Comprehensive Assessment Of Long-term Effects Research Articles

Changes in body weight, adherence, and appetite during 2 years of calorie restriction: the CALERIE 2 randomized clinical trial.

Background/Objectives:The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE) study showed that individuals who are non-obese were able to undergo significant calorie restriction (CR), yet the time course changes in adherence, weight, and appetite are unknown. This analysis aimed to investigate the time course changes in adherence, body weight, and appetite during the CALERIE study.Subjects/Methods:Overall, 143 participants (body mass index: 21.9–28.0 kg/m2) were randomized to a CR group that aimed to achieve 25% CR for 2 years. Throughout the intervention, body weight was measured, and appetite was assessed through visual analogue scales. Algorithms were utilized with body weight measurements to calculate adherence percentile score. Participants targeted an adherence percentile score of 50, though being between 80 (lowest acceptable adherence) and 10 (highest acceptable adherence) was adequate. Polynomial regression analyses were used to assess time course changes.Results:Polynomials indicated that adherence percentile score increased above 50 after approximately week 20, although adherence remained acceptable (adherence percentile score less than 80) (R2 = 0.89; P < 0.001). Weight loss occurred until approximately week 60 and then plateaued (R2 ≥ 0.92; P < 0.001). Hunger and thirst increased (R2 ≥ 0.30; P < 0.001), but the total increase in scale scores were less than 10 mm throughout the intervention.Conclusions:In individuals who are non-obese, adherence to 25% CR declines after 20 weeks, but two years of CR that stimulates a meaningful reduction in weight, promotes aging-related benefits and negligibly affects appetite is viable.

Does exclusion of extreme reporters of energy intake (the “Goldberg cutoffs”) reliably reduce or eliminate bias in nutrition studies? Analysis with illustrative associations of energy intake with health outcomes

The Goldberg cutoffs are used to decrease bias in self-reported estimates of energy intake (EISR). Whether the cutoffs reduce and eliminate bias when used in regressions of health outcomes has not been assessed. We examined whether applying the Goldberg cutoffs to data used in nutrition studies could reliably reduce or eliminate bias. We used data from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE), the Interactive Diet and Activity Tracking in American Association of Retired Persons (IDATA) study, and the National Diet and Nutrition Survey (NDNS). Each data set included EISR, energy intake estimated from doubly labeled water (EIDLW) as a reference method, and health outcomes including baseline anthropometric, biomarker, and behavioral measures and fitness test results. We conducted 3 linear regression analyses using EISR, a plausible EISR based on the Goldberg cutoffs (EIG), and EIDLW as an explanatory variable for each analysis. Regression coefficients were denoted ${\hat{\beta }_{\rm SR}}$, ${\hat{\beta }_{\rm G}}$, and ${\hat{\beta }_{\rm DLW}}$, respectively. Using the jackknife method, bias from ${\hat{\beta }_{\rm SR}}$ compared with ${\hat{\beta }_{\rm DLW}}$ and remaining bias from ${\hat{\beta }_{\rm G}}$ compared with ${\hat{\beta }_{\rm DLW}}$ were estimated. Analyses were repeated using Pearson correlation coefficients. The analyses from CALERIE, IDATA, and NDNS included 218, 349, and 317 individuals, respectively. Using EIG significantly decreased the bias only for a subset of those variables with significant bias: weight (56.1%; 95% CI: 28.5%, 83.7%) and waist circumference (WC) (59.8%; 95% CI: 33.2%, 86.5%) with CALERIE, weight (20.8%; 95% CI: -6.4%, 48.1%) and WC (17.3%; 95% CI: -20.8%, 55.4%) with IDATA, and WC (-9.5%; 95% CI: -72.2%, 53.1%) with NDNS. Furthermore, bias significantly remained even after excluding implausible data for various outcomes. Results obtained with Pearson correlation coefficient analyses were qualitatively consistent. Some associations between EIG and outcomes remained biased compared with associations between EIDLW and outcomes. Use of the Goldberg cutoffs was not a reliable method for eliminating bias.

Parsing metabolic heterogeneity in mood disorders: A hypothesis-driven cluster analysis of glucose and insulin abnormalities.

Metabolically based distinctions for disturbances in glucose and insulin may provide meaningful insights both clinically and mechanistically. Data were derived from 352 subjects of previously completed clinical studies with a mood disorder (MD) (bipolar disorder: n=179, major depressive disorder: n=173) and 218 healthy controls from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy. We conducted a factor analysis to replicate a priori dissociable factors informed by glucose and insulin levels and indices of insulin resistance and beta-cell function: elevated insulin and insulin resistance ("insulin-IR"), and increased fasting glucose and reduced insulin secretion ("glucotoxicity"). Cluster analyses were conducted, separately in men and women, to evaluate the clinical relevance of subtyping individuals with MDs using insulin-IR and glucotoxicity (GT) factor scores. Factors insulin-IR and GT explained 92.64% and 92.09% of the variance in men and women respectively. Three clusters were replicated in men and women separately: metabolically healthy (MH), high GT, and insulin-resistant (IR). After adjusting for age, gender, study cohort, MD diagnosis, and antipsychotics use, body mass index (BMI) and mean arterial pressure were higher in IR- vs GT- or MH-clustered individuals; GT-clustered individuals had more metabolic syndrome components and higher C-reactive protein. Glucotoxic-clustered subjects reported greater impairments in cognitive function and global functioning when compared to MH- or IR-clustered subjects. Using simple, cost-effective, and accessible measures, we identified stable, gender-convergent, subgroups of individuals that significantly diverged on measures of cognitive dysfunction, self-reported anhedonia, functional disability, BMI, and blood pressure.

Change in self-efficacy, eating behaviors and food cravings during two years of calorie restriction in humans without obesity

Calorie restriction (CR) enhances longevity in humans who are normal weight, overweight and obese. While dietary regimens can change self-efficacy, eating behaviors, and food cravings in individuals with obesity, the responses of these measures to prolonged CR in individuals who are exclusively not obese is unknown. The aim of this analysis was to test the effects of a two-year CR intervention on self-efficacy and eating attitudes and behaviors in humans without obesity by analyzing data from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE 2) study. Participants (n = 218, BMI range = 21.3–29.0 kg/m2) were randomized to a 25% CR group or an ad libitum (AL) group. Eating attitudes and behaviors and self-efficacy were assessed using validated questionnaires at baseline, month 12, and month 24. Dietary restraint and self-efficacy increased in the CR compared to the AL group (ES ≥ 0.32). Increased self-efficacy was negatively related to weight change (ρ < −0.24). In the CR group, males showed a reduction in cravings for carbohydrates and fats at month 24, whereas females did not. The CR group showed elevations in state hunger, which were transient, and disinhibited eating (ES ≥ 0.37). In individuals without obesity, dietary restraint and self-efficacy could be important in promoting long-term CR for individuals looking to use CR as a tool to improve longevity.

Peripheral interleukin-6 levels and working memory in non-obese adults: A post-hoc analysis from the CALERIE study.

This analysis aimed to investigate the association among interleukin 6 (IL-6) levels, caloric intake, and working memory and to explore the potential mediators of these associations using the public dataset from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) clinical trial. The CALERIE study was designed to evaluate the effects of 2 y of prolonged caloric restriction in humans. Individuals were randomized to caloric restriction (CR; n = 145) or an ad libitum diet (AL; n = 75) for 2 y. The outcome measures used herein were spatial working memory tests (i.e., total number of errors and strategy). Generalized estimating equations were used to assess the effects of treatment, time, and potential moderators (e.g., sleep and physical activities). At baseline, there was an effect of hours of sleep, alcohol intake, and physical activities (i.e., mean total metabolic equivalent of task hours per day [MET-hours/day]) on IL-6 levels. The association between IL-6 and energy intake was moderated by MET-hours/day. The longitudinal analysis indicated that there was an effect of time, but not of treatment, on IL-6 levels, with decreasing values in both the CR and AL groups. Changes in IL-6 levels were associated with changes in working memory performance, but there were no between-group (i.e., CR vs. AL) differences. We observed an association between changes in IL-6 levels and improvement in spatial working memory tests. IL-6 was associated with higher caloric consumption, poorer sleep quality, and lower levels of physical activity.

Simulating long-term human weight-loss dynamics in response to calorie restriction

Mathematical models have been developed to predict body weight (BW) and composition changes in response to lifestyle interventions, but these models have not been adequately validated over the long term. We compared mathematical models of human BW dynamics underlying 2 popular web-based weight-loss prediction tools, the National Institutes of Health Body Weight Planner (NIH BWP) and the Pennington Biomedical Research Center Weight Loss Predictor (PBRC WLP), with data from the 2-year Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study. Mathematical models were initialized using baseline CALERIE data, and changes in body weight (ΔBW), fat mass (ΔFM), and energy expenditure (ΔEE) were simulated in response to time-varying changes in energy intake (ΔEI) objectively measured using the intake-balance method. No model parameters were adjusted from their previously published values. The PBRC WLP model simulated an exaggerated early decrease in EE in response to calorie restriction, resulting in substantial underestimation of the observed mean (95% CI) BW losses by 3.8 (3.5, 4.2) kg. The NIH WLP simulations were much closer to the data, with an overall mean ΔBW bias of -0.47 (-0.92, -0.015) kg. Linearized model analysis revealed that the main reason for the PBRC WLP model bias was a parameter value defining how spontaneous physical activity expenditure decreased with caloric restriction. Both models exhibited substantial variability in their ability to simulate individual results in response to calorie restriction. Monte Carlo simulations demonstrated that ΔEI measurement uncertainties were a major contributor to the individual variability in NIH BWP model simulations. The NIH BWP outperformed the PBRC WLP and accurately simulated average weight-loss and energy balance dynamics in response to long-term calorie restriction. However, the substantial variability in the NIH BWP model predictions at the individual level suggests cautious interpretation of individual-level simulations. This trial was registered at clinicaltrials.gov as NCT00427193.

Effects of Two Years of Calorie Restriction on Aerobic Capacity and Muscle Strength.

ABSTRACTPurposeCalorie restriction (CR) improves health span and delays age-related diseases in many species. The multicenter Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study was the first randomized controlled trial of CR in nonobese humans. The aim of this investigation was to determine the effects of CR on V˙O2max and muscle strength in the CALERIE trial.MethodsHealthy, normal-weight, and mildly overweight women and men (n = 218, mean ± SE age = 37.9 ± 0.5 yr) were randomized to 25% CR or an ad libitum (AL) control condition in a 2:1 allocation (143 CR, 75 AL). V˙O2max was determined with an incremental treadmill test; the strength of the knee flexors and extensors was assessed by dynamometry at baseline, 1 yr, and 2 yr.ResultsThe CR group achieved an average 11.9% ± 0.7% CR during the 2-yr intervention. Body weight decreased in CR (−7.7 ± 0.4 kg), but not AL (+0.2 ± 0.5 kg). Absolute V˙O2max (L·min−1) decreased at 1 and 2 yr with CR, whereas V˙O2max expressed relative to body mass increased at both time points (1 yr: +2.2 ± 0.4; 2 yr: +1.9 ± 0.5 mL·kg−1·min−1) and relative to AL. The CR group increased their treadmill test time and workload at 1 and 2 yr. Strength results in CR were similar, with decreases in absolute flexor and extensor strength, but increases when expressed relative to body mass. No changes were observed for V˙O2max expressed relative to lean body mass or leg lean mass.ConclusionsTwo years of modest CR without a structured exercise component did not appear to compromise aerobic capacity in healthy nonobese adults. The clinical implications of the observed changes in V˙O2max and muscle strength will be important to explore in future studies.

Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: a 2-y randomized controlled trial of calorie restriction in nonobese humans1–3

Background: Calorie restriction (CR) retards aging and increases longevity in many animal models. However, it is unclear whether CR can be implemented in humans without adverse effects on body composition.Objective: We evaluated the effect of a 2-y CR regimen on body composition including the influence of sex and body mass index (BMI; in kg/m2) among participants enrolled in CALERIE-2 (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), a multicenter, randomized controlled trial.Design: Participants were 218 nonobese (BMI: 21.9–28.0) adults aged 21–51 y who were randomly assigned to 25% CR (CR, n = 143) or ad libitum control (AL, n = 75) in a 2:1 ratio. Measures at baseline and 12 and 24 mo included body weight, waist circumference, fat mass (FM), fat-free mass (FFM), and appendicular mass by dual-energy X-ray absorptiometry; activity-related energy expenditure (AREE) by doubly labeled water; and dietary protein intake by self-report. Values are expressed as means ± SDs.Results: The CR group achieved 11.9% ± 0.7% CR over 2-y and had significant decreases in weight (−7.6 ± 0.3 compared with 0.4 ± 0.5 kg), waist circumference (−6.2 ± 0.4 compared with 0.9 ± 0.5 cm), FM (−5.4 ± 0.3 compared with 0.5 ± 0.4 kg), and FFM (−2.0 ± 0.2 compared with −0.0 ± 0.2 kg) at 24 mo relative to the AL group (all between-group P < 0.001). Moreover, FFM as a percentage of body weight at 24 mo was higher, and percentage of FM was lower in the CR group than in the AL. AREE, but not protein intake, predicted preservation of FFM during CR (P < 0.01). Men in the CR group lost significantly more trunk fat (P = 0.03) and FFM expressed as a percentage of weight loss (P < 0.001) than women in the CR group.Conclusions: Two years of CR had broadly favorable effects on both whole-body and regional adiposity that could facilitate health span in humans. The decrements in FFM were commensurate with the reduced body mass; although men in the CR group lost more FFM than the women did, the percentage of FFM in the men in the CR group was higher than at baseline. CALERIE was registered at clinicaltrials.gov as NCT00427193.

Effect of Calorie Restriction on Mood, Quality of Life, Sleep, and Sexual Function in Healthy Nonobese Adults

Calorie restriction (CR) increases longevity in many species and reduces risk factors for chronic diseases. In humans, CR may improve health span, yet concerns remain about potential negative effects of CR. To test the effect of CR on mood, quality of life (QOL), sleep, and sexual function in healthy nonobese adults. A multisite randomized clinical trial (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 [CALERIE 2]) was conducted at 3 academic research institutions. Adult men and women (N = 220) with body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 22.0 to 28.0 were randomized to 2 years of 25% CR or an ad libitum (AL) control group in a 2:1 ratio favoring CR. Data were collected at baseline, 12 months, and 24 months and examined using intent-to-treat analysis. The study was conducted from January 22, 2007, to March 6, 2012. Data analysis was performed from July 18, 2012, to October 27, 2015. Two years of 25% CR or AL. Self-report questionnaires were administered to measure mood (Beck Depression Inventory-II [BDI-II], score range 0-63, higher scores indicating worse mood, and Profile of Mood States [POMS], with a total mood disturbance score range of -32 to 200 and higher scores indicating higher levels of the constructs measured), QOL (Rand 36-Item Short Form, score range 0-100, higher scores reflecting better QOL, and Perceived Stress Scale, score range 0-40, higher scores indicating higher levels of stress), sleep (Pittsburgh Sleep Quality Index [PSQI], total score range 0-21, higher scores reflecting worse sleep quality), and sexual function (Derogatis Interview for Sexual Function-Self-report, total score range 24-188, higher scores indicating better sexual functioning). In all, 218 participants (152 women [69.7%]; mean [SD] age, 37.9 (7.2) years; mean [SD] BMI, 25.1 [1.6]) were included in the analyses. The CR and AL groups lost a mean (SE) of 7.6 (0.3) kg and 0.4 (0.5) kg, respectively, at month 24 (P < .001). Compared with the AL group, the CR group had significantly improved mood (BDI-II: between-group difference [BGD], -0.76; 95% CI, -1.41 to -0.11; effect size [ES], -0.35), reduced tension (POMS: BGD, -0.79; 95% CI, -1.38 to -0.19; ES, -0.39), and improved general health (BGD, 6.45; 95% CI, 3.93 to 8.98; ES, 0.75) and sexual drive and relationship (BGD, 1.06; 95% CI, 0.11 to 2.01; ES, 0.35) at month 24 as well as improved sleep duration at month 12 (BGD, -0.26; 95% CI, -0.49 to -0.02; ES, -0.32) (all P < .05). Greater percent weight loss in the CR group at month 24 was associated with increased vigor (Spearman correlation coefficient, ρ = -0.30) and less mood disturbance (ρ = 0.27) measured with the POMS, improved general health (ρ = -0.27) measured with the SF-36, and better sleep quality per the PSQI total score (ρ = 0.28) (all P < .01). In nonobese adults, CR had some positive effects and no negative effects on health-related QOL. clinicaltrials.gov Identifier: NCT00427193.

Validation of an inexpensive and accurate mathematical method to measure long-term changes in free-living energy intake

Accurate measurement of free-living energy intake (EI) over long periods is imperative for understanding obesity and its treatment. Unfortunately, traditional methods rely on self-report and are notoriously inaccurate. Although EI can be indirectly estimated by the intake-balance method, this technique is prohibitively labor-intensive and expensive, requiring repeated measures of energy expenditure via doubly labeled water (DLW) along with multiple dual-energy X-ray absorptiometry (DXA) scans to measure changes in body energy stores. Our objective was to validate a mathematical method to measure long-term changes in free-living energy intake. We measured body weight and EI changes (ΔEI) over 4 time intervals by using the intake-balance method in 140 individuals who underwent 2 y of caloric restriction as part of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy study. We compared the ΔEI values calculated by using DLW/DXA with those obtained by using a mathematical model of human metabolism whose only inputs were the initial demographic information and repeated body weight data. The mean ΔEI values calculated by the model were within 40 kcal/d of the DLW/DXA method throughout the 2-y study. For individual subjects, the overall root mean square deviation between the model and DLW/DXA method was 215 kcal/d, and most of the model-calculated ΔEI values were within 132 kcal/d of the DLW/DXA method. Accurate and inexpensive estimates of ΔEI that are comparable to the DLW/DXA method can be obtained by using a mathematical model and repeated body weight measurements.

Effect of dietary adherence on the body weight plateau: a mathematical model incorporating intermittent compliance with energy intake prescription , ,

Clinical weight loss in individuals typically stabilizes at 6 mo. However, validated models of dynamic energy balance have consistently shown weight plateaus between 1 and 2 y. The cause for this discrepancy is unclear. We developed 2 mathematical models on the basis of the first law of thermodynamics to investigate plausible explanations for reaching an early weight plateau at 6 mo. The first model was an energy-expenditure adaptation model and was applied to determine the degree of metabolic adaptation required to generate this plateau. The second model was an intermittent lack-of-adherence model formulated by using a randomly fluctuating energy intake term accounting for intermittent noncompliance in dietary intake to reach this plateau. To set model variables, validate models, and compare free-living weight-loss patterns to in-residence supervised programs, we applied the following 4 different studies: The US NHANES 1999-2004, Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) weight-loss study, the Bouchard Twin overfeeding study, and the Minnesota Starvation Experiment. The metabolic adaptation model increased final weight but did not affect the predicted plateau time point. The intermittent lack-of-adherence model generated oscillating weight graphs that have been frequently observed in weight-loss studies. The model showed that a 6-mo weight-loss plateau can be attained despite what can be considered as high diet adherence. The model was programmed as a downloadable application. An intermittent lack of diet adherence, not metabolic adaptation, is a major contributor to the frequently observed early weight-loss plateau. The new weight-loss prediction software, which incorporates an intermittent lack of adherence, can be used to guide and inform patients on realistic levels of adherence on the basis of patient lifestyle.

The Doubly Labeled Water Method Produces Highly Reproducible Longitudinal Results in Nutrition Studies

The doubly labeled water (DLW) method is considered the reference method for the measurement of energy expenditure under free-living conditions. However, the reproducibility of the DLW method in longitudinal studies is not well documented. This study was designed to evaluate the longitudinal reproducibility of the DLW method using 2 protocols developed and implemented in a multicenter clinical trial—the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). To document the longitudinal reproducibility of the DLW method, 2 protocols, 1 based on repeated analysis of dose dilutions over the course of the clinical trial (dose-dilution protocol) and 1 based on repeated but blinded analysis of randomly selected DLW studies (test-retest protocol), were carried out. The dose-dilution protocol showed that the theoretical fractional turnover rates for 2H and 18O and the difference between the 2 fractional turnover rates were reproducible to within 1% and 5%, respectively, over 4.5 y. The Bland-Altman pair-wise comparisons of the results generated from 50 test-retest DLW studies showed that the fractional turnover rates and isotope dilution spaces for 2H and 18O, and total energy expenditure, were highly reproducible over 2.4 y. Our results show that the DLW method is reproducible in longitudinal studies and confirm the validity of this method to measure energy expenditure, define energy intake prescriptions, and monitor adherence and body composition changes over the period of 2.5–4.4 y. The 2 protocols can be adopted by other laboratories to document the longitudinal reproducibility of their measurements to ensure the long-term outcomes of interest are meaningful biologically. This trial was registered at clinicaltrials.gov> as NCT00427193.

Energy requirements in nonobese men and women: results from CALERIE

The energy intake necessary to maintain weight and body composition is called the energy requirement for weight maintenance and can be determined by using the doubly labeled water (DLW) method. The objective was to determine the energy requirements of nonobese men and women in the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy 2 study. Energy requirements were determined for 217 healthy, weight-stable men and women [aged >21 to <50 y; 70% female, 77% white; body mass index (BMI; in kg/m(2)) 22 to <28; 52% overweight] over 28 d with 2 consecutive 14-d DLW assessments in addition to serial measures of body weight and fat-free mass and fat mass by dual-energy X-ray absorptiometry. Energy intake and physical activity were also estimated by self-report over ≥6 consecutive d in each DLW period. Total daily energy expenditure (TDEE) was consistent between the 2 DLW studies (TDEE1: 2422 ± 404 kcal/d; TDEE2: 2465 ± 408 kcal/d; intraclass correlation coefficient = 0.90) with a mean TDEE of 2443 ± 397 kcal/d that was, on average, 20% (580 kcal/d) higher in men than in women (P < 0.0001). The regression equation relating mean TDEE to demographics and weight was as follows: TDEE (kcal/d) = 1279 + 18.3 (weight, kg) + 2.3 (age, y) - 338 (sex: 1 = female, 0 = male); R(2) = 0.57. When body composition was included, TDEE (kcal/d) = 454 + 38.7 (fat-free mass, kg) - 5.4 (fat mass, kg) + 4.7 (age in y) + 103 (sex: 1 = female, 0 = male); R(2) = 0.65. Individuals significantly underreported energy intake (350 kcal/d; 15%), and underreporting by overweight individuals (~400 kcal/d; 16%) was greater (P < 0.001) than that of normal-weight individuals (~270 kcal/d; 12%). Estimates of TDEE from a 7-d physical activity recall and measured resting metabolic rate also suggested that individuals significantly underreported physical activity (~400 kcal/d; 17%; P < 0.0001). These new equations derived over 1 mo during weight stability can be used to estimate the free-living caloric requirements of nonobese adults. This trial was registered at clinicaltrials.gov as NCT00427193.

Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE Phase 2) screening and recruitment: Methods and results

The Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE) study is a systematic investigation of sustained 25% calorie restriction (CR) in non-obese humans. CALERIE is a multicenter (3 clinical sites, one coordinating center), parallel group, randomized controlled trial. Participants were recruited, screened, and randomized to the CR or control group with a 2:1 allocation. Inclusion criteria included ages 21–50years for men and 21–47years for women, and a body mass index (BMI) of 22.0≤BMI<28.0kg/m2. Exclusion criteria included abnormal laboratory markers, significant medical conditions, psychiatric/behavioral problems, and an inability to adhere to the rigors of the evaluation/intervention schedule. A multi-stage screening process (telephone screen and 3 in-clinic visits) was applied to identify eligible participants. Recruitment was effective and enrollment targets were met on time. 10,856 individuals contacted the clinical sites, of whom 9787 (90%) failed one or more eligibility criteria. Of the 1069 volunteers who started the in-clinic screening, 831 (78%) were either ineligible or dropped. 238 volunteers were enrolled (i.e., initiated the baseline evaluations), 220 were randomized, and 218 started the assigned intervention (2% from the first screening step). This study offered lessons for future multi-center trials engaging non-disease populations. Recruitment strategies must be tailored to specific sites. A multi-disciplinary screening process should be applied to address medical, physical, and psychological/behavioral suitability of participants. Finally, a multi-step screening process with simple criteria first, followed by more elaborate procedures has the potential to reduce the use of study resources.

Energy content of weight loss: kinetic features during voluntary caloric restriction

The classic rule stating that restricting intake by 3500 kcal/wk will lead to a 1-lb/wk rate of weight loss has come under intense scrutiny. Generally not a component of most weight loss prediction models, the “early” rapid weight loss phase may represent a period during which the energy content of weight change (ΔEC/ΔW) is low and thus does not follow the classic “rule.” The current study tested this hypothesis. Dynamic ΔEC/ΔW changes were examined in 23 Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Study overweight men and women evaluated by dual-energy x-ray absorptiometry during weight loss at treatment weeks 4 to 24. Changes from baseline in body energy content were estimated from fat and fat-free mass. Repeated-measures analysis of variance was used to determine if ΔEC/ΔW changed significantly over time. The evaluation was expanded with addition of the Kiel 13-week weight loss study of 75 obese men and women to test with adequate power if there are sex differences in ΔEC/ΔW. The analysis of variance CALERIE time effect was significant (P < .001), with post hoc tests indicating that ΔEC/ΔW (kilocalories per kilogram) increased significantly from week 4 (X ± SEM; 4, 858 ± 388) to 6 (6, 041 ± 376, P < .01) and changed insignificantly thereafter; ΔEC/ΔW was significantly larger for Kiel women (6, 804 ± 226) vs men (6, 119 ± 240, P < .05). Sex-specific dynamic relative changes in body composition and related ΔEC/ΔW occur with weight loss initiation that extend for 1 month or more. These observations provide new information for developing energy balance models and further define limitations of the 3500-kcal energy deficit → 1-lb weight loss rule.

The Fall in Leptin Concentration Is a Major Determinant of the Metabolic Adaptation Induced by Caloric Restriction Independently of the Changes in Leptin Circadian Rhythms

Leptin is involved in the hormonal regulation of the reproductive, somatotropic, thyroid, and autonomic axes and ultimately in the regulation of energy balance. In parallel to the metabolic adaptation observed in response to caloric restriction (CR), plasma leptin concentrations are substantially decreased, suggesting a role for this hormone in the drop in energy expenditure beyond that predicted by the changes in body composition (metabolic adaptation). The aim of the study was to explore the changes in 24-h leptin circadian rhythm in response to CR and to investigate the relationship between these changes and metabolic adaptation. In a randomized, controlled trial (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy), 48 subjects were assigned to a control group or one of three CR groups for 6 months. Leptin concentration was assessed every 30 min for 24 h, and leptin circadian variations were fitted by Cosinor analysis. Sedentary energy expenditure and urinary catecholamine excretion were measured for 24 h in a metabolic chamber. Six months of CR decreased body weight by -11.4 ± 0.6% (mean ± sem; P < 0.001). Mean 24-h circulating leptin concentration decreased by -44 ± 3% (P < 0.001), whereas leptin diurnal amplitude slightly increased over the 6 months of CR. CR caused a metabolic adaptation of -126 ± 25 kcal/d (P <0.001) and a significant decrease in urinary norepinephrine (-13 ± 3%) and T(3) concentrations (10 ± 2%). The metabolic adaptation was significantly and independently related to the changes in 24-h leptin (r(2) = 0 .22, P < 0.01) but not to the changes in leptin amplitude. Our results confirm an important role for leptin as an independent determinant of the metabolic adaptation in response to CR.

Dietary Adherence to Long‐Term Controlled Feeding in a Calorie‐Restriction Study in Overweight Men and Women

The success of clinical dietary interventions depends on the motivation and willingness of study participants to adhere to the prescribed or provided diet. The aim of this study was to assess participants' adherence to their provided diet over the 6-month duration of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). Investigators assessed the dietary adherence of 46 men and women who completed the first phase of the CALERIE trial. Volunteers were randomized to 1 of 4 dietary intervention groups: control, calorie restriction, calorie restriction with exercise, and low-calorie diet. Participants were provided with foods during 2 weeks of baseline and during the first 12 weeks and the last 2 weeks of the intervention as outpatients, and they completed a daily self-report form to assess diet adherence. The data are expressed as mean ± standard deviation or standard error of the mean. Pearson's correlation coefficient was determined to examine the relationship between assigned energy levels and total energy intake. Deviations reported were for eating nonstudy foods as well as not eating study foods. There were few deviations, and when converted to mean calories per day these did not affect total energy (weeks -3 to 2 = 10.25 ± 4.82, weeks 1-4 = 9.93 ± 12.52, weeks 5-11 = 8.38 ± 7.42, weeks 22-23 = 0.53 ± 3.97 kcal/d). The associations between assigned energy level and actual intake were high for all groups (P = .001), weeks -3 to -2 (r = 0.999), weeks 1-4 (r = 0.998), weeks 5-11 (r = 0.999), and weeks 22-23 (r = 0.998). The data provide evidence that dietary adherence is good when all foods are provided and when participants are highly motivated.

Impact of 6‐month Caloric Restriction on Autonomic Nervous System Activity in Healthy, Overweight, Individuals

Caloric restriction (CR) increases maximum lifespan but the mechanisms are unclear. Dominance of the sympathetic nervous system (SNS) over the parasympathetic nervous system (PNS) has been shown to be a strong risk factor for cardiovascular disease. Obesity and aging are associated with increased SNS activity, and weight loss and/or exercise seem to have positive effects on this balance. We therefore evaluated the effect of different approaches of CR on autonomic function in 28 overweight individuals participating in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial. Participants were randomized to either control, CR: 25% decrease in energy intake, CREX: 12.5% CR + 12.5% increase in energy expenditure, or LCD: low-calorie diet until 15% weight reduction followed by weight maintenance. Autonomic function was assessed by spectral analysis of heart-rate variability (HRV) while fasting and after a meal. Measurements were performed at baseline and 6 months. HR and SNS index decreased and PNS index increased in all intervention groups but reached significance only in CREX. HR and SNS index increased and PNS index decreased in response to the meal in all intervention groups. The results therefore suggest that weight loss improved SNS/PNS balance especially when CR is combined with exercise.

A Low-Glycemic Load Diet Facilitates Greater Weight Loss in Overweight Adults With High Insulin Secretion but Not in Overweight Adults With Low Insulin Secretion in the CALERIE Trial

Lifestyle changes, in particular reducing energy intake, are the cornerstone of current approaches to weight loss and prevention of type 2 diabetes. However, there is currently no consensus that one dietary regimen is more effective than another for weight loss (1) or whether particular diets work better for identifiable groups of individuals. There is evidence, however, to suggest that both insulin resistance and insulin secretion play a role in body weight regulation (2–12). Therefore, dietary factors such as the dietary glycemic load (glycemic load = glycemic index [GI] × available carbohydrate amount) that influence these parameters may theoretically interact with subject-specific characteristics of glucose-insulin dynamics to influence the effect of different hypocaloric diets on weight loss or maintenance (13,14). Weight loss studies using the concept of the dietary glycemic index or glycemic load have shown conflicting results for heterogeneous groups of individuals (15–21). In a 6-month controlled feeding trial in healthy overweight adults with normal glucose tolerance, we tested the hypothesis that individuals with higher insulin secretion lose more weight when randomized to a low–glycemic load diet compared with a high–glycemic load diet. This study was performed as part of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial at the Human Nutrition Research Center on Aging at Tufts University with approval from the Tufts-New England Medical Center Human Investigation Review Committee. Written informed consent was obtained from all participants. Healthy women and men aged 24–42 …