Alternate-day fasting in nonobese subjects: effects on body weight,
body composition, and energy metabolism
Leonie K Heilbronn, Steven R Smith, Corby K Martin, Stephen D Anton, and Eric Ravussin
Background: Prolonged dietary restriction increases the life span in
rodents. Some evidence suggests that alternate-day fasting may also
prolong the life span.
Objective: Our goal was to determine whether alternate-day fasting
is a feasible method of dietary restriction in nonobese humans and
whether it improves known biomarkers of longevity.
Design: Nonobese subjects (8 men and 8 women) fasted every other
day for 22 d. Body weight, body composition, resting metabolic rate
(RMR), respiratory quotient (RQ), temperature, fasting serum glu-
cose, insulin, free fatty acids, and ghrelin were assessed at baseline
and after 21 d (12-h fast) and 22 d (36-h fast) of alternate-day fasting.
Visual analogue scales were used to assess hunger weekly.
Results: Subjects lost 2.5 앐 0.5% of their initial body weight (P 쏝
0.001) and 4 앐 1% of their initial fat mass (P 쏝 0.001). Hunger
increased on the first day of fasting and remained elevated (P 쏝
0.001). RMR and RQ did not change significantly from baseline to
day 21, but RQ decreased on day 22 (P 쏝 0.001), which resulted in
an average daily increase in fat oxidation of 욷15 g. Glucose and
ghrelin did not change significantly from baseline with alternate-day
fasting, whereas fasting insulin decreased 57 앐 4% (P 쏝 0.001).
Conclusions: Alternate-day fasting was feasible in nonobese sub-
jects, and fat oxidation increased. However, hunger on fasting days
did not decrease, perhaps indicating the unlikelihood of continuing
this diet for extended periods of time. Adding one small meal on a
fasting day may make this approach to dietary restriction more
acceptable. Am J Clin Nutr 2005;81:69 –73.
KEY WORDS Resting metabolic rate, fat oxidation, insulin,
glucose, biomarkers of longevity
Prolonged dietary restriction (DR) is the only proven method
of increasing the life span in rodents, flies, yeast, and worms (1).
The mechanism or mechanisms by which DR increases life span
are unclear, but the effects of DR include reduced metabolic rate,
reduced oxidative damage, altered neuroendocrine signaling,
and improved insulin sensitivity (2). The effect of prolonged DR
on the life span in nonhuman primates is currently being inves-
tigated (3–5). Although conclusive results are years away, many
improvements in biomarkers of longevity, including reduced
core temperature, resting metabolic rate (RMR), dehydroepi-
androsterone sulfate, glucose, and insulin, have already been
observed. Prolonged DR also alters the expression of many genes
from skeletal muscle, brain, and liver, including genes encoding
heat shock proteins and uncoupling proteins and genes involved
in oxidative damage (6 – 8). Recent microarray results in mouse
liver indicate that there is significant overlap of genes that are
up-regulated by short-term starvation and by prolonged DR (9).
Alternate-day fasting may therefore be an alternative to pro-
longed DR as a method of increasing maximal life span. Good-
rick et al (10) found that alternate-day fasting increased median
and maximal life span in C57Bl/6 mice when it was introduced
at 1.5 and 6 mo of age and increased maximal, but not median, life
span in A/J mice. Recently, Anson et al (11) observed that mice
fed every other day consumed the same total energy as did ad
libitum fed animals and had similar body weights but had re-
duced glucose and insulin concentrations and increased resis-
tance to endotoxic stress (11).
A pilot study testing the feasibility and effects of long-term DR
on biomarkers of longevity in nonobese humans is currently
under investigation. This randomized clinical trial named
CALERIE (sponsored by the National Institute of Aging) is
testing numerous behavioral strategies and diets (ranging from
liquid energy to 20–30% DR to increased energy expenditure by
physical activity) to determine which of these will prove the most
viable in today’s “obesogenic” environment. However, the fea-
sibility and efficacy of alternate-day fasting is not being inves-
tigated. Given the difficulty that individuals have in estimating
energy intake (12–14), alternate-day fasting may prove to be a
less complicated method than prolonged DR in humans. Indeed,
one study investigated the effects of alternate-day DR for 3 y
(15). In that study, the subjects were allowed1Lofmilk and 2–3
pieces of fruit on their energy-restricted day and 9600 kJ/d on the
other day. The control group was fed 9600 kJ/d every day. The
subjects randomly assigned to alternate-day DR spent less time
in the infirmary and had a lower death rate than in the control
group (6 versus 13; NS) (16). The present study was undertaken
to determine the feasibility of alternate-day fasting in nonobese
subjects. In addition, the effects of alternate-day fasting on body
weight, RMR, fat oxidation, and biomarkers of longevity were
From the Pennington Biomedical Research Center, Baton Rouge, LA.
Reprints not available. Address correspondence to E Ravussin, Penning-
ton Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA,
70808. E-mail: firstname.lastname@example.org.
Received May 27, 2004.
Accepted for publication September 2, 2004.
69Am J Clin Nutr 2005;81:69–73. Printed in USA. © 2005 American Society for Clinical Nutrition
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SUBJECTS AND METHODS
Healthy, nonobese [body mass index (in kg/m
) range: 20.0 –
30.0] men (n ҃ 8) and women (n ҃ 8) aged between 23 and 53 y
were recruited (Table 1). The subjects had different levels of
physical activity: 7 were sedentary, 3 were moderately active
(exercised 1–2 times/wk), and 6 were quite active (exercised 4 –5
times/wk). Competitive athletes and subjects with type 2 diabe-
tes were excluded. The Institutional Review Board of the Pen-
nington Biomedical Research Center approved the study, and the
subjects gave their written informed consent.
The subjects attended the clinical research center on 2 con-
secutive days at baseline (days Ҁ2 and Ҁ1) and on 2 consecutive
days after 3 wk of alternate-day fasting following a “feast” day
(day 21) and following a “fast” day (day 22). The subjects had
therefore fasted 12 h (overnight) on days Ҁ2, Ҁ1, and 21 and 36 h
on day 22. The subjects were instructed to avoid exercise, alco-
hol, and coffee for 욷24 h before each visit. At each visit, the
subjects arrived in the clinic at 0700 and were weighed while
wearing a hospital gown. Blood pressure was measured with the
subject in a seated position after a 5-min rest, oral temperature
was recorded (SureTemp; Welch Allyn Inc, NY), and a fasting
blood sample was drawn. RMR was measured for 30 min with a
DeltaTrac metabolic monitor (SensorMedics, Yorba Linda, CA)
after a 20-min resting period while the subjects were awake in a
semirecumbent position. On days Ҁ2 and 21, body composition
was measured by dual-energy X-ray absorptiometry (QDR 4500;
Hologic Inc, Bedford, MA). At baseline and on days 1, 7, 15, and
21 (fasting days), the subjects completed visual analogue scales
(VASs) at 1000, 1200, 1400, and 1600 to assess their feelings of
hunger, fullness, desire to eat, satisfaction, and prospective food
consumption (17). Briefly, the participants were asked to place a
mark on a 100-mm line anchored by “not at all” and “extremely”
to record subjective levels of hunger or satiety. The VASs were
scored by measuring from the left end of the line to the mark in
mm, and mean ratings were calculated for each day. At baseline,
the subjects also completed the Eating Inventory questionnaire,
which assessed dietary restraint (the intent and ability to restrict
caloric intake), disinhibition (the tendency to overeat), and hun-
ger (18). The subjects also completed a nine-item self-report
questionnaire, which was developed for this study, to assess
eating attitudes and behaviors with the use of an 8-point scale.
This questionnaire (Eating Behaviors Questionnaire) assessed
whether the subjects consider themselves “dieters” who watch
what they eat or “big eaters” who tend to eat 1 or 2 large meals per
After baseline testing was completed, the subjects fasted from
midnight to the subsequent midnight on alternating days for 22 d.
On each fasting day, the subjects were allowed to consume
energy-free beverages, tea, coffee, and sugar-free gum and were
instructed to keep their water intake high. On each feasting day,
the subjects were instructed to eat whatever they wished and were
informed that double their usual food intake would be required to
maintain their usual body weight. The subjects were provided
with calibrated digital scales (Tanita, Arlington Heights, IL) to
record their morning fasting body weight, urinary sticks to test
for the presence of ketones, and a diet diary to record anything
that was consumed on the fasting day. On day 20, the subjects
were required to fast from 1900 so that a 12-h overnight fast
would be completed before testing began the following morning
at 0700. They did not break this fast until after their clinic visit on
Glucose was analyzed by using a glucose oxidase electrode
(Syncron CX7; Beckman, Brea, CA). Free fatty acids were mea-
sured on a Synchron CX5 by using reagents from Wako (Rich-
-Hydroxybutyrate was measured on a Synchron
CX5 by using reagents from Sigma (St Louis). Insulin was mea-
sured by using an immunoassay on a DPC 2000 (Diagnostic
Product Corporation, Los Angeles). Ghrelin was measured by
using a radioimmunoassay kit from Linco (St Charles, MO).
Data are expressed as means 앐 SEMs. SAS 8.2 (SAS Institute
Inc, Cary, NC) and SPSS 11.0.1 (SPSS Inc, Chicago) were used
for data analysis. Baseline measures (days Ҁ2 and Ҁ1) were
averaged. Statistics were performed by one- and two-factor
repeated-measures analysis of variance. Post hoc analysis was
performed with Tukey’s tests where necessary. RMR was ana-
lyzed by using linear regression to adjust for fat mass and fat-free
mass. Correlations were performed with Pearson’s correlation
coefficient. Significance was set at P 쏝 0.05. Fasting insulin
values below the detection limit of the assay (쏝2.0 mU/L) were
assigned a value of 1.0 mU/L. Insulin values were log trans-
formed for analysis.
The subjects’ characteristics by sex are given in Table 1. On
the basis of their self-recorded diet diaries and weight logs (Fig-
ure 1), the subjects complied with the protocol. Urinary ketones
were not useful as a measure of compliance because they were
not consistently detected in all subjects (data not shown). On the
basis of daily regressed body weights, the subjects lost 2.5 앐
0.5% of their initial body weight. This self-reported weight loss
was confirmed by weights measured in the clinic at baseline and
on days 21 and 22 (P 쏝 0.001). Significant reductions were
observed in fat mass (P 쏝 0.001) and fat-free mass (P 쏝 0.05)
after the intervention (Figure 1).
Baseline characteristics of the participants by sex
(n ҃ 8)
(n ҃ 8)
Age (y) 34 앐 330앐 1
Weight (kg) 80.6 앐 4.4 59.7 앐 1.7
25.2 앐 1.1 22.6 앐 0.6
Fat mass (%) 22 앐 225앐 1
Cholesterol (mmol/L) 4.9 앐 0.4 4.7 앐 0.2
HDL (mmol/L) 1.0 앐 0.1 1.8 앐 0.1
Triacylglycerols (mmol/L) 2.5 앐 0.6 1.1 앐 0.1
Systolic blood pressure (mm Hg) 116 앐 2 104 앐 3
Diastolic blood pressure (mm Hg) 75 앐 368앐 2
All values are x 앐 SEM.
Significantly different from men, P 쏝 0.01 (one-factor ANOVA).
70 HEILBRONN ET AL
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On average, the men considered themselves “big eaters,” and
the women reported that they “watched what they ate.” Percent-
age weight loss did not differ significantly between the men and
the women, but weight loss correlated negatively with consider-
ing oneself a big eater after adjustment for sex (r ҃Ҁ0.63, P ҃
0.04). The dietary restraint and disinhibition scales of the Eating
Inventory questionnaire did not significantly predict weight loss.
VASs were completed for all days by only 8 of 16 subjects.
First, baseline results were compared with the first day of fasting.
As expected, a significant increase was found in feelings of
hunger (from 37 앐 5to56앐 4 mm; P 쏝 0.001), and a significant
decrease was noted in feelings of fullness (from 43 앐 3to23앐
4 mm; P 쏝 0.001). However, repeated-measures analysis over
time (days 1, 7, 15, and 21) showed no significant changes in the
subjects’ perception of hunger, thirst, desire to eat, or feelings of
satisfaction, although feelings of fullness increased slightly over
time (P 쏝 0.05).
Temperature (data not shown) and absolute and relative rest-
ing metabolic rate (adjusted for fat-free mass and fat mass) were
not significantly different from baseline (Table 2). Respiratory
quotient (RQ) was also not significantly different from baseline
at day 21; however, RQ was lower on day 22 (P 쏝 0.001; Table
2). More specifically, fat oxidation increased from 64 g/24 h at
baseline to 101 g/24 h, and carbohydrate oxidation decreased
from 175 to 81 g/24 h. The change in RQ from baseline to day 21
was related to weight loss (r ҃Ҁ0.76, P 쏝 0.001).
The women had significantly lower glucose, insulin, free fatty
acid, triacylglycerol, and LDL-cholesterol concentrations and
significantly higher HDL-cholesterol and ghrelin concentrations
than did the men (P 쏝 0.05). Fasting glucose was not signifi-
cantly changed from baseline in the men or the women (Figure
2). Fasting insulin was lower on day 22 in both the men and the
women (P 쏝 0.001), and fasting
-hydroxybutyrate and free
fatty acid concentrations were higher on day 22 in both the men
and the women (Figure 2; P 쏝 0.001). Fasting ghrelin was not
significantly altered from baseline on day 21 (results not shown)
or day 22 (from 1019 앐 128 to 1063 앐 158 pg/mL in the men and
from 1403 앐 63 to 1493 앐 139 pg/mL in the women). Systolic
and diastolic blood pressure were not significantly altered by the
intervention (data not shown). HDL was elevated from baseline
in the women only (P 쏝 0.001; data not shown), and triacylglyc-
erol was significantly reduced from baseline in the men only (P 쏝
0.05; data not shown).
Alternate-day fasting may be an alternative to prolonged DR
for increasing the life span (11). In the present study, we report
that alternate-day fasting is feasible for short time periods in
nonobese subjects. One participant reported feeling lightheaded
once, and 4 subjects reported constipation. No subjects withdrew
during the study, but many reported feeling irritable on their
fasting days, perhaps indicating the unlikelihood of continuing
this diet for extended periods of time. The results from the VASs
suggest that feelings of fullness may have increased from the first
fasting day over the course of the study, but other subjective
states related to food intake motivation did not habituate, includ-
ing hunger. This result contrasts with the results of studies using
liquid-based, very-low-energy diets where hunger diminishes
despite a marked energy deficit (19). Overall, these results sug-
gest that a prolonged schedule of fasting and feasting would be
marred by aversive subjective states (eg, hunger and irritability),
which would likely limit the ability of most individuals to sustain
this eating pattern.
This is the first study, to our knowledge, to test the effects of
alternate-day fasting on body weight and other metabolic vari-
ables in humans. Body weight was clearly reduced from baseline
after 3 wk of alternate-day fasting, indicating that the subjects
were unable to consume enough food on the feasting days to
FIGURE 1. Top panel: mean (앐SEM) percentage change in daily self-
recorded body weight (n ҃ 16). Body weight was measured before breaking
an overnight fast (odd days) or after 24 –36-h fasts (even days). Bottom panel:
mean (앐SEM) fat mass (FM) and fat-free mass (FFM) by dual-energy X-ray
absorptiometry measured after 12-h fasts at baseline (day Ҁ2) and on day 21.
Significantly different from baseline, P 쏝 0.001 for FM and P 쏝 0.05 for
FFM (one-factor ANOVA).
Resting metabolic rate (RMR), respiratory quotient (RQ), and fat and
carbohydrate oxidation measured at baseline and after a fed day (day 21)
and a fast day (day 22)
Baseline Day 21 Day 22
RMR (kJ/d) 6675 앐 283 6292 앐 268 6329 앐 260
RQ 0.85 앐 0.01 0.86 앐 0.02 0.79 앐 0.01
Fat oxidation (g/24 h)
64 앐 854앐 10 101 앐 9
Carbohydrate oxidation (g/24 h)
175 앐 17 184 앐 24 81 앐 16
All values are x 앐 SEM. Two consecutive days at baseline were
averaged for analysis.
Significantly different from baseline, P 쏝 0.001 (one-factor repeated-
Calculated by assuming that protein oxidation was 15% of RMR.
ALTERNATE-DAY FASTING IN NONOBESE HUMANS 71
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maintain their weight. This is opposite the results observed in
rodents, where mice fed every other day maintained their body
weight and consumed roughly the same amount of food in 1 d that
ad libitum–fed animals consumed over 2 d (11). We hypothe-
sized that the subjects with a self-reported ability to overeat or eat
large amounts of food would maintain their body weight, and this
hypothesis was supported: considering oneself a “big eater” was
negatively associated with weight loss when sex was controlled
for by partial correlation. Whether alternate-day fasting would
lead to weight loss in obese participants remains unclear. The
negative subjective states associated with the study cast doubt on
the ability of individuals to voluntarily engage in alternate-day
fasting for prolonged periods of time. Altering the clock time that
the subjects are asked to fast (eg, from 1900 to 1900) or adding
a small meal (10 –20% of caloric needs) to the fasting day may
make alternate-day fasting more acceptable in all populations.
Ghrelin is a peptide secreted in the gut that is reduced on
feeding and has been implicated in the regulation of feeding
behavior and energy balance. Obese subjects have lower fasting
ghrelin concentrations than do lean subjects (20) but have im-
paired suppression of plasma ghrelin in response to a meal (21).
Furthermore, ghrelin is increased after weight loss in obese sub-
jects (22, 23), perhaps driving the common phenomenon of
weight regain after weight loss. In the present study, the women
had significantly higher ghrelin concentrations than did the men.
This has been reported previously (24) but is not consistently
observed (25) and may be related to central adiposity. In contrast
with the large increases in reported hunger, plasma ghrelin was
unchanged in both the men and the women, even after 36 h of
fasting. Studies in rodents have found that 24-h fasts increase
plasma ghrelin (26). However, fasting for 72 h did not change
plasma ghrelin in lean men (24). The results of these fasting
studies in humans call into question the role of ghrelin in the
hunger drive and highlight the need for further research in this
A hallmark of rodent studies of longevity is reduced fasting
glucose and insulin concentrations and increased insulin sensi-
tivity in dietary-restricted animals (27). Reduced fasting insulin
has also been associated with increased longevity in humans
(27). In the present study, insulin was reduced after a fast day,
suggesting improved insulin sensitivity. However, plasma free
fatty acids were also elevated after fasting; these elevated con-
centrations may impair insulin-mediated glucose disposal and
the suppression of hepatic glucose production (28). We also
found that alternate-day fasting did not significantly change fast-
ing glucose or insulin from baseline after a 12-h fast. This is in
contrast with results in mice, in which glucose and insulin con-
centrations were lower after 14-h fasts than in ad libitum fed–
mice or mice fed energy-restricted diets. Thus, humans may need
to fast for longer than 12 h for this effect to be observed. Alter-
natively, this could be due to the already low glucose concentra-
tions of our population or that 3 wk of alternate-day fasting was
insufficient to produce this response. The study design may also
have affected these results, because the subjects anecdotally re-
ported eating even more than usual on day 20 (knowing they were
about to enter a longer than usual fast day).
RMR was not significantly changed after 3 wk of alternate-day
fasting. The effects of 36-h fasts on RMR have not been previ-
ously reported. Horton and Hill (29) observed no differences in
metabolic rate (measured for 12 h in a metabolic chamber after a
mixed meal) between overnight or 3-d fasts. We did observe that
subjects oxidized more fat on day 22 as evidenced by a reduction
in RQ from 0.85 to 0.79. However, RQ was not altered on day 21.
This suggests that there were no sustained increases in fat oxi-
dation on fed days. Caution must be exercised when interpreting
this result, because the subjects did not consume standardized
FIGURE 2. Mean (앐SEM) fasting glucose, fasting insulin, fasting
-hydroxybutyrate (BHBA), and fasting free fatty acids (FFA) at baseline, day 21, and
day 22 in men (n ҃ 8) and women (n ҃ 8).
Significantly different from baseline, P 쏝 0.01 [two-factor (time and sex) repeated-measures ANOVA].
72 HEILBRONN ET AL
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diets and RQ is heavily dependent on fat intake and energy
balance. However, it is more likely that we underestimated fat
oxidation, because the subjects were coming out of positive en-
ergy balance and because overall fat oxidation was increased by
an average of 욷15 g/d. Furthermore, because weight loss is
positively correlated with increased fat oxidation, the results
suggest that the subjects with a greater ability to oxidize fat lost
more weight. Alternatively, it could be argued that the subjects
who had a greater caloric deficit had increased fat oxidation.
In conclusion, alternate-day fasting is feasible in nonobese
subjects for short time periods, although unlike rodents, the sub-
jects were unable to maintain their body weight. Furthermore, fat
oxidation was increased and translated into fat mass loss. Hunger
on fasting days did not habituate over the course of the study,
which perhaps indicates the unlikelihood of subjects continuing
on this diet for extended periods of time. Whether alternate-day
fasting would promote weight loss in an obese population is
We acknowledge the clinical research staff for their assistance in perform-
ing this study and Julia Volaufova for assistance with the statistical analysis.
LKH, SRS, and ER were involved in developing the study protocol and the
experimental design. CKM and SA administered and analyzed the VAS and
psychological questionnaires. LKH wrote the draft manuscript with contri-
butions from ER, SRS, and CKM. None of the authors had any financial
interests in organizations sponsoring this research.
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