Search

Methods to quantify biological aging are emerging as new measurement tools for epidemiology and population science and have been proposed as surrogate measures for healthy lifespan extension in geroscience clinical trials. Publicly available software packages to compute biological aging measurements from DNA methylation data have accelerated dissemination of these measures and generated rapid gains in knowledge about how different measures perform in a range of datasets. Biological age measures derived from blood chemistry data were introduced at the same time as the DNA methylation measures and, in multiple studies, demonstrate superior performance to these measures in prediction of healthy lifespan. However, their dissemination has been slow by comparison, resulting in a significant gap in knowledge. We developed a software package to help address this knowledge gap. The BioAge R package, available for download at GitHub (http://github.com/dayoonkwon/BioAge), implements three published methods to quantify biological aging based on analysis of chronological age and mortality risk: Klemera-Doubal biological age, PhenoAge, and homeostatic dysregulation. The package allows users to parametrize measurement algorithms using custom sets of biomarkers, to compare the resulting measurements to published versions of the Klemera-Doubal method and PhenoAge algorithms, and to score the measurements in new datasets. We applied BioAge to safety lab data from the CALERIE™ randomized controlled trial, the first-ever human trial of long-term calorie restriction in healthy, non-obese adults, to test effects of intervention on biological aging. Results contribute evidence that CALERIE intervention slowed biological aging. BioAge is a toolkit to facilitate measurement of biological age for geroscience. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00480-5.

INTRODUCTION: Changes to mental, physical, and physiological functions drive the complex processes underlying the variable progression of human aging. Nutritional interventions are one of the most promising non-pharmacological therapeutics to attenuate aging in humans. This narrative review aims to describe the implications of moderate and prolonged calorie restriction (CR) in healthy adults without obesity that occur beyond weight loss. AREAS COVERED: Findings from CR studies, such as the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trials, the most rigorous trials to date examining a prolonged 25% CR, are described. The main areas covered include; changes to anthropometrics, energy metabolism, cardiometabolic health, inflammation and immune function, physical fitness, health behaviors, and mental health in response to weight loss (1-year) and weight loss maintenance (2-year). EXPERT OPINION: CR presents a novel and effective therapeutic approach for improving healthspan and biomarkers of lifespan. To date, scientific evidence suggests that continued CR, under medical supervision, is accompanied with persistent and beneficial effects on health outcomes independent of weight loss. Mechanisms are yet to be fully elucidated, and novel dietary approaches that may similarly attenuate aging-related conditions should be explored and compared to traditional CR.

Identification and quantification of insulin resistance require specific blood test which is complex, time-consuming, and much more invasive, making it difficult to track the changes daily. With the advancement in machine learning approaches, identification of insulin resistance can be carried out without clinical processes. In this work, insulin resistance is identified for individuals with triglycerides and HDL-c ratio using non-invasive techniques employing machine learning approaches. Eighteen parameters are used for identification purposes like age, sex, waist size, height, etc., and combinations of these parameters. Experiments are conducted over the CALERIE dataset. Each output of the attribute selection system is modeled over distinct calculations like logistic regression, CARTs, SVM, LDA, KNN, extra trees classifier. The proposed work is validated with a stratified cross-validation test. Results show that KNN and CatBoost show the best results with an accuracy of 74% and 73% respectively and 1% variance compared to 66% with Bernardini et al. and Stawiski et al. and 83% with Farran et al. With the proposed approach an individual can predict the insulin resistance and hence prospective chances of diabetes might be tracked daily using non-clinical approaches. While the same is not practically possible with clinical processes daily.

Caloric restriction (CR) is a strategy that attenuates aging in multiple nonhuman species. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trials are part of a research program aiming to test the effects of CR on aging and longevity biomarkers in humans. Building on CALERIE phase 1, CALERIE phase 2 (CALERIE 2) was the largest study to date to assess sustained CR in healthy humans without obesity. In a 24-month randomized controlled trial comprising 218 participants at baseline, CALERIE 2 showed that moderate CR, 11.9% on average, induced improvements in aging-related biomarkers without adversely affecting psychological or behavioral outcomes. The objectives of this report are to summarize and review the highlights of CALERIE 2 and report previously unpublished results on eating disorder symptoms and cognitive function. This article specifically summarizes the physiological, psychological, aging, behavioral, and safety results of the trial. Also provided are research directions beyond CALERIE 2 that highlight important opportunities to investigate the role of CR in aging, longevity, and health span in humans.

PURPOSE: Calorie restriction (CR) is an effective treatment for obesity-related liver and metabolic disease. However, CR studies in individuals without obesity are needed to see if CR could delay disease onset. Liver biomarkers indicate hepatic health and are linked to cardiometabolic disease. Our aim was to examine the effects of a two-year CR intervention on liver biomarkers in healthy individuals without obesity. METHODS: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study was a two-year randomized controlled trial. Overall, 218 participants (body mass index: 25.1±1.7 kg/m(2)) were enrolled into control group (n=75) that ate ad libitum (AL) or a CR group (n=143) that aimed to decrease energy intake by 25%. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and bilirubin were measured during the trial. RESULTS: At month 24, relative to the AL group, ALP (−7±1 IU/L; P0.99) or AST (2±2 IU/L; P=0.68) were revealed. However, sex-by-treatment-by-time interactions (P

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.

Calorie restriction (CR) slows aging and increases healthy lifespan in model organisms. We tested if CR slowed biological aging in humans using DNA methylation analysis of blood samples from N=197 participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) randomized controlled trial. We quantified CR effects on biological aging by comparing change scores for six epigenetic-clock and Pace-of-Aging measures between n=128 CR-group and n=69 ad-libitum-control-group participants at 12- and 24-month follow-ups. CR effects were strongest for DunedinPACE Pace of Aging (12-month Cohen’s d=0.3; 24-month Cohen’s d=0.2, p0.08). CR effects for other epigenetic clocks were in the opposite direction (all p>0.15). CALERIE intervention slowed Pace of Aging but showed minimal effect on epigenetic clocks hypothesized to reflect longer term accumulation of aging burden.

Background 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. Objective We examined whether applying the Goldberg cutoffs to data used in nutrition studies could reliably reduce or eliminate bias. Methods 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. Results 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. Conclusions 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.

Objective.We aim to evaluate the effect of caloric restriction (CR) in cognition by comparing performance in neuropsychological tests for working memory between a group of non-obese healthy subjects doing CR for 2 years with another consuming ad libitum diet (AL).Methods.This study was part of a larger multicenter trial called CALERIE that consisted of a randomized clinical trial with parallel-group comparing 2 years of 25% CR and AL in 220 volunteers with a BMI between 22 and 28 kg/m2, across 3 sites. The cognitive tests used were the Cambridge Neuropsychological Tests Automated Battery (CANTAB) for Spatial Working Memory (SWM) including the total number of errors (SWMTE) and strategy (SWMS). Included as possible moderators were sleep quality, mood states, perceived stress, and energy expenditure. Analyses were performed at baseline and months 12 and 24.Results.After adjustments, there was a significantly greater improvement in working memory assessed by the SWM for CR individuals, compared to AL. At month 24, it was related mostly to lower protein intake, compared to other macronutrients. Changes in SWM were moderated by changes in sleep quality, physical activity, and energy expenditure.Conclusion.On the long term, CR in healthy individuals seems to have a slightly positive effect on working memory. The study of brain CR targets opens new possibilities to prevent and treat cognitive deficits.

Objectives 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. Methods 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). Results 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. Conclusions 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.

BACKGROUND: Sustained calorie restriction (CR) promises to extend the lifespan. The effect of CR on changes in body mass across tissues and organs is unclear. OBJECTIVES: We used whole-body MRI to evaluate the effect of 2 y of CR on changes in body composition. METHODS: In an ancillary study of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, 43 healthy adults [25–50 y; BMI (kg/m(2)): 22–28] randomly assigned to 25% CR (n = 28) or ad libitum (AL) eating (n = 15) underwent whole-body MRI at baseline and month 24 to measure adipose tissue in subcutaneous, visceral, and intermuscular depots (SAT, VAT, and IMAT, respectively); skeletal muscle; and organs including brain, liver, spleen, and kidneys but not heart. RESULTS: The CR group lost more adipose tissue and lean tissue than controls (P < 0.05). In the CR group, at baseline, total tissue volume comprised 32.1%, 1.9%, and 1.0% of SAT, VAT, and IMAT, respectively. The loss of total tissue volume over 24 mo comprised 68.4%, 7.4%, and 2.2% of SAT, VAT, and IMAT, respectively, demonstrating preferential loss of fat vs. lean tissue. Although there is more muscle loss in CR than AL (P < 0.05), the loss of muscle over 24 mo in the CR group comprised only 17.2% of the loss of total tissue volume. Changes in organ volumes were not different between CR and AL. The degree of CR (% decrease in energy intake vs. baseline) significantly (P < 0.05) affected changes in VAT, IMAT, muscle, and liver volume (standardized regression coefficient ± standard error of estimates: 0.43 ± 0.15 L, 0.40 ± 0.19 L, 0.55 ± 0.17 L, and 0.45 ± 0.18 L, respectively). CONCLUSIONS: Twenty-four months of CR (intended, 25%; actual, 13.7%) in young individuals without obesity had effects on body composition, including a preferential loss of adipose tissue, especially VAT, over the loss of muscle and organ tissue. This trial was registered at www.clinicaltrials.gov as NCT02695511.

OBJECTIVES: There is persistent controversy over the extent to which different components of energy expenditure disproportionately decrease after weight loss and contribute to weight regain through decreased energy requirements. We conducted a secondary analysis of the CALERIE I study to test the hypothesis that decreased resting metabolic rate (RMR) and energy expenditure for physical activity (EEPA) after a 6-month calorie restriction intervention would predict weight regain at 12 months, with a greater decrease in RMR than EEPA. METHODS: Participants (n = 46) received all food and energy-containing beverages for 6 months. Outcome measures included total energy expenditure by doubly labeled water, RMR by indirect calorimetry, and body composition by BOD POD. Predictions for RMR and EEPA were derived from baseline linear regression models including age, sex, fat mass, and fat free mass. Baseline regression coefficients were used to calculate the predicted RMR and EEPA at 6 months. Residuals were calculated as the difference between measured and predicted values and were adjusted for body weight. The presence of metabolic adaptation was evaluated by a paired t-test comparing measured and predicted RMR at 6 months. Differences between 6-month RMR and EEPA residuals were evaluated by the same method. Linear regression was used to assess the association between 6-month residuals and weight loss maintenance (% weight change, 6 to 12 months). RESULTS: Mean weight loss was 6.9% at 6 months with 2.1% regain from 6 to 12 months. No adaptation in RMR was observed at 6 months (mean residual: 19 kcal; 95% confidence interval: −9, 48; P = 0.18). However, significant adaptation was observed in EEPA (mean residual: −199 kcal; −126, −272; P

Many adults receive inadequate sleep, which elevates obesity and type 2 diabetes risk and may hinder benefits of calorie restriction (CR). We hypothesized that short sleepers would experience less weight loss and diminished glycemic benefits compared to adequate sleepers during CR. We performed secondary analyses in participants randomized to 25% CR in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy- Phase 2 (CALERIE 2) trial. Body weight, dual-energy x-ray absorptiometry-measured body composition, fasting glucose, insulin, and HOMA-IR were assessed at baseline, 12, and 24 months. Self-reported sleep duration identified participants with stable sleep as short (≤7 hrs, n=45) or adequate sleepers (>7 hrs, n=65). Sex, BMI, weight, and race-adjusted linear mixed models identified differences over time and between sleepers. Short and adequate sleepers had similar body weight and composition values at all timepoints and experienced equivalent CR-induced reductions over time. Baseline HOMA-IR (1.2 vs. 1.0; P=0.047) was higher in short sleepers, with trends noted for glucose (81.7 vs. 83.5 mg/dL; P=0.093) and insulin (5.7 vs. 4.9 µU/mL; P=0.077). Both phenotypes demonstrated enhanced glycemic control relative to baseline at 12 and 24 months. While there were no 12-month differences in absolute glycemic values between sleepers, initial differences re-emerged at 24 months, with higher HOMA-IR (0.9 vs. 0.7; P=0.01) and insulin concentrations (4.3 vs. 3.4 µU/mL; P Disclosure K. K. Hoddy: None. P. Singh: None. J. L. Dorling: None. R. A. Beyl: None. J. P. Kirwan: None. K. Huffman: None. S. B. Racette: None. S. Das: None. C. K. Martin: Advisory Panel; Self; EHE Health, Board Member; Self; NaturallySlim, Other Relationship; Self; ABGIL, Academy of Nutrition and Dietetics, Research Support; Self; American Society for Nutrition, Leona M. and Harry B. Helmsley Charitable Trust, Lilly, National Institutes of Health, Patient-Centered Outcomes Research Institute, U. S. Department of Agriculture, WW. Funding National Institute on Aging (U01AG022132, U01AG020478, U01AG020487, U01AG020480, R01AG060499, U24AG047121, U24AG047121); Agricultural Research Service (1950-51000-071-01S); American Heart Association (20POST35210907); National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK07247615); National Institute of General Medical Sciences (U54GM104940)

Dynamic phosphorus MRS ((31)P-MRS) is a method used for in vivo studies of skeletal muscle energetics including measurements of phosphocreatine (PCr) resynthesis rate during recovery of submaximal exercise. However, the molecular events associated with the PCr resynthesis rate are still under debate. We assessed vastus lateralis PCr resynthesis rate from (31)P-MRS spectra collected from healthy adults as part of the CALERIE II study (caloric restriction) and assessed associations between PCr resynthesis and muscle mitochondrial signature transcripts and proteins (NAMPT, NQO1, PGC-1α, and SIRT1). Regression analysis indicated that higher concentration of nicotinamide phosphoribosyltransferase (NAMPT) protein, a mitochondrial capacity marker, was associated with faster PCr resynthesis. However, PCr resynthesis was not associated with greater physical fitness (VO(2) peak) or messenger ribonucleic acid levels of mitochondrial function markers such as NQO1, PGC-1α, and SIRT1, suggesting that the impact of these molecular signatures on PCr resynthesis may be minimal in the context of an acute exercise bout. Together, these findings suggest that (31)P-MRS based PCr resynthesis may represent a valid non-invasive surrogate marker of mitochondrial NAMPT in human skeletal muscle.

Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972–1973. Rates of change in each biomarker over ages 26–38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person’s pace of biological aging., eLife digest People’s bodies age at different rates. Age-related biological changes that increase the risk of disease and disability progress rapidly in some people. In others, these processes occur at a slower pace, allowing those individuals to live longer, healthier lives. This observation has led scientists to try to develop therapies that slow aging. The hope is that such treatments could prevent or delay diseases like heart disease or dementia, for which older age is the leading risk factor. Studies in animals have identified treatments that extend the creatures’ lives and slow age-related disease. But testing these treatments in humans is challenging. Our lives are much longer than the worms, flies or mice used in the experiments. Scientists would have to follow human study participants for decades to detect delays in disease onset or an extension of their lives. An alternative approach is to try to develop a test that measures the pace of aging, or essentially “a speedometer for aging”. This would allow scientists to more quickly determine if treatments slow the aging process. Now, Belsky et al. show a blood test designed to measure the pace of aging predicts which people are at increased risk of poor health, chronic disease and an earlier death. First, data about chemical changes to an individual’s DNA, called DNA methylation, were analyzed from white blood cell samples collected from 954 people in a long-term health study known as “The Dunedin Study”. Using the data, Belsky et al. then developed an algorithm – named “DunedinPoAm” – that identified people with an accelerated or slowed pace of aging based on a single blood test. Next, they used the algorithm on samples from participants in three other long-term studies. This verified that those people the algorithm identified as aging faster had a greater risk of poor health, developing chronic diseases or dying earlier. Similarly, those identified as aging more slowly performed better on tests of balance, strength, walking speed and mental ability, and they also looked younger to trained raters. Additionally, Belsky et al. used the test on participants in a randomized trial testing whether restricting calories had potential to extend healthy lifespan. The results suggested that the calorie restriction could counter the effects of an accelerated pace of aging. The test developed by Belsky et al. may provide an alternate way of measuring whether age-slowing treatments work. This would allow faster testing of treatments that can extend the healthy lifespan of humans. The test may also help identify individuals with accelerated aging. This might help public health officials test whether policies or programs can help people lead longer, healthier lives.

Physical activity (PA) has been proposed as a determinant of cognitive function and is one component of energy balance (EB). EB is the difference between energy intake (EI) and the total daily energy expenditure (TDEE). TDEE is a combination of resting metabolic rate (RMR), thermic effect of food and PA. The potential role of each of these components on cognitive function has not yet been systemically investigated. We aim to evaluate the association between each component of EB on cognition, using baseline and longitudinal data from a clinical trial of caloric restriction (CR). This is a parallel-group, randomized clinical trial comparing two years of 25% CR with two years of ad libitum diet (AL), with 220 healthy volunteers of both sex, aged between 21 and 50 years and initial BMI ≥ 22 kg/m2 and28 kg/m2. Body weight, fat mass (FM), fat-free mass (FFM), and bone mineral content were evaluated, as well as RMR, TDEE, cognitive performance and baseline energy intake. A 30 min/day of a moderate level on a minimum of 5 days/week was advised as PA measure. Longitudinal analysis demonstrated that the influence of CR in the improvement of cognitive performance was moderated by changes in RMR, suggesting that in individuals submitted to CR, the cognitive performance and the RMR improved proportionally, independently of changes in EI and body mass. EB and homeostasis are crucial to modulate the RMR. Moreover, RMR presents an important influence on cognitive function in individuals submitted to CR in a long term.

Background 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. Objective 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. Design 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. Results 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. Conclusions 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.

Objective This paper reviews the literature pertaining to the structure and content of intensive lifestyle interventions (ILIs) for overweight/obesity since Richard Stuart described this new treatment approach in 1967. A consensus opinion has formed that behavioral/lifestyle treatment of overweight and obesity should be viewed as a mainstream intervention for the treatment and prevention of type 2 diabetes and medical complications associated with obesity. Methods The development of modern ILIs and demonstration of their efficacy are compared by structure, content, and efficacy of four major randomized controlled trials: Diabetes Prevention Program (DPP), Look AHEAD, POUNDS Lost, and CALERIE. Results The results of these studies indicated that modification of lifestyle behaviors related to nutrition and physical activity can yield weight loss and prevention or improvement of a variety of medical conditions associated with obesity in a variety of subpopulations. Conclusions Recommendations for the structure and length of behavioral/lifestyle interventions have been recently adopted by agencies and institutions that approve reimbursement for medical services. These recommendations represent a giant step in the effort to recognize ILIs as a mainstream approach for the treatment of obesity and comorbid medical conditions. Nevertheless, they do not adequately represent advances made since the publication of the DPP results.

Background: Calorie restriction (CR) influences aging processes and extends average and maximal life spans. The CALERIE 2 (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy Phase 2) study was the first randomized clinical trial to examine the metabolic and psychological effects of CR in nonobese humans.Objective: We conducted a 2-y follow-up study of adults who underwent 2 y of CR or ad libitum (control) consumption and determined whether weight loss and acquired behaviors persisted after the study ended when participants determined their own lifestyle behaviors.Design: In this prospective, longitudinal study, we assessed differences in weight, body composition, psychological function, and energy expenditure in 39 nonobese [body mass index (in kg/m2): 22-28] men and women (25% CR: n = 24; control: n = 15) 12 and 24 mo after they completed the CALERIE 2 study at Pennington Biomedical.Results: Of 39 participants who were in the follow-up study, 29 subjects (CR: n = 18; control: n = 11) completed all visits at follow-up months 12 and 24. After the CR intervention, a mean ± SEM weight loss of 9.0 ± 0.6 kg was observed in the CR group, in which only 54% of the weight was regained 2 y later. Despite such a regain, weight, the percentage of body fat, and fat mass remained significantly reduced from baseline throughout follow-up and remained significantly less than in the control group (P < 0.05). At follow-up, the CR group retained higher degrees of dietary restraint and avoidance of certain foods.Conclusion: After a 2-y intensive CR intervention, ∼50% of CR-induced weight loss was maintained 2 y later, which was probably the result of lasting effects on acquired behaviors and dietary restraint. This trial was registered at clinicaltrials.gov as NCT00943215.

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.

Commentary by: Dr James Kimpton and Dr Teck Khong Clinical Pharmacology, St George's, University of London, UKSeries Editor: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UKCommentary on: Kraus WE, Bhapkar M, Huffman KM, et al. 2 years of calorie restriction and cardiometabolic (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinol 2019; 7: 673–83

In the United States, 2 out of 3 adults are overweight or obese. To lose weight, individuals engage in a variety of dietary and exercise interventions. Despite successful weight loss initially, weight loss is typically less than expected and most individuals regain weight. Both phenomena have been linked to a reduction in resting metabolic rate (RMR) secondary to weight loss. Objective To characterize the independent contributions of changes in body composition, the major predictor of RMR, and adaptive thermogenesis to the observed decline in RMR associated with weight loss. We predict that changes in fat-free mass and adaptive thermogenesis will both contribute to RMR decline. Methods Secondary data analysis was conducted on a publically available data set from CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), a 2-year observational calorie restriction study. CALERIE data used for the present analysis examined changes in RMR, body composition, and metabolic hormones over 12 months of 25\% calorie restriction in 117 non-obese (BMI between 22–27.9 kg/m2) men and women with complete data. Changes in RMR were compared between quartiles based on loss of body weight, fat-free mass, and fat mass. Adaptive thermogenesis was quantified as the reduction in RMR that exceeded the reduction in RMR predicted from changes in organ mass, which was assessed by Dual-energy X-ray absorptiometry. Results After 12 months, mean weight loss was 7.9 ± 0.3 kg (−10.9 ± 0.4\%, p

Summary Background For several cardiometabolic risk factors, values considered within normal range are associated with an increased risk of cardiovascular morbidity and mortality. We aimed to investigate the short-term and long-term effects of calorie restriction with adequate nutrition on these risk factors in healthy, lean, or slightly overweight young and middle-aged individuals. Methods CALERIE was a phase 2, multicentre, randomised controlled trial in young and middle-aged (21–50 years), healthy non-obese (BMI 22·0–27·9 kg/m2) men and women done in three clinical centres in the USA. Participants were randomly assigned (2:1) to a 25% calorie restriction diet or an ad libitum control diet. Exploratory cardiometabolic risk factor responses to a prescribed 25% calorie restriction diet for 2 years were evaluated (systolic, diastolic, and mean blood pressure; plasma lipids; high-sensitivity C-reactive protein; metabolic syndrome score; and glucose homoeostasis measures of fasting insulin, glucose, insulin resistance, and 2-h glucose, area-under-the curve for glucose, and insulin from an oral glucose tolerance test) analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00427193. Findings From May 8, 2007, to Feb 26, 2010, of 238 participants that were assessed, 218 were randomly assigned to and started a 25% calorie restriction diet (n=143, 66%) or an ad libitum control diet (n=75, 34%). Individuals in the calorie restriction group achieved a mean reduction in calorie intake of 11·9% (SE 0·7; from 2467 kcal to 2170 kcal) versus 0·8% (1·0) in the control group, and a sustained mean weight reduction of 7·5 kg (SE 0·4) versus an increase of 0·1 kg (0·5) in the control group, of which 71% (mean change in fat mass 5·3 kg [SE 0·3] divided by mean change in weight 7·5 kg [0·4]) was fat mass loss. Calorie restriction caused a persistent and significant reduction from baseline to 2 years of all measured conventional cardiometabolic risk factors, including change scores for LDL-cholesterol (p Interpretation 2 years of moderate calorie restriction significantly reduced multiple cardiometabolic risk factors in young, non-obese adults. These findings suggest the potential for a substantial advantage for cardiovascular health of practicing moderate calorie restriction in young and middle-aged healthy individuals, and they offer promise for pronounced long-term population health benefits. Funding National Institute on Aging and National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

// Sergei V. Romashkan 1 , Sai Krupa Das 2 , Dennis T. Villareal 3,4 , Eric Ravussin 5 , Leanne M. Redman 5 , James Rochon 6,7 , Manjushri Bhapkar 7 , William E. Kraus 7 for the CALERIE Study Group 1 National Institute on Aging, Bethesda, MD, USA 2 Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA 3 Washington University School of Medicine, St Louis, MO, USA 4 Baylor College of Medicine and Michael E DeBakey VA Medical Center, Houston, TX, USA 5 Pennington Biomedical Research Center, Baton Rouge, LA, USA 6 Rho Federal Systems, Chapel Hill, NC, USA 7 Duke Clinical Research Institute and Duke University School of Medicine, Durham, NC, USA Correspondence to: Sai Krupa Das, email: // Keywords : calorie restriction, safety, humans, dietary energy restriction, Gerotarget Received : February 10, 2016 Accepted : February 28, 2016 Published : March 15, 2016 Abstract Background: The extent to which sustained caloric restriction (CR) in healthy non-obese adults is safe has not been previously investigated. Objective: Assess the safety and tolerability of sustained two-year CR intervention in healthy, non-obese adults. Design: A multi-center, randomized controlled trial. Participants were randomized using a 2:1 allocation in favor of 25% CR vs. Ad-Libitum intake (AL). Adverse and serious adverse events (AE, SAE), safety laboratory tests, and other safety parameters were closely monitored. Results: Three participants were withdrawn from the CR intervention because of the safety concerns. No deaths and one SAE was reported by participants in the CR group. Although the difference in AE between AL and CR groups was not significant, within the CR group, the incidence of nervous system ( p = 0.02), musculoskeletal ( p = 0.02) and reproductive system ( p = 0.002) disorders was significantly higher in the normal-weight than in the overweight participants. At months 12 and 24, bone mineral densities at the lumbar spine, total hip, and femoral neck of participants in the CR group were significantly lower than in those in the AL group. Conclusions: Two-years of CR at levels achieved in CALERIE was safe and well tolerated. Close monitoring for excessive bone loss and anemia is important.

OBJECTIVES: Anti-inflammatory diets have been suggested to improve psychological health. This research evaluated the combined effects of consuming an anti-inflammatory diet and caloric restriction (CR) on changes in perceived stress and health-related quality of life in a healthy, non-obese population. METHODS: We conducted a secondary analysis of the publicly available CALERIE data. Participants were randomized to a 2 year CR intervention (n = 143) or an ad libitum Control group (n = 75) and self-selected their dietary intake. An energy-adjusted dietary inflammatory index (DII) was calculated based on 28 components from self-reported food records. Self-reported stress and general health outcomes were measured using validated questionnaires. Linear mixed models were used to assess changes in each outcome from baseline to 12 and 24 months. Models were adjusted for age, sex, baseline outcome measure, change in body fat, and a treatment by DII interaction term. RESULTS: On average, participants were 38.1 ± 7.2 years old with a BMI of 25.1 ± 1.7 kg/m(2). Baseline characteristics, including the DII, stress, and general health, did not differ with randomization. There was no significant association between temporal changes in DII and changes in stress or general health in the CR or Control groups. On average, both groups tended to report higher stress at 12 months; however, there was no difference in perceived stress between groups (adjusted mean difference [MD]: 0.5; 95% confidence interval [CI]: −0.4, 1.5; P = 0.25). There was an improvement in reported general health in the CR group at 12 months (MD: 4.1; 95% CI: 2.2, 6.0; P

Summary Calorie restriction (CR) without malnutrition slows aging in animal models. Oxidative stress reduction was proposed to mediate CR effects. CR effect on urinary F2-isoprostanes, validated oxidative stress markers, was assessed in CALERIE, a two-year randomized controlled trial. Healthy volunteers (n = 218) were randomized to prescribed 25% CR (n = 143) or ad libitum control (AL, n = 75) stratifying the randomization schedule by site, sex, and BMI. F2-isoprostanes were quantified using LC-MS/MS in morning, fasted urine specimens at baseline, at 12 and 24 months. The primary measure of oxidative status was creatinine-adjusted 2,3-dinor-iPF(2α)-III concentration, additional measured included iPF(2α)-III, iPF2a-VI, and 8,12-iso-iPF2a-VI. Intention-to-treat analyses assessed change in 2,3-dinor-iPF(2α)-III using mixed models assessing treatment, time, and treatment-by-time interaction effects, adjusted for blocking variables and baseline F2-isoprostane value. Exploratory analyses examined changes in iPF(2α)-III, iPF(2α)-VI, and 8,12-iso-iPF(2α)-VI. A factor analysis used aggregate information on F2-isoprostane values. In CR group, 2,3-dinor-iPF(2α)-III concentrations were reduced from baseline by 17% and 13% at 12 and 24 months, respectively; these changes were significantly different from AL group (p

Calorie restriction (CR) triggers benefits for healthspan including decreased risk of cardiometabolic disease (CVD). In an ancillary study to CALERIE 2, a 24-mo 25% CR study, we assessed the cardiometabolic effects of CR in 53 healthy, nonobese (BMI: 22–28 kg/m2) men ( n = 17) and women ( n = 36). The aim of this study was to investigate whether CR can reduce risk factors for CVD and insulin resistance in nonobese humans and, moreover, to assess whether improvements are exclusive to a period of weight loss or continue during weight maintenance. According to the energy balance method, the 25% CR intervention ( n = 34) produced 16.5 ± 1.5% (mean ± SE) and 14.8 ± 1.5% CR after 12 and 24 mo (M12, M24), resulting in significant weight loss (M12 −9 ± 0.5 kg, M24 −9 ± 0.5 kg, P < 0.001). Weight was maintained in the group that continued their habitual diet ad libitum (AL, n = 19). In comparison to AL, 24 mo of CR decreased visceral (−0.5 ± 0.01 kg, P < 0.0001) and subcutaneous abdominal adipose tissue (−1.9 ± 0.2kg, P < 0.001) as well as intramyocellular lipid content (−0.11 ± 0.05%, P = 0.031). Furthermore, CR decreased blood pressure (SBP −8 ± 3 mmHg, P = 0.005; DBP −6 ± 2 mmHg, P < 0.001), total cholesterol (−13.6 ± 5.3 mg/dl, P = 0.001), and LDL-cholesterol (−12.9 ± 4.4 mg/dl, P = 0.005), and the 10-yr risk of CVD-disease was reduced by 30%. Homeostasis model assessment of insulin resistance (HOMA-IR) decreased during weight loss in the CR group (−0.46 ± 0.15, P = 0.003), but this decrease was not maintained during weight maintenance (−0.11 ± 0.15, P = 0.458). In conclusion, sustained CR in healthy, nonobese individuals is beneficial in improving risk factors for cardiovascular and metabolic disease such as visceral adipose tissue mass, ectopic lipid accumulation, blood pressure, and lipid profile, whereas improvements in insulin sensitivity were only transient.

Metabolic interventions involving undernutrition but not malnutrition (e.g., caloric restriction, CR) are effective strategies for improving both health and longevity in species ranging from lower organisms to nonhuman primates. Initial human trials to test the effects of sustained, reduced energy intake have yielded promising health benefits. Through intense research efforts in understanding the molecular mechanisms of CR, three cellular pathways have now been identified although the precise details remain unknown. More recently, circadian regulation has been recognized as a novel mediator for CR effects in mice. Harnessing the molecular insights into CR, novel nutritional interventions and pharmacological application of CR mimetics have been tested showing great promise in simultaneously improving metabolic function and providing overall health benefits. Additional research is needed to identify efficacious therapeutics that can be safely and practically translated to human studies in promoting healthspan.

In a randomized clinical trial of calorie restriction (CR), we demonstrated that important cardiovascular disease (CVD) biomarkers were favorably influenced by CR alone and in conjunction with physical exercise. The aim of this study was to examine the effects of CR with or without exercise on copper bound to ceruloplasmin (CuCp), a well-known biomarker for CVD, in overweight men and women enrolled in the CALERIE phase 1 study. Forty-six individuals were randomized to one of four groups for 6 months: control, healthy weight maintenance; CR, 25% CR from baseline energy requirements; CR+exercise, 12.5% CR and 12.5% through aerobic exercise; and low-calorie diet, low-calorie diet until 15% reduction in body weight followed by weight maintenance diet. CuCp was determined in fasting blood samples by a high-performance liquid chromatography-inductively coupled plasma mass spectrometry methodology and compared with changes in body composition and markers of CVD. After 6 months, CR combined with exercise induced a decrease in plasma concentration of CuCp. CuCp was inversely correlated with insulin sensitivity at baseline and after 6 months of intervention. A cluster analysis showed that the percent change of weight after 6 months of intervention was the most important variable that could discriminate the intervention groups. The percent change of CuCp was the only other variable selected by the analysis. Decreased CuCp in overweight subjects by CR combined with exercise suggests a positive effect of this intervention on metabolic health. Further studies to explain the relationship between weight loss and CuCp and its relevance for cardiovascular health are needed.

Purpose Calorie 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. Methods Healthy, 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. Results The 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. Conclusions Two 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.

Calorie restriction (CR), a nutritional intervention of reduced energy intake but with adequate nutrition, has been shown to extend healthspan and lifespan in rodent and primate models. Accumulating data from observational and randomized clinical trials indicate that CR in humans results in some of the same metabolic and molecular adaptations that have been shown to improve health and retard the accumulation of molecular damage in animal models of longevity. In particular, moderate CR in humans ameliorates multiple metabolic and hormonal factors that are implicated in the pathogenesis of type 2 diabetes, cardiovascular diseases, and cancer, the leading causes of morbidity, disability and mortality. In this paper, we will discuss the effects of CR in non-obese humans on these physiological parameters. Special emphasis is committed to recent clinical intervention trials that have investigated the feasibility and effects of CR in young and middle-aged men and women on parameters of energy metabolism and metabolic risk factors of age-associated disease in great detail. Additionally, data from individuals who are either naturally exposed to CR or those who are self-practicing this dietary intervention allows us to speculate on longer-term effects of more severe CR in humans.

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 2 H and 18 O 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 2 H and 18 O, 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. J. Nutr. 144: 777–783, 2014.

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/m(2)) 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, 12, and 24 months. 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.

The effects of caloric restriction (CR) on in vivo muscle mitochondrial function in humans are controversial.We evaluated muscle mitochondrial function and associated transcriptional profiles in nonobese humans after 12 months of CR.Individuals from an ancillary study of the CALERIE 2 randomized controlled trial were assessed at baseline and 12 months after a 25% CR or ad libitum (control) diet.The study was performed at Pennington Biomedical Research Center in Baton Rouge, LA.Study participants included 51 (34 female subjects, 25 to 50 years of age) healthy nonobese individuals randomized to 1 of 2 groups (CR or control).This study included 12 months of a 25% CR or ad libitum (control) diet.In vivo mitochondrial function [maximal ATP synthesis rate (ATPmax), ATPflux/O2 (P/O)] was determined by 31P-magnetic resonance spectroscopy and optical spectroscopy, and body composition was determined by dual-energy X-ray absorptiometry. In a subset of individuals, a muscle biopsy was performed for transcriptional profiling via quantitative reverse transcription polymerase chain reaction and microarrays.Weight, body mass index (BMI), fat, and fat-free mass (P0.001 for all) significantly decreased at month 12 after CR vs control. In vivo ATPmax and P/O were unaffected by 12 months of CR. Targeted transcriptional profiling showed no effects on pathways involved in mitochondrial biogenesis, function, or oxidative stress. A subgroup analysis according to baseline P/O demonstrated that a higher (vs lower) P/O was associated with notable improvements in ATPmax and P/O after CR.In healthy nonobese humans, CR has no effect on muscle mitochondrial function; however, having a "more coupled" (versus "less coupled") phenotype enables CR-induced improvements in muscle mitochondrial function.

Globally, the aging population is growing rapidly, creating an urgent need to attenuate age-related health conditions, including metabolic disease and disability. A promising strategy for healthy aging based on consistently positive results from studies with a variety of species, including non-human primates (NHP), is calorie restriction (CR), or the restriction of energy intake while maintaining intake of essential nutrients. The burgeoning evidence for this approach in humans is reviewed and the major study to date to address this question, CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy), is described. CALERIE findings indicate the feasibility of CR in non-obese humans, confirm observations in NHP, and are consistent with improvements in disease risk reduction and potential anti-aging effects. Finally, the mechanisms of CR in humans are reviewed which sums up the fact that evolutionarily conserved mechanisms mediate the anti-aging effects of CR. Overall, the prospect for further research in both NHP and humans is highly encouraging.

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.

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.

Animal studies have shown that life span is extended by caloric restriction (CR). This manuscript describes the design and methodology of an innovative CR intervention, which is the treatment arm of the CALERIE Study. This study is a multi-center, randomized controlled trial examining the effects of 2 years of CR on biomarkers of longevity among non-obese (BMI ≥ 22 kg/m(2) and

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.

Decreasing oxidative stress and increasing antioxidant defense has been hypothesized as one mechanism by which caloric restriction (CR) increases longevity in animals. A total of 46 moderately overweight volunteers (BMI: 252-30 kg/m2), ages 20–42 yr were randomized to either high glycemic (HG) or low glycemic (LG) dietary load CR regimen at either 10% (n=12) or 30% (n=34) of basal caloric intake. All food was provided to participants for 6 mo. Overall, after controlling for CR levels and dietary regimen for 6 mo, plasma glutathione peroxidase activity increased (p=0.04) and plasma protein carbonyl levels decreased (p=0.02) and a non-significant decrease in plasma 8-epi-prostaglandin F2α level was observed (p=0.09). No significant change was observed in other plasma antioxidants such as superoxide dismutase and catalase. These findings indicate that short term CR (10% or 30%) in moderately overweight subjects modulates some but not all measures of antioxidant defense and oxidative stress.

Background:Thereremainsnoconsensusabouttheoptimaldietary composition for sustained weight loss. Objective: The objective was to examine the effects of 2 dietary macronutrient patterns with different glycemic loads on adherence to a prescribed regimen of calorie restriction (CR), weight and fat loss, and related variables. Design: A randomized controlled trial (RCT) of diets with a high glycemic load (HG) or a low glycemic load (LG) at 30% CR was conducted in 34 healthy overweight adults with a mean (! SD) age of35! 6yandbodymassindex(kg/m 2 )of27.6! 1.4.Allfoodwas providedfor6moindietscontrolledforconfoundingvariables,and subjectsself-administeredtheplansfor6additionalmonths.Primary andsecondaryoutcomesincludedenergyintakemeasuredbydoubly labeled water, body weight and fatness, hunger, satiety, and resting metabolic rate. Results: All groups consumed significantly less energy during CR than at baseline (P " 0.01), but changes in energy intake, body weight, body fat, and resting metabolic rate did not differ significantly between groups. Both groups ate more energy than provided (eg,21%and28%CRat3moand16%and17%CRat6mowithHG and LG, respectively). Percentage weight change at 12 mo was # 8.04! 4.1%intheHGgroupand# 7.81! 5.0%intheLGgroup. There was no effect of dietary composition on changes in hunger, satiety, or satisfaction with the amount and type of provided food during CR. Conclusions: These findings provide more detailed evidence to suggest that diets differing substantially in glycemic load induce comparable long-term weight loss. Am J Clin Nutr 2007;85: 1023‐30.

There is debate over the independent and combined effects of dieting and increased physical activity on improving metabolic risk factors (body composition and fat distribution).The objective of the study was to conduct a randomized, controlled trial (CALERIE) to test the effect of a 25% energy deficit by diet alone or diet plus exercise for 6 months on body composition and fat distribution.This was a randomized, controlled trial.The study was conducted at an institutional research center.Thirty-five of 36 overweight but otherwise healthy participants (16 males, 19 females) completed the study.Participants were randomized to either control (healthy weight maintenance diet, n = 11), caloric restriction (CR; 25% reduction in energy intake, n = 12), or caloric restriction plus exercise (CR+EX; 12.5% reduction in energy intake + 12.5% increase in exercise energy expenditure, n = 12) for 6 months.Changes in body composition by dual-energy x-ray absorptiometry and changes in abdominal fat distribution by multislice computed tomography were measured.The calculated energy deficit across the intervention was not different between CR and CR+EX. Participants lost approximately 10% of body weight (CR: - 8.3 +/- 0.8, CR+EX: - 8.1 +/- 0.8 kg, P = 1.00), approximately 24% of fat mass (CR: - 5.8 +/- 0.6, CR+EX: - 6.4 +/- 0.6 kg, P = 0.99), and 27% of abdominal visceral fat (CR: 0.9 +/- 0.2, CR+EX: 0.8 +/- 0.2 kg, P = 1.00). Both whole-body and abdominal fat distribution were not altered by the intervention.Exercise plays an equivalent role to CR in terms of energy balance; however, it can also improve aerobic fitness, which has other important cardiovascular and metabolic implications.