Sai Krupa Das

Design and Conduct of the CALERIE Study: Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy

BACKGROUND In a robust and consistent manner, sustained caloric restriction (CR) has been shown to retard the aging process in a variety of animal species. Nonhuman primate studies suggest that CR may have similar effects in longer-lived species. The CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy) research program is the first systematic investigation of CR in nonobese human beings. In the phase 2 study, it is hypothesized that 2 years of sustained CR, involving a 25% reduction of ad libitum energy intake, results in beneficial effects similar to those observed in animal studies. This article presents the design and implementation of this study. METHODS The study is a multicenter, parallel-group, randomized controlled trial. A sample of 225 participants (22.0 ≤ body mass index [BMI] < 28.0 kg/m(2)) is being enrolled with 2:1 allocation to CR. RESULTS An intensive dietary and behavioral intervention was developed to achieve 25% CR and sustain it over the 2 years. Adherence is monitored using a doubly labeled water technique. Primary outcomes are resting metabolic rate and core temperature, and are assessed at baseline and at 6-month intervals. Secondary outcomes address oxyradical formation, cardiovascular risk markers, insulin sensitivity and secretion, immune function, neuroendocrine function, quality of life and cognitive function. Biologic materials are stored in a central repository. CONCLUSIONS An intricate protocol has been developed to conduct this study. Procedures have been implemented to safeguard the integrity of the data and the conclusions drawn. The results will provide insight into the detrimental changes associated with the human aging process and how CR mitigates these effects.

The Effects of the Dietary Glycemic Load on Type 2 Diabetes Risk Factors during Weight Loss

Objective: To compare the effects of two calorie‐restricted diets that differ in glycemic load (GL) on glucose tolerance and inflammation.

Effects of a Cereal Rich in Soluble Fiber on Body Composition and Dietary Compliance during Consumption of a Hypocaloric Diet

Objectives: To investigate the effects of oats, a cereal rich in soluble fiber, on body composition changes and dietary compliance during consumption of a weight loss diet. Methods: Subjects were 41 healthy men and women aged 18 to 78 years. Weight maintenance energy requirements were established over two weeks during consumption of a control diet with low soluble fiber content. Subjects then consumed a hypocaloric diet for six weeks, either consuming a low soluble fiber control diet or a diet containing 45 g/1000 kcal rolled oats, a whole grain cereal rich in soluble fiber (mean energy deficit −895 ± 18 kcal/day relative to weight maintenance energy requirements). Changes in body fat and fat-free mass were determined by underwater weighing, and dietary compliance was assessed using the urinary osmolar excretion rate technique. In a final phase of the study, subjects ate ad libitum for six months, and changes in body weight and composition were monitored. Results: There was no significant effect of the oat-containing diet on body weight or composition changes during the hypocaloric regimen or in the subsequent ad libitum period. In addition, fecal energy excretion was not significantly different between groups. However, there were non-significant trends indicating reduced hunger in the oat group compared to controls (frequency of hunger 2.5±0.5 vs. 3.6±0.4, P=0.1). In addition, fewer oat subjects were non-compliant (four versus seven subjects dropped out or had urinary osmolar excretions greater than 130% of values predicted from dietary intake), but again the difference was not significant. Conclusions: These results suggest that use of a cereal rich in soluble fiber in a closely monitored hypocaloric feeding regimen does not improve weight loss or dietary compliance. Further studies are needed to examine the possibility that cereals containing soluble fiber may have effects on hunger and dietary compliance that could be important in less tightly controlled protocols than the one described here.

Effect of Two-Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non-Obese Younger Adults: A Randomized Clinical Trial

Although caloric restriction (CR) could delay biologic aging in humans, it is unclear if this would occur at the cost of significant bone loss. We evaluated the effect of prolonged CR on bone metabolism and bone mineral density (BMD) in healthy younger adults. Two-hundred eighteen non-obese (body mass index [BMI] 25.1 ± 1.7 kg/m(2) ), younger (age 37.9 ± 7.2 years) adults were randomly assigned to 25% CR (CR group, n = 143) or ad libitum (AL group, n = 75) for 2 years. Main outcomes were BMD and markers of bone turnover. Other outcomes included body composition, bone-active hormones, nutrient intake, and physical activity. Body weight (-7.5 ± 0.4 versus 0.1 ± 0.5 kg), fat mass (-5.3 ± 0.3 versus 0.4 ± 0.4 kg), and fat-free mass (-2.2 ± 0.2 versus -0.2 ± 0.2 kg) decreased in the CR group compared with AL (all between group p < 0.001). Compared with AL, the CR group had greater changes in BMD at 24 months: lumbar spine (-0.013 ± 0.003 versus 0.007 ± 0.004 g/cm(2) ; p < 0.001), total hip (-0.017 ± 0.002 versus 0.001 ± 0.003 g/cm(2) ; p < 0.001), and femoral neck (-0.015 ± 0.003 versus -0.005 ± 0.004 g/cm(2) ; p = 0.03). Changes in bone markers were greater at 12 months for C-telopeptide (0.098 ± 0.012 versus 0.025 ± 0.015 μg/L; p < 0.001), tartrate-resistant acid phosphatase (0.4 ± 0.1 versus 0.2 ± 0.1 U/L; p = 0.004), and bone-specific alkaline phosphatase (BSAP) (-1.4 ± 0.4 versus -0.3 ± 0.5 U/L; p = 0.047) but not procollagen type 1 N-propeptide; at 24 months, only BSAP differed between groups (-1.5 ± 0.4 versus 0.9 ± 0.6 U/L; p = 0.001). The CR group had larger increases in 25-hydroxyvitamin D, cortisol, and adiponectin and decreases in leptin and insulin compared with AL. However, parathyroid hormone and IGF-1 levels did not differ between groups. The CR group also had lower levels of physical activity. Multiple regression analyses revealed that body composition, hormones, nutrients, and physical activity changes explained ∼31% of the variance in BMD and bone marker changes in the CR group. Therefore, bone loss at clinically important sites of osteoporotic fractures represents a potential limitation of prolonged CR for extending life span. Further long-term studies are needed to determine if CR-induced bone loss in healthy adults contributes to fracture risk and if bone loss can be prevented with exercise.

Approaches for quantifying energy intake and %calorie restriction during calorie restriction interventions in humans: the multicenter CALERIE study.

Calorie restriction (CR) is a component of most weight loss interventions and a potential strategy to slow aging. Accurate determination of energy intake and %CR is critical when interpreting the results of CR interventions; this is most accurately achieved using the doubly labeled water method to quantify total energy expenditure (TEE). However, the costs and analytical requirements of this method preclude its repeated use in many clinical trials. Our aims were to determine 1) the optimal TEE assessment time points for quantifying average energy intake and %CR during long-term CR interventions and 2) the optimal approach for quantifying short-term changes in body energy stores to determine energy intake and %CR during 2-wk DLW periods. Adults randomized to a CR intervention in the multicenter CALERIE study underwent measurements of TEE by doubly labeled water and body composition at baseline and months 1, 3, and 6. Average %CR achieved during the intervention was 24.9 ± 8.7%, which was computed using an approach that included four TEE assessment time points (i.e., TEE(baseline, months 1, 3, and 6)) plus the 6-mo change in body composition. Approaches that included fewer TEE assessments yielded %CR values of 23.4 ± 9.0 (TEE(baseline,) months 3 and 6), 25.0 ± 8.7 (TEE(baseline,) months 1 and 6), and 20.9 ± 7.1% (TEE(baseline, month 6)); the latter approach differed significantly from approach 1 (P < 0.001). TEE declined 9.6 ± 9.9% within 2-4 wk of CR beginning and then stabilized. Regression of daily home weights provided the most reliable estimate of short-term change in energy stores. In summary, optimal quantification of energy intake and %CR during weight loss necessitates a TEE measurement within the first month of CR to capture the rapid reduction in TEE.

Calorie Restriction Enhances T-Cell–Mediated Immune Response in Adult Overweight Men and Women

Calorie restriction (CR) enhances immune response and prolongs life span in animals. However, information on the applicability of these results to humans is limited. T-cell function declines with age. We examined effects of CR on T-cell function in humans. Forty-six overweight, nonobese participants aged 20-42 years were randomly assigned to 30% or 10% CR group for 6 months. Delayed-type hypersensitivity (DTH), T-cell proliferation (TP), and prostaglandin E(2) (PGE(2)) productions were determined before and after CR. DTH and TP to T-cell mitogens were increased in both groups over baseline (p < or = .019). However, number of positive responses to DTH antigens (p = .016) and TP to anti-CD3 reached statistical significance only after 30% CR (p = .001). Lipopolysaccharide-stimulated PGE(2) was reduced in both groups but reached statistical significance after 30% CR (p < or = .029). These results, for the first time, show that 6-month CR in humans improves T-cell function.

Effect of calorie restriction on the free-living physical activity levels of nonobese humans: results of three randomized trials

The objective of this study was to evaluate the influence of calorie restriction (CR) on free-living physical activity levels among humans. Data were from three CALERIE phase I site-specific protocols. Participants were nonobese (body mass index = 23.5-29.9 kg/m² adults randomly assigned to 25% CR, low-calorie diet (LCD, 890 kcal/day supplement diet until 15% weight loss, then weight maintenance), or control at Pennington Biomedical Research Center (PBRC); 30% or 10% CR at Tufts University; and 20% CR or control at Washington University School of Medicine (WUSM). Activity was measured at months 0, 3, and 6 (PBRC) and at months 0, 3, 6, 9, and 12 (WUSM and Tufts). Total daily energy expenditure (TEE) by doubly labeled water and resting metabolic rate (RMR) were used to compute activity energy expenditure: AEE = TEE - RMR - 0.1 * TEE. Accelerometry and 7-day recall categorized activities by intensity. At Tufts, the 10% and 30% CR groups experienced significant decreases in AEE at months 6, 9, and 12. At month 6, a larger decrease in AEE was observed in the CR than the control group at WUSM. At months 3 and 6, larger decreases in AEE were observed in the CR and LCD groups than the control group at PBRC. Accelerometry and 7-day PAR did not consistently detect changes in activity categories. CR-associated changes in AEE were variable but, generally, reduced the energy deficit, which would reduce the expected rate of weight loss. Accelerometry and recall did not consistently explain reduced AEE, suggesting that increased muscle efficiency and/or decreased fidgeting accounted for decreased AEE. Inaccuracy of accelerometry and recall also likely negatively affected sensitivity.

Lifestyle intervention reduces body weight and improves cardiometabolic risk factors in worksites

BACKGROUND Worksites are potentially effective locations for obesity control because they provide opportunities for group intervention and social support. Studies are needed to identify effective interventions in these settings. OBJECTIVE We examined the effects of a multicomponent lifestyle intervention on weight loss and prevention of regain in 4 worksites (2 intervention and 2 control sites). DESIGN Overweight and obese employees (n = 133) enrolled in this pilot worksite-randomized controlled trial with a 0-6-mo weight-loss phase and a 6-12-mo structured weight-maintenance phase. The intervention combined recommendations to consume a reduced-energy, low-glycemic load, high-fiber diet with behavioral change education. Outcome measurements included changes in body weight and cardiometabolic risk factors. RESULTS The mean ± SEM weight loss was substantial in intervention participants, whereas control subjects gained weight (-8.0 ± 0.7 compared with +0.9 ± 0.5 kg, respectively; P < 0.001), and 89% of participants completed the weight-loss phase. Intervention effects were not significant at the 0.05 level but would have been at the 0.10 level (P = 0.08) in a mixed model in which the worksite nested within group was a random factor. There were also significant improvements in cardiometabolic risk factors in intervention compared with control subjects regarding fasting total cholesterol, glucose, systolic blood pressure, and diastolic blood pressure (P ≤ 0.02 for each). No significant weight regain was observed in participants who enrolled in the structured weight-maintenance program (0.5 ± 0.7 kg; P = 0.65), and overweight and obese employees in intervention worksites who were not enrolled in the weight-loss program lost weight compared with subjects in control worksites (-1.3 ± 0.5 compared with +0.7 ± 0.2 kg, respectively; P = 0.02). CONCLUSION Worksites can be effective for achieving clinically important reductions in body weight and improved cardiometabolic risk factors. This trial was registered at clinicaltrials.gov as NCT01470222.

Relationship of cravings with weight loss and hunger. Results from a 6 month worksite weight loss intervention

We examined the association of food cravings with weight loss and eating behaviors in a lifestyle intervention for weight loss in worksites. This research was part of a randomized controlled trial of a 6-month weight loss intervention versus a wait-listed control in 4 Massachusetts worksites. The intervention emphasized reducing energy intake by adherence to portion-controlled menu suggestions, and assessments were obtained in 95 participants at baseline and 6 months including non-fasting body weight, food cravings (Craving Inventory and Food Craving Questionnaire for state and trait) and the eating behavior constructs restraint, disinhibition and hunger (Eating Inventory). There were statistically significant reductions in all craving variables in the intervention group compared to the controls. Within the intervention group, changes in craving-trait were significantly associated with weight loss after controlling for baseline weight, age, gender and worksite. However, in a multivariate model with craving-trait and eating behaviors (restraint, disinhibition and hunger), hunger was the only significant predictor of weight change. In contrast to some previous reports of increased food cravings with weight loss in lifestyle interventions, this study observed a broad reduction in cravings associated with weight loss. In addition, greater reductions in craving-trait were associated with greater weight change, but craving-trait was not a significant independent correlate of weight change when hunger was included in statistical models. Studies are needed to examine the effectiveness of hunger suppressing versus craving-suppressing strategies in lifestyle interventions for obesity.

Accuracy of Stated Energy Contents of Restaurant Foods

CONTEXT National recommendations for the prevention and treatment of obesity emphasize reducing energy intake. Foods purchased in restaurants provide approximately 35% of the daily energy intake in US individuals but the accuracy of the energy contents listed for these foods is unknown. OBJECTIVE To examine the accuracy of stated energy contents of foods purchased in restaurants. DESIGN AND SETTING A validated bomb calorimetry technique was used to measure dietary energy in food from 42 restaurants, comprising 269 total food items and 242 unique foods. The restaurants and foods were randomly selected from quick-serve and sit-down restaurants in Massachusetts, Arkansas, and Indiana between January and June 2010. MAIN OUTCOME MEASURE The difference between restaurant-stated and laboratory-measured energy contents, which were corrected for standard metabolizable energy conversion factors. RESULTS The absolute stated energy contents were not significantly different from the absolute measured energy contents overall (difference of 10 kcal/portion; 95% confidence interval [CI], -15 to 34 kcal/portion; P = .52); however, the stated energy contents of individual foods were variable relative to the measured energy contents. Of the 269 food items, 50 (19%) contained measured energy contents of at least 100 kcal/portion more than the stated energy contents. Of the 10% of foods with the highest excess energy in the initial sampling, 13 of 17 were available for a second sampling. In the first analysis, these foods contained average measured energy contents of 289 kcal/portion (95% CI, 186 to 392 kcal/portion) more than the stated energy contents; in the second analysis, these foods contained average measured energy contents of 258 kcal/portion (95% CI, 154 to 361 kcal/portion) more than the stated energy contents (P <.001 for each vs 0 kcal/portion difference). In addition, foods with lower stated energy contents contained higher measured energy contents than stated, while foods with higher stated energy contents contained lower measured energy contents (P <.001). CONCLUSIONS Stated energy contents of restaurant foods were accurate overall. However, there was substantial inaccuracy for some individual foods, with understated energy contents for those with lower energy contents.