* * * ARTICLE * * * Study - 3 meals/day vs. 1 meal/day
I found this while researching IF diets and thought it might be of some interest, even to people who aren't interested in IF per se:
A controlled trial of reduced meal frequency without caloric restriction in healthy, normal-weight, middle-aged adults
Kim S Stote, David J Baer, Karen Spears, David R Paul, G Keith Harris, William V Rumpler, Pilar Strycula, Samer S Najjar, Luigi Ferrucci, Donald K Ingram, Dan L Longo and Mark P Mattson
1 From the Beltsville Human Nutrition Research Center, US Department of Agriculture, Agriculture Research Service, Beltsville, MD (KSS, DJB, KS, DRP, GKW, and WVR), and the Clinical Research Branch (PS and LF), and the Laboratories of Cardiovascular Science (SSN), Experimental Gerontology (DKI), Immunology (DLL), and Neurosciences (MPM), National Institute on Aging Intramural Research Program, Baltimore, MD
2 Supported by the National Institute on Aging and the US Department of Agriculture.
ABSTRACT
Background:Although consumption of 3 meals/d is the most common pattern of eating in industrialized countries, a scientific rationale for this meal frequency with respect to optimal health is lacking. A diet with less meal frequency can improve the health and extend the lifespan of laboratory animals, but its effect on humans has never been tested.
Objective:A pilot study was conducted to establish the effects of a reduced-meal-frequency diet on health indicators in healthy, normal-weight adults.
Design:The study was a randomized crossover design with two 8-wk treatment periods. During the treatment periods, subjects consumed all of the calories needed for weight maintenance in either 3 meals/d or 1 meal/d.
Results:Subjects who completed the study maintained their body weight within 2 kg of their initial weight throughout the 6-mo period. There were no significant effects of meal frequency on heart rate, body temperature, or most of the blood variables measured. However, when consuming 1 meal/d, subjects had a significant increase in hunger; a significant modification of body composition, including reductions in fat mass; significant increases in blood pressure and in total, LDL-, and HDL-cholesterol concentrations; and a significant decrease in concentrations of cortisol.
Conclusions:Normal-weight subjects are able to comply with a 1 meal/d diet. When meal frequency is decreased without a reduction in overall calorie intake, modest changes occur in body composition, some cardiovascular disease risk factors, and hematologic variables. Diurnal variations may affect outcomes.
Key Words: Caloric restriction meal frequency intermittent fasting cholesterol metabolism blood pressure controlled diet normal-weight adults
INTRODUCTION
Overeating is a major cause of morbidity and mortality in humans, and, accordingly, caloric restriction has multiple health benefits for the obese (1, 2). Caloric restriction may also improve the health of persons who are not considered overweight (3). Whereas nutrient-dense, low-calorie diets have numerous health benefits, the influence of meal frequency on health has not been established. However, studies of various laboratory animals (4-6) and specifically of rodents (5, 7-9) have shown that dietary restriction (caloric restriction or intermittent fastinglong-term intermittent fasting in the case of rodents) can increase lifespan and protect against or suppress disease processes responsible for cardiovascular disease (CVD), cancer, diabetes, and neurodegenerative disorders. The latter studies (5, 7-9) showed beneficial effects of intermittent fasting on blood pressure, glucose metabolism, and vulnerability of cardiac and brain cells to injury. Despite a general perception among the public at large that it is important to eat ≥3 meals/d, no controlled studies have directly compared the effects of different meal frequencies on human health. This knowledge gap has been identified by the 2005 Dietary Guidelines Advisory Committee Report as a future research direction (10, 11).
Studies of rodents and monkeys have led to several hypotheses concerning the cellular and molecular mechanisms whereby dietary restriction extends lifespan and protects against disease. The oxidative stress hypothesis proposes that aging and age-related diseases result from cumulative oxidative damage to proteins, lipids, and nucleic acids; by decreasing the amount of oxyradicals produced in mitochondria, dietary restriction retards aging and disease (12). A second hypothesis is that dietary restriction is beneficial primarily because of its effects on energy metabolism; ie, it increases insulin sensitivity (13). A third hypothesis, which may have a particular relation to the beneficial effects of reduced meal frequency/intermittent fasting, is that dietary restriction induces a mild cellular stress response in which cells up-regulate the expression of genes that enable them to cope with severe stress (12). Several physiologic variables have been shown to change in animals maintained on caloric restriction or intermittent fasting regimens (or both), including decreased plasma insulin and glucose concentrations, decreased blood pressure and heart rate, and enhanced immune function (8, 14-16)
The current pilot study was conducted to determine the feasibility of controlled meal frequency in normal-weight, middle-aged men and women. Several physiologic outcomes and biomarkers of health were also investigated.
SUBJECTS AND METHODS
Subjects
Healthy men and women aged 4050 y were recruited by newspaper advertisement from the greater Washington, DC, metropolitan area. Inclusion in the study was based on a body mass index (BMI; in kg/m2) between 18 and 25 and a usual eating pattern of 3 meals/d. Subjects were excluded if they reported tobacco use, recent pregnancy or lactation, history of CVD or medication use for CVD, hypertension, diabetes, psychiatric condition, cancer, or employment in high-risk occupations (this last exclusion criterion was due to the potential for dizziness or weakness during the meal-skipping phase). Study entry was approved by a physician on the basis of medical history, blood and urine test screening results, and a physical examination.
All subjects gave written informed consent. The experimental protocol was approved by the Johns Hopkins University Bloomberg School of Public Health Committee on Human Research and the MedStar Research Institute Institutional Review Board. The subjects were compensated for their participation in the study.
Study design
This study was a randomized crossover design with two 8-wk treatment periods. During the treatment periods, subjects consumed all of their calories for weight maintenance distributed in either 3 meals/d (control diet) or 1 meal/d (experimental diet). An 11-wk washout period was included between treatments. The control diet consisted of 3 meals/d (breakfast, lunch, and dinner) and the experimental "meal-skipping" (or 1 meal/d) diet consisted of the same daily allotment of food eaten within a 4-h period in the early evening. The subjects were fed at an energy intake that would maintain body weight so that meal frequency would be the only major change in their diet during the course of the study. The study was a collaborative effort between the US Department of Agriculture, Beltsville Human Nutrition Research Center (BHNRC; Beltsville, MD), and the National Institute on Aging (NIA; Baltimore, MD).
Study diets
Each day, subjects consumed dinner at the BHNRC Human Study Facility under the supervision of a registered dietitian. At the end of dinner, subject meal trays were inspected to ensure complete consumption of the food. All breakfasts and lunches were packed for carry-out. Only foods provided by the Human Study Facility were allowed to be consumed during the study. A 7-d menu cycle of typical American foods was formulated by using NUTRITIONIST PRO software (version 1.3; Axxya Systems, Stafford TX).
During the first 2 wk of the study, subjects randomly assigned to the 1 meal/d diet were fed 2 meals/d (lunch and dinner); for the next 6 wk, all food was consumed between 1700 and 2100, which created a minimum fast of 20 h/d. While maintaining the same macronutrient distribution between experimental and control diets, breakfast and lunch food items were substituted for traditional evening meal items. Energy-dense foods were chosen to assist in reducing the volume of food to be consumed.
Subjects were allowed unlimited amounts of calorie-free foods such as water, coffee (without sugar or milk), diet soft drinks, salt, and pepper. A 2-d emergency supply of food that met the study protocol was provided to each subject for use during any inclement weather. Subjects were required to consume all of the foods and only the foods provided by the Human Study Facility at specified times during the controlled feeding periods.
Body weight was measured every day before the evening meal, when subjects arrived at the facility. So that subjects could maintain constant body weight during the study, energy intake was adjusted in 200-kcal increments. Energy requirements for weight maintenance were calculated by using the Harris-Benedict formula, which estimates basal energy expenditure, and multiplied by an activity factor of 1.31.5. This formula has proven successful in estimating weight-maintenance energy requirements at our facility. Subjects completed a daily questionnaire regarding their general health; any consumption of prescription or over-the-counter medications; factors related to dietary compliance; and exercise performed; the questionnaire also gave subjects the opportunity to write in questions of their own about the diet. Subjects were encouraged to maintain their normal exercise routine throughout the study.
Physiologic measurements
Physiologic variables measured were blood pressure, heart rate, body temperature, and body composition. These measurements were collected at baseline, 4 wk, and at the end of each of the 2 treatment periods. Briefly, subjects were seated in a quiet room for ≈5 min, and blood pressure and heart rate were measured 3 times with a Dinamap Compact Monitor (Model TS; Critikon, Tampa, FL). Body temperature was measured on either a Dinamap or a portable oral digital thermometer (ADtempIII; American Diagnostic Corp, Hauppauge, NY). Body composition was measured by using bioelectrical impedance analysis (BIA) (model TBF-300A; Tanita, Arlington Heights, IL). Subjects fasted and refrained from heavy exercise before these measurements. Subjective satiety and hunger were assessed daily before consumption of the evening meal, in both the experimental and control diets, by using 4 visual analogue scales (VASs) that described hunger, desire to eat, the amount of food that could be eaten, and stomach fullness. The VASs were all 100-mm long, and they were anchored at either end with terms indicating opposite descriptors.
Biological sample collection and analysis
Blood was collected at baseline, 4 wk, and the end of each of the 2 treatment periods after a minimum of 12 h of fasting. All of the baseline samples were collected in the morning. The 4-wk and end-of-treatment samples were collected in the morning from subjects following the control diet and in the evening (before dinner) from subjects following the 1 meal/d diet. In addition, as a measure of compliance, blood samples were collected at unannounced times on 3 occasions from the subjects when they were consuming 1 meal/d and were analyzed for fasting blood glucose and triacylglycerol concentrations. The collected blood samples were used to prepare 0.82.0-mL aliquots of plasma, serum, and red blood cells that were stored at 80 °C in cryovials. Sample analyses included a lipid profile, a comprehensive metabolic panel, complete blood count (CBC), and cortisol concentration. Analyses were performed at the Core Laboratory of the NIA, National Institutes of Health (Baltimore, MD) and at Fairfax Medical Laboratory (Chantilly, VA) by using standard procedures and quality-control measures from the Clinical Laboratory Improvement Amendments [(CLIA) Internet: http://www.cms.hhs.gov/clia (accessed 1 January 2006)]. Plasma total cholesterol, HDL cholesterol, and triacyglycerol were measured enzymatically with commercial kits (Johnson & Johnson/Ortho Clinical Diagnostics, Raritan, NJ) on a Vitros 250 analyzer (Johnson & Johnson/Ortho Clinical Diagnostics). LDL-cholesterol concentrations were calculated by using the equation of Friedewald et al (17). Serum cortisol concentrations were analyzed on a chemiluminescence immunoassay analyzer (IMMULITE 2000; Diagnostic Products Corp, Los Angeles, CA) with intraassay and interassay CVs of 5.3% and 7.2%, respectively.
Physical activity assessment
Physical activity monitoring (PAM) was assessed with the use of the Actigraph accelerometer (MTI AM 71641.2; Manufacturing Technology Inc, Fort Walton Beach, FL) over the course of 7 d to obtain the average daily and weekly activity counts. Measurements were obtained during week 2 (baseline) and week 7 (end of treatment) of each treatment period. Subjects were instructed to wear the activity monitor a long as possible every day. The activity monitor, worn as a snugly fitting belt around the waist with the manufacturer's "notch" facing upward, was set to read the data in 1-min segments. Subjects were asked to wear the monitor on the right hip, unless they reported being unable to do so. Regardless of the activity monitor placement, each subject wore the monitor on the same side and at the same location throughout the study. In addition to wearing the monitors, subjects maintained a small daily log to detail the times when the monitor was worn, the activities that were carried out when the monitor was not worn (ie, sleeping or showering), and any exercise performed (whether the monitor was worn or not). In each of the treatment periods, subjects were asked to wear the monitor for 9 d, with the intention of obtaining 7 full days of data. If a subject reported not wearing the activity monitor for a given day, he or she was asked to wear the monitor an extra day. Physical activity data obtained from the Actigraph accelerometer were processed by using a procedure developed in our facility. Briefly, most subjects typically remove the monitors periodically during the day or at night for sleep (or both). Analyses from our laboratory indicate that these missing data points can have a detrimental effect on the prediction of physical activity, so we developed a procedure that treats each monitoring day as a 24-h day no matter how long the monitor was worn on any day. Monitor files are scanned by a program that estimates the time spent sleeping and imputes a constant value for those times. Other missing strings of data >20 min long are "filled in" by imputation, on the basis of the monitor removal times reported in the log. These data processing procedures dramatically reduce the variability inherent with activity monitor data.
Statistical analysis
An analysis of variance (ANOVA) appropriate for a 2-period crossover study with repeated measures within period was used to evaluate meal frequency effects on outcome variables using the MIXED procedure in SAS software (version 9.0; SAS Institute, Cary NC). The statistical model included sequence, meal frequency, period, time within period, and time x meal frequency interaction as fixed effects. Period and time were modeled as repeated measures. The factor subject nested in sequence was included in the model as a random effect. The first observation within a period was included as a covariate. When the time xmeal frequency interaction was significant (P < 0.05), within-time meal frequency effects were evaluated by using repeated-measures ANOVA. If this interaction was not significant, the main effect of meal frequency was evaluated. Data are presented as means ± SEMs.
RESULTS
Subject characteristics
Sixty-nine persons attended the study information meeting. Thirty-five gave written informed consent, and 32 completed the screening process. Twenty-one subjects (14 women, 7 men) ultimately were randomly assigned to the treatments. Fifteen subjects (10 women, 5 men) completed the feeding phase of the study. Complete data were analyzed and are presented for 15 subjects. In the 3 meal/d diet arm, 1 subject withdrew because of food dislikes. During the 1 meal/d diet, 5 subjects withdrew because of scheduling conflicts and health problems unrelated to the study. Only 1 of the 5 subjects withdrew specifically because of an unwillingness to consume the 1 meal/d diet. The mean BMI indicated that subjects were within the normal range. The physical characteristics of the 15 subjects at baseline are presented in Table 1.
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TABLE 1 Subject characteristics before the start of the controlled feeding1
Diets
The composition of the 2 diets is shown in Table 2. Subject adherence to the controlled diets was judged to be excellent on the basis of observed consumption of the meals in the facility and review of the responses on the daily questionnaires. The random fasting triacylglycerol and glucose concentrations indicated that compliance with the 1 meal/d diet was acceptable. The mean triacylglycerol and glucose concentrations were 64.4 ± 5.7 and 79.7 ± 1.9 mg/dL, respectively. Thirty of 1650 evening meals (1.8%) provided during the entire study were packed for consumption away from the facility. The average daily energy intake across treatments was 2364 kcal in the 1 meal/d diet and 2429 kcal in the 3 meals/d diet. No significant differences were found in the percentages of macronutrients, fatty acids, cholesterol, and fiber between the 2 controlled diets.
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TABLE 2 Composition of the controlled diets1
Blood pressure
Systolic and diastolic blood pressures were significantly lowered by ≈6% during the period when subjects were consuming 3 meals/d than when they were consuming 1 meal/d. No significant effect of time (measurements taken at week 4 and week 8) or of treatment sequence on blood pressure was seen. No significant differences in heart rate and body temperature were observed between the 2 diet regimens (Table 3).
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TABLE 3 Blood pressure and body composition of subjects after consumption of either 1 meal/d or 3 meals/d1
Visual analogue scales
There was a significant treatment effect between the 2 diets on ratings of hunger, desire to eat, fullness, and prospective consumption (ie, the amount of food subjects thought they could eat). The 1 meal/d diet was significantly higher for hunger (P = 0.003), desire to eat (P = 0.004), and prospective consumption (P = 0.006) than was the 3 meals/d diet. Feelings of fullness were significantly (P = 0.001) lower in the 1 meal/d than in the 3 meals/d diet. In addition to the significant treatment effect by diet, a significant time effect (day of study) was observed for hunger, desire to eat, fullness, and prospective consumption. Over time, hunger, desire to eat, and prospective consumption were significantly higher in the 1 meal/d than in the 3 meals/d diet. Fullness was significantly lower over time in the 1 meal/d diet than in the 3 meals/d diet (Figure 1).
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FIGURE 1. Least-squares (±SEM) values for subjective ratings of hunger and satiety (A, hunger; B, desire to eat; C, fullness; and D, prospective meal consumption) measured daily by using visual analogue scales (100 mm) during each study period. n = 15 (10 F, 5 M). There was a significant treatment effect between the 1 meal/d and the 3 meals/d diets for all 4 ratings, P < 0.05 (from within-period repeated-measures ANOVA). Significant time x treatment interaction (▴), P < 0.05.
Body weight and composition
Subjects' weight and body fat mass were lowered (1.4 and 2.1 kg, respectively) after consumption of the 1 meal/d diet but not after consumption of the 3 meals/d diet. No significant differences in fat-free mass and total body water were observed between the diet groups (Table 3). Even with an 11-wk washout period between the 2 diet protocols, no significant differences from baseline were seen in body weight, fat mass, fat-free mass, or total body water in either period of the study.
Physical activity
No evidence was found of a significant difference in physical activity after consumption of the 1 meal/d or the 3 meals/d diet.
Biological samples
Consumption of 1 meal/d lowered blood urea nitrogen by 13.4%. The serum liver enzymes alkaline phosphatase, serum glutamic pyruvic transaminase, and serum glutamic oxaloacetic transaminase were higher 4.6%, 17.5%, and 16.0% higher, respectively, when subjects consumed 1 meal/d than when they consumed 3 meals/d. Serum albumin was 4.5% higher and cortisol concentrations were 48.9% lower after consumption of 1 meal/d than after consumption of 3 meals/d. Total, LDL, and HDL cholesterol were 11.7%, 16.8%, and 8.4% higher, respectively, in subjects consuming 1 meal/d than in those consuming 3 meals/d. The hematologic variables that differed significantly between the diet groups were those of hemoglobin, hematocrit and red blood cells. Serum concentrations of creatinine, glucose, total protein, uric acid, and all other metabolic variables were not significantly affected by the diets (Table 4).
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TABLE 4 Metabolic panel, lipids, and hematologic variables after consumption of 1 meal/d or 3 meals/d1
DISCUSSION
This study is among the first controlled randomized clinical trials to evaluate the effects of controlled meal frequency on normal-weight, middle-aged adults. We found that the consumption of a meal-skipping diet (ie, 1 meal/d), rather than the traditional 3 meals/d diet, is feasible for a short duration.
Our study withdrawal rate was 28.6%. Typical rates of withdrawal from human feeding studies at our facility are ≈47% (18-20). We can hypothesize that subject withdrawals increased because the subjects were asked to consume all food for the day in 1 meal; however, only 1 subject specifically stated this reason for withdrawing. Most subjects were able to consume all calories in the 1 meal/d diet. Study withdrawals were reported to be due to subject scheduling conflicts and health problems that were unrelated to the study.
Only a few experimental studies have tested the effect of meal frequency on satiety measures. The results of the VASs suggest that subjects did not become habituated to the 1 meal/d diet. Over time, hunger, desire to eat, and prospective consumption increased, whereas feelings of fullness decreased. Similarly, subjects who followed an alternate-day-fast diet for 3 wk had a significant increase in hunger and desire to eat on their fasting days than at baseline, but they did not become habituated to the alternate-day-fast diet, and they were just as hungry on their first day of fasting as on the last day (21). Although subjective hunger and satiety assessments were not made after the evening meal, in comments during consumption of the 1 meal/d diet, most subjects reported extreme fullness after the meal and had difficulty finishing their food in the allotted time. Further research is required to gain a better understanding of subjective satiety on meal frequency.
Although within normal values, both systolic and diastolic blood pressures were higher than baseline during consumption of the 1 meal/d diet. Experimental data for normal-weight men and women on the effects of consumption of 1 meal/d rather than 3 meals/d on blood pressure have not previously been reported. Overweight men and women showed that consumption of 1 meal/d, with caloric restriction, improved blood pressure and heart rate after exercise (22). In animal models, intermittent fasting without caloric restriction has been shown to decrease blood pressure and heart rate (15). The observed increase in blood pressure in our subject population consuming 1 meal/d may be due to a circadian rhythm in blood pressure (23). Diurnal changes may have occurred, because blood pressure measurements were obtained in the late afternoon in the 1 meal/d diet versus early morning in the 3 meals/d.
It is interesting that body weight and body fat decreased in the 1 meal/d diet, which may be partially explained by a slight deficit of 65 kcal in daily energy intake. This change in body composition may also be influenced by the effect that eating patterns could have on metabolic activity. Rats that followed a nibbling diet and then a diet that consisting of 1 large meal developed an increase net flux of free fatty acids from fat deposits and an increase in gluconeogenesis (24, 25). Similar alterations in metabolism may have occurred in our subjects, which may have contributed to weight and fat mass loss. Gluconeogenesis typically begins 46 h after the last meal and becomes fully active as stores of liver glycogen are depleted. Free fatty acids and amino acids that are substrates for gluconeogenesis are used for the energy supply (26, 27).
