-bolic milieu, which predisposes in-dividuals to the development ofobesity, diabetes, cardiovascular dis-ease, and cancer. See a recent review byLongo and Mattson33 for a detailed re-view of the molecular mechanismspotentially linking fasting with healthoutcomes.
Circadian BiologyIntermittent fasting regimens that limitfood consumption to daytime mayleverage circadian biology to improvemetabolic health. Organisms evolved torestrict their activity to the night or dayby developing an endogenous circadian
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Figure 3. The human circadian rhythm regulates eating, sleeping, hormones, physiologic processes, and coordinates metabolismand energetics.
PRACTICE APPLICATIONS
clock to ensure that physiologic pro-cesses are performed at the optimaltimes.34 Time of day plays a major rolein the integration of metabolism andenergetics as well as physiologic in-dexes such as hormone secretion pat-terns, physical coordination, and sleep(Figure 3).35 In mammals, the masterbiologic clock is located in the supra-chiasmatic nuclei of the hypothalamusand is entrained to light and darkstimuli. Similar clock oscillators havebeen found in peripheral tissues suchas the liver, with feeding as the domi-nant timing cue (ie, zeitgeber). It ishypothesized that desynchronizationbetween the suprachiasmatic nucleimaster clock and peripheral circadianclocks disrupts energy balance36 andleads to increased risk of chronic dis-eases.37 Some fasting regimens andtime-restricted feeding may impose adiurnal rhythm in food intake, result-ing in improved oscillations in circa-dian clock gene expression thatreprogram molecular mechanisms of
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energy metabolism and body weightregulation.22 We refer interestedreaders to detailed reviews on themechanisms underlying circadianbiology.34-39
The evidence that nutrient signalsand meal timing are circadian syn-chronizers is based largely on animalresearch.38,39 However, in human be-ings there is a large and robust litera-ture indicating that shift work disruptscircadian rhythms and is associatedwith increased risk of obesity, diabetes,cardiovascular disease, and cancer(particularly breast cancer).40-44 Simi-larly, data from trials and prospectivecohorts support the hypothesis thatconsuming the majority of the day’senergy earlier in the day is associatedwith lower weight and improvedhealth.45-49
GASTROINTESTINAL (GUT)MICROBIOTAMany functions of the gastrointestinaltract exhibit robust circadian or sleep-
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wake rhythms. For example, gastricemptying and blood flow are greaterduring the daytime than at night andmetabolic responses to a glucose loadare slower in the evening than in themorning.50 Therefore, it is plausible thata chronically disturbed circadian profilemay affect gastrointestinal functionand impair metabolism and health.51
Intermittent fasting may directly in-fluence the gut microbiota, which isthe complex, diverse, and vast micro-bial community that resides in theintestinal tract. Studies suggest thatchanges in composition and metabolicfunction of the gut microbiota inobese individuals may enable an“obese microbiota” to harvest moreenergy from the diet than a “leanmicrobiota” and thereby influence netenergy absorption, expenditure, andstorage.52-54 In addition, obesity-related changes in gut microbiota canalter gut permeability and bacterialtranslocation to promote systemicinflammation,55 a hallmark of obesity
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and obesity-related diseases. Finally, itis notable that a recent study56 haslinked jet lag in mice and human be-ings to abberrant microbiota diurnalfluctuations and dysbiosis that leads toglucose intolerance and obesity.
Modifiable Lifestyle BehaviorsEnergy Intake. Metabolic unit studiesof alternate and modified day fastinghave documented decreased energyconsumption. However, studies offasting regimens in free-living adultsare dependent on self-reported energyintake, which correlates poorly withobjective markers of energy intake.57
Weight change offers an indirect as-sessment of the effect of intermittentfasting on energy intake and, as shownin the Table, statistically significantweight reduction was observed in85% of intermittent fasting trials.Most fasting regimens reduce the totalnumber of hours available for eatingand thereby may reduce overall energyintake and risk of obesity. In addition,research in shift and night workershas demonstrated alterations inappetite-regulating hormones (ie, lep-tin, ghrelin, and xenin) that may lead toincreases in total energy intake.58-60
Energy Expenditure. Animal studiesindicate that the circadian clock regu-lates locomotion. Mice on a time-restricted, isocaloric feeding regimenhave shown improved muscle coordi-nation and increased activity and en-ergy expenditure toward the end of thefeeding period.22 However, data in hu-man beings are sparse or nonexistentas to whether intermittent fastingregimens affect energy expenditureamong free-living adults.
Sleep. Numerous observational studieshave reported that nighttime eating isassociated with reduced sleep durationand poor sleep quality,61,62 which canlead to insulin resistance and increasedrisk of obesity, diabetes, cardiovasculardisease, and cancer.63-68 Specifically,eating meals at abnormal circadiantimes (ie, late at night) is hypothesizedto lead to circadian desynchronization69
and subsequent disruption of normalsleep patterns. To our knowledge, nostudies have directly examined associa-tions between intermittent fasting andsleep in free-living adults.
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CONCLUSIONSIt is well known that in human beings,even a single fasting interval (eg, over-night) can reduce basal concentrationsof metabolic biomarkers associated withchronic disease such as insulin andglucose. For example, patients arerequired to fast for 8 to 12 hours beforeblood draws to achieve steady-statefasting levels for many metabolic sub-strates. Therefore, the important clinicaland scientific question is whetheradoption of a regular intermittent fast-ing regimen is a feasible and sustainablepopulation-based strategy for promot-ing metabolic health. In addition,research is needed to test whether theseregimens can complement or replaceenergy restriction and, if so, whetherthey support long-term weight man-agement. Below, we briefly summarizethe major conclusions that can bedrawn based on the current evidence.
� Studies in rodents and othernocturnal mammals support thehypothesis that intermittent fast-ing and restricting the availabilityof chow to the normal nighttimefeeding cycle improves metabolicprofiles and reduces the risk ofobesity, obesity-related condi-tions such as nonalcoholic fattyliver disease, and chronic diseasessuch as diabetes and cancer.
� In healthy, normal weight, over-weight, or obese adults, there islittle evidence that intermittentfasting regimens are harmfulphysically or mentally (ie, interms of mood).
� It appears that almost any inter-mittent fasting regimen can re-sult in some weight loss. Amongthe 13 intervention trials in-cluded in this review, 11 (84.6%)reported statistically significantweight loss ranging from 1.3% ina crossover trial with a 2-weekintervention23 to 8.0% in a 1-arm trial of 8 weeks’ duration.13
� Based on only three studies,alternate-day fasting appears toresult in weight loss as well asreductions in glucose and insulinconcentrations. However, thispattern may not be practicalbecause of intense hunger onfasting days.
� Modified alternate-day fastingregimens result in reduced
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weight, ranging from 3.2% incomparison to a control group16
over a 12-week period to 8.0%in a one-arm trial over an 8-week period.13 There waslimited and mixed evidence forreductions in insulin concentra-tions, improvements in lipidlevels, or reductions in inflam-matory factors.
� Research to date has not demon-strated that alternate-day fastingregimens produce superiorweightloss in comparison to standard,continuous calorie restrictionweight-loss plans.
� There are limited data fromstudies in human beings to sup-port the robust rodent dataregarding the positive effectsof time-restricted feeding (ie,eating patterns aligned withnormal circadian rhythms) onweight or metabolic health.
� There are considerable observa-tional data on various forms ofreligious fasting, most of whichsuggest that these regimens re-sult in transitory weight losswith mixed influence on otherbiomarkers.
� Data are lacking regarding theeffects of intermittent fasting onother health behaviors such asdiet, sleep, and physical activity.
� There are little or no publisheddata linking intermittent fa-sting regimens with clinicaloutcomes such as diabetes, car-diovascular disease, cancer, orother chronic diseases such asAlzheimer disease.
A Research Agenda onIntermittent FastingIntermittent fasting regimens attemptto translate the positive effects offasting regimens in rodents and othermammals into a practical eatingpattern for reducing the risk of chronicdisease in human beings. Below wegive suggestions for a future researchagenda investigating intermittent fast-ing and metabolic health.
Modified fasting regimens appear topromote weight loss and may improvemetabolic health. However, thereare insufficient data to determinethe optimal fasting regimen, includingthe length of the fasting interval, the
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PRACTICE APPLICATIONS
number of fasting days per week, de-gree of energy restriction needed onfasting days, and recommendations fordietary behavior on nonfasting days.Several lines of evidence support the
hypothesis that eating patterns thatreduce or eliminate nighttime eatingand prolong nightly fasting intervalscould result in sustained improve-ments in human health. Although thishypothesis has not been tested in hu-man beings, support from animalresearch is striking and data fromtime-restricted feeding studies in hu-man beings are suggestive. Prolongednightly fasting may be a simple,feasible, and potentially effective dis-ease prevention strategy at the popu-lation level.Large-scale randomized trials of
intermittent fasting regimens in free-living adults are needed and shouldlast for at least a year to see if behaviorand metabolic changes are sustainableand whether they have long-termeffects on biomarkers of aging andlongevity. Future studies shouldincorporate objective measures of en-ergy intake, sleep, and energy expen-diture; assess numerous markers ofdisease risk; and enroll diverse pop-ulations who disproportionatelyexperience obesity and related healthmaladies.Current recommendations for weight
loss frequently include advice to eatregular meals to avoid becominghungry. Some guidelines also advisethe consumption of regular snacksthroughout the day. However, it is notclear that periods of fasting (ie, hunger)necessarily lead to periods of over-eating. This overview suggests thatintermittent fasting regimens may be apromising approach to lose weight andimprove metabolic health for peoplewho can tolerate intervals of not eating,or eating very little, for certain hours ofthe day or days of the week. If shown tobe efficacious, these eating regimensmay offer promising nonpharmacologicapproaches to improving health at thepopulation level with multiple publichealth benefits.
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DISCLOSURESSTATEMENT OF POTENTIAL CONFLICT OF INTERESTNo potential conflict of interest was reported by the authors.
FUNDING/SUPPORTThis work was supported (in part) by the National Cancer Institute Centers for Transdisciplinary Research on Energetics and Cancer (grant no.1U54CA155435-01) and the National Cancer Institute, Comprehensive Partnerships to Advance Cancer Health Equity grants (nos. U54CA132384and U54CA132379). S. J. Hartman is supported by grant no. 1K07CA181323 from the National Cancer Institute, National Institutes of Health. C.Marinac is a recipient of a National Cancer Instituteesponsored Ruth L. Kirschstein National Research Service Award (no. 1F31CA183125-01A1).A. Villaseñor is supported by a Diversity Research Supplement from the Continuing Umbrella of Research Experiences training program, as part ofthe National Cancer Institute Center to Reduce Cancer Health Disparities (no. 3U54CA155435-02S2).
