Comprehensive Assessment Of Long-term Effects Of Reducing Intake Of Energy Research Articles

Principal component-based clinical aging clocks identify signatures of healthy aging and targets for clinical intervention.

Clocks that measure biological age should predict all-cause mortality and give rise to actionable insights to promote healthy aging. Here we applied dimensionality reduction by principal component analysis to clinical data to generate a clinical aging clock (PCAge) identifying signatures (principal components) separating healthy and unhealthy aging trajectories. We found signatures of metabolic dysregulation, cardiac and renal dysfunction and inflammation that predict unsuccessful aging, and we demonstrate that these processes can be impacted using well-established drug interventions. Furthermore, we generated a streamlined aging clock (LinAge), based directly on PCAge, which maintains equivalent predictive power but relies on substantially fewer features. Finally, we demonstrate that our approach can be tailored to individual datasets, by re-training a custom clinical clock (CALinAge), for use in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study of caloric restriction. Our analysis of CALERIE participants suggests that 2 years of mild caloric restriction significantly reduces biological age. Altogether, we demonstrate that this dimensionality reduction approach, through integrating different biological markers, can provide targets for preventative medicine and the promotion of healthy aging.

A 2-Year Calorie Restriction Intervention Improves Diet Quality Without Compromising Nutritional Adequacy: The CALERIE Trial

Background: The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) was the first randomized controlled trial of calorie restriction (CR) on biomarkers of aging and cardiometabolic health in humans without obesity. Objective: To determine diet quality and nutritional adequacy during a 2y calorie restriction intervention among healthy adults without obesity. Design: CALERIE phase 2 was a multi-site, randomized controlled trial of 2y of CR vs. ad libitum (AL) control. CR participants received extensive dietary education and support. Food diaries were completed at baseline and months 6, 12, 18, and 24 and analyzed using NDSR. Diet quality was evaluated using the PANDiet diet quality index. Nutritional adequacy was defined using sex- and age-specific Estimated Average Requirement (EAR) or Adequate Intake (AI) criteria for each nutrient. Results: 220 participants completed baseline assessments and were randomized (145 CR, 75 AL; 70% women, age 38±7 y, BMI 25.1±1.7 kg/m2); 86% completed the 2y study. The level of calorie restriction achieved averaged 11.9±0.7% during the 2y intervention. Diet quality improved in the CR group (BL 74.3±5.1%; CR average 76.3±5.3%, p < 0.0001), but not in the AL group ( p < 0.0002 between groups). Nutritional adequacy improved modestly in CR, but not in AL. More than 90% of CR participants achieved 100% of EAR or AI during CR for protein, carbohydrate, 6 of 12 vitamins (A, B1, B2, B3, B6, B12), and 5 of 9 minerals (copper, iron, phosphorus, selenium, sodium). Nutrients for which <90% of participants achieved adequacy included fiber, omega-3 fatty acids, vitamins B5, B9, C, E, and K, and the minerals calcium, magnesium, potassium, and zinc. Conclusion: A 2y CR intervention designed to promote healthy aging and comprised of comprehensive nutrition counseling promoted improvements in diet quality and maintenance or improvements in nutritional adequacy. This research was supported by grants U01AG020478, U01AG020480, U01AG020487, U01AG022132, U24AG047121, R33AG070455, and R01AG071717 from the National Institute on Aging. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

EFFECT OF LONG-TERM CALORIC RESTRICTION ON THE PACE OF BIOLOGICAL AGING IN HEALTHY ADULTS FROM THE CALERIE TRIAL

Abstract The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients, can change molecular processes associated with aging, including DNA methylation (DNAm), and increases healthy lifespan in multiple species. Here we report results of a post-hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n=220 non-obese adults were randomized to 25% CR or ad libitum control diet for 2years. We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm clock, but did not lead to significant changes in PhenoAge- or GrimAge-clock-measured biological age. Treatment effects were small; changes in DunedinPACE suggest a ~3% slowing of the pace of aging. Nevertheless, this small effect may be substantive; in an independent study of older adults, 3% slower DunedinPACE is associated with a 15% lower risk of death. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies and contrasting with reports that biological aging may not be modifiable. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1–3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5–7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11–13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14–16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18–20.

No Effect of Calorie Restriction or Dietary Patterns on Spatial Working Memory During a 2-Year Intervention: A Secondary Analysis of the CALERIE Trial

BackgroundThe effect of calorie restriction (CR) on cognitive function is not well understood, and the impact of the dietary patterns consumed during CR has not been investigated. ObjectivesWe analyzed the combined association of CR and dietary quality with spatial working memory (SWM) in healthy adults without obesity. MethodsThe Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial was a 2-y, multisite clinical trial. This trial was registered at clinicaltrials.gov as NCT00427193. Participants were randomized to a 25% reduction in EI (n = 143) or an ad libitum Control (n = 76). The Dietary Inflammatory Index (DII) and the Healthy Eating Index (HEI) captured dietary quality, with a lower DII and higher HEI score indicating a healthier diet. The Cambridge Neuropsychological Test Automated Battery battery was used to assess SWM. Longitudinal associations between each dietary pattern index and SWM for CR and Control were assessed by multivariable negative binomial models that included baseline, 12-mo, and 24-mo visits. ResultsParticipants were aged 38.1 ± 7.2 y with a BMI of 25.1 ± 1.7 kg/m2. A total of 70% of the participants were female. Baseline mean DII and HEI scores were −0.15 (range: −3.77, 4.21) and 59.1 (24.1, 91.0) and did not differ between groups. Improvements in DII and HEI were significantly different between CR and Control over 2 y (both P-interaction = 0.001). In longitudinal analyses, there was no association of either index with SWM. Furthermore, though within-group improvements in SWM were observed at 12 mo, there was no statistically significant difference between CR (SWM errors: 9.0; 95% CI: 1.9, 41.6) and Control (11.7; 95% CI: 2.6, 53.5; P > 0.99), holding DII constant. Comparable results were observed at 24 mo and for the HEI. ConclusionsDietary quality during CR was not associated with measures of SWM over 2 y in healthy adults without obesity. These results suggest that, in healthy populations, dietary patterns and CR may have a limited impact on working memory. Further research is required to understand the concurrent effect of these nutritional strategies.

IMPACT OF CALORIE RESTRICTION ON PLASMA ALZHEIMER’S DISEASE BIOMARKERS IN HEALTHY YOUNG AND MIDDLE-AGED ADULTS

Abstract Midlife cardiometabolic risk factors are associated with an increased risk of Alzheimer’s dementia (AD). Moderate calorie restriction (CR) in healthy, non-obese young and middle-aged adults improves cardiometabolic risk factors. Plasma concentrations of amyloid β oligomers (Aβ-42 and Aβ-40) and total tau are emerging biomarkers of AD pathology. Our objective was to determine the impact of two years of CR in healthy young and middle-aged adults on Aβ-42, Aβ-40, and total tau in the Comprehensive Assessment of Long term Effects of Reducing Intake of Energy (CALERIE) Study. Participants were randomized 2:1 to 24 months of CR (prescribed as 25% reduction in baseline calorie requirements) versus an ad libitum (AL) diet. We quantified plasma Aβ-42, Aβ-40, and total tau using the ultrasensitive single molecule array (SIMOA) technology at baseline and two years in a subset of CALERIE (N=133). We used linear regression to evaluate the impact of CR, including age, sex, and presence/absence of the APOE-ε4 risk allele as covariates. We hypothesized that there would be differential CR effects based on APOE-ε4 carrier status; to test this, we included an interaction term. As compared to AL, there was a trend towards decreased Aβ-40, controlling for age, baseline Aβ-40 concentrations, and APOE-ε4 carrier status (β=-12.59, 95% CI[-27.14, 1.96], p=0.093) with 12% (average achieved) CR. The CR*APOE-ε4 carrier status interaction term was significant at a pre-defined threshold of p<0.10 (p=0.062). Stratified by APOE-ε4 carrier status, CR was associated with a decrease in plasma Aβ-40 (β=-33.72, 95% CI[-65.16,-2.09], p=0.041). In conclusion, moderate CR in healthy, non-obese young and middle-aged adults impacts plasma biomarkers of AD risk, primarily in APOE-ε4 carriers.

Associations between the timing of eating and weight-loss in calorically restricted healthy adults: Findings from the CALERIE study.

Calorie restriction (CR) and time-restricted eating (TRE) are distinctly different dietary management strategies with overlapping health outcomes. After two years of CR, healthy participants in the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study showed significant weight-loss relative to the ad libitum intake control group and achieved 12% CR on average. Preclinical rodent studies have shown that sustaining a consistent eating interval of 8-12h between the first and last calories of each day-without reducing daily calorie intake-can impart health benefits that partly overlap with those imparted by CR. Preclinical CR protocols often inadvertently restrict eating interval, and conversely, clinical studies of TRE often inadvertently result in modest CR. Other factors related to daily timing of food intake, such as breakfast skipping, and early food intake also impact health outcomes. These observations have raised the possibility that CR protocols can be further optimized by adopting relevant aspects of eating patterns to boost weight loss and health outcomes. With a goal to inform CR protocols that aim to optimize eating patterns, the objective of this secondary analysis was to test aspects of daily timing of food intake associated with greater weight loss in the CALERIE study participants. We found no difference in the daily time window of energy intake between the CR and control arms. In the CALERIE trial, weight change was used as a proxy for adherence to CR, and hence we used linear models to test the relationships among CR, weight loss, and temporal aspects of daily eating pattern. We found that CR alone could explain 41% of the variance in weight loss. We tested the contribution of eating interval, time to 50% daily calorie intake, and day-to-day shifts in the time of the first (breakfast) or last meal consumed. We found that eating interval and variation in the timing of the first and last meals significantly influenced weight loss after controlling for CR. Our models suggest that shorter eating intervals are associated with greater CR (1% of the variance explained) and facilitate additional weight loss. Our models suggest that less day to day variation in first mealtime is directly associated with weight loss (6% of the variance explained). More regular first meal timing is also associated with greater CR (2% of the variance explained). Likewise, regular timing of the last daily meal is directly associated with weight loss (1% of the variance explained) and greater CR (1% of the variance explained). The time to 50% of daily calorie intake or consuming half the caloric intake earlier in the day is associated with additional CR (2% of the variance explained). In summary, these secondary analyses on CALERIE data suggest that - in order to maximize CR and weight loss - future CR protocols should encourage participants to adopt consistent timing of their first and last meals, a shorter eating window, and earlier consumption of food.

Anti-aging mechanism of calorie restriction in humans

Animal studies have demonstrated that calorie restriction lowers the incidence of age-related diseases and leads to longer lifespans.1 However, a question that has not been answered is whether long-term calorie restriction has similar beneficial effects in humans. A recent study by Spadaro et al. attempted to address this question by leveraging data from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) clinical trial.2

Effect of 2-year caloric restriction on organ and tissue size in nonobese 21- to 50-year-old adults in a randomized clinical trial: the CALERIE study

Sustained calorie restriction (CR) promises to extend the lifespan. The effect of CR on changes in body mass across tissues and organs is unclear. We used whole-body MRI to evaluate the effect of 2 y of CR on changes in body composition. 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/m2): 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. 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). 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.

Abstract 13507: The Role of Weight Loss in Mediating the Effects of a 2-year Caloric Restriction Regimen on Cardiometabolic Risk Markers in Individuals Without Obesity

Introduction: Caloric restriction (CR) improves cardiometabolic risk, even among individuals without obesity. However, it is unclear whether these aging-related benefits are mediated by weight loss. Mediation analyses inform mechanisms underlying relationships between an exposure and outcome. Using mediation analyses, our aim was to test if 2-year weight loss mediates the beneficial effects of CR on cardiometabolic risk markers in individuals without obesity. Methods: Participants without obesity were randomized 2:1 to CR or ad libitum (AL) as part of the 2-year trial, Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). The CR group aimed to enact 25% CR for 2 years, while AL maintained habitual energy intake. Baseline and year 2 assessments included weight and cardiometabolic risk markers. Using the approaches of Valeri and VanderWeele, mediation was quantified as the natural indirect effect (NIE), defined as the impact of an exposure on an outcome through a mediator. Here, the NIE was the effect of CR (exposure) on cardiometabolic risk markers (outcome) that was accounted for by weight change (mediator). Results: In total, 117 and 71 participants in the CR and AL groups, respectively, completed the trial. The CR group achieved 11.9 (± 0.7)% CR and 7.6 (± 0.3) kg of weight loss ( P &lt; 0.01 versus AL). Weight loss significantly mediated the CR-induced improvements in total cholesterol (NIE = -10.4 ± 3.5 mg/dL), low-density lipoprotein cholesterol (NIE = -8.5 ± 2.8 mg/dL), high-density lipoprotein cholesterol (NIE = 2.9 ± 1.3 mg/dL), triglycerides (NIE = -0.20 ± 0.05 log mg/dL), the homeostatic model assessment of insulin resistance (NIE = -0.22 ± 0.06), and C-reactive protein (NIE = -0.39 ± 0.15 log ug/mL) ( P ≤ 0.02). Weight loss did not mediate CR-induced reductions in systolic (NIE = -0.9 ± 1.4 mmHg) and diastolic (NIE = -1.0 ± 1.1 mmHg) blood pressure ( P ≥ 0.37). Conclusion: In individuals without obesity, CR-induced improvements in multiple cardiometabolic risk markers are driven by weight loss after 2 years. These findings emphasize that, even in individuals without obesity, weight loss after prolonged CR plays a role in improving cardiometabolic disease risk; however, some CR benefits still occur independent of weight loss.

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.

Contribution of Changes in Body Composition and Adaptive Thermogenesis to the Decline in Resting Metabolic Rate During Prolonged Calorie‐Restricted Weight Loss

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.ObjectiveTo 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.MethodsSecondary 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.ResultsAfter 12 months, mean weight loss was 7.9 ± 0.3 kg (−10.9 ± 0.4%, p&lt;0.001 vs. baseline), and RMR declined by 101 ± 11 kcal/d (−6.8 ± 0.8%, p&lt;0.001 vs. baseline). Individuals who lost the most weight (Q1ΔBW) demonstrated a greater RMR decline than individuals who lost the least weight (Q4ΔBW, p&lt;0.01). The change in RMR did not differ between quartiles based on fat free mass loss (p=0.15), but it was positively associated with the amount of fat loss (p=0.03). In addition, participants who lost the greatest amount of fat mass (Q1ΔFM) exhibited a more pronounced adaptive thermogenic effect (−79 ± 19 kcal/d) than participants with the least amount of fat loss (Q4ΔFM; −10 ± 26 kcal/d, p&lt;0.05 vs. Q1ΔFM). Adaptive thermogenesis was correlated with declines in leptin (r=0.27, p&lt;0.01), T3 (r=0.19, p &lt; 0.05), and insulin (r=0.25, p&lt;0.05).ConclusionsDuring weight loss, the loss of fat mass and adaptive thermogenesis appear to be stronger predictors of RMR decline when compared to the loss of fat‐free mass.Support or Funding InformationThis work was funded in part by the University of Nebraska‐Lincoln McNair Scholars Program and the Undergraduate Creative Activities and Research Experience.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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.

Metabolomics and Lipidomics Analysis of the NIA CALERIE Trial

Calorie Restriction (CR) is the most potent, robust, and reproducible known means of extending longevity and decreasing morbidity in a vast range of animal species short of primates. Despite 80 years of research, the relevance of this observation for humans remains unknown. Relevance is supported by the established link between obesity and morbidity in humans, and the health status of individuals voluntarily participating in a caloric restricted lifestyle. Other potential linkages are being directly studied in the NIA/NIH‐sponsored CALERIE (Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy) clinical trial. CALERIE enrolled 238 individuals and collected blood samples at 6 time points over 24 months. We previously examined metabolomics (via HPLC separation with coulometric electrode array‐based detection) and lipidomics (via high resolution LC‐MS‐based lipidomics) effects of the CALERIE intervention and compared these data to those previously obtained in studies of ad libitum fed and calorically restricted FBFN1 rats (males/females, different ages and extents and durations of CR). The results were, surprisingly, nearly completely negative. Retrospective Post‐Hoc analyses identified three potential reasons for these negative findings. First the original trial and our analyses intended to strictly follow trial design (i.e., intention to treat analysis), were powered for a 25% drop in caloric intake – a larger and more consistent goal than was obtained. Second, many individuals on the low calorie diet intervention lost weight in year one but gained in year two – a shift in caloric balance for which our analyses initially were, again in accordance with an intent‐to‐treat design, unprepared to compensate. Third, and most important, we determined that exposure of the forearm to high temperatures prior to some phlebotomy (termed “hot‐box”) time points — which was essential to assess one listed secondary clinical outcome of the trial — destroyed self‐similarity for our measures, rendering the baseline sample unusable for our standard normalization and control methods. Correcting for this revealed some of the expected biological/biochemical differences and provided a potentially interesting signal related to altered stress response in relationship to some aspect of caloric intake, obesity, and/or energy expenditure, consistent with the cognate literature in animal models of normal and delayed aging. We will discuss the results, the implication for metabolomics and lipidomics studies, and initial, promising re‐analysis of these CALERIE data.Support or Funding InformationNIA/NIH

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 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.

Longevity Research Focuses on Inside and Outside Influences

WASHINGTON – Despite years of research and therapy advances, the keys to longevity remain elusive. While people are living longer today, many questions remain about the role of genetics, caloric restriction, stress reduction, social engagement, environmental changes, and other factors found among many of the “oldest old.” In a presentation to the American Society of Consultant Pharmacists recent annual meeting, Dr. Marie Bernard, deputy director of the National Institute on Aging (NIA), discussed emerging and sometimes surprising fi ndings from the latest research on aging. For one, obesity is increasing in the elderly. While weight loss traditionally has been health professionals’ major concern for frail seniors, data now indicate that obesity has grown 10% in the past 20 years among whites aged 65 and older and nearly 20% among elderly African Americans. More people are becoming obese as they age, and obese people are living longer, Dr. Bernard observed. “We’re successfully treating blood pressure, diabetes, and heart problems, and obese people are living longer. This suggests that [systems of care for elderly people] will have a real challenge as we move forward.” There will have to be an unprecedented emphasis on healthy diets and physical activity in the elderly population, she said. On the other hand, Dr. Bernard said that studies are leavening early excitement about caloric restriction potentially prolonging lives. Specifi cally, a recent 25-year study of rhesus monkeys showed that genetics and the composition of the animals’ diets contributed more to longevity than did a low-calorie diet per se. Dr. Bernard didn’t discount the potential advantages of calorie restriction in healthy adults. She pointed to the ongoing CALERIE (Comprehensive Assessment of Long-term Eff ects of Reducing Intake of Energy) study, whose early results showed that people who reduced caloric intake by 25% for 6 months lowered their insulin resistance, low-density lipoprotein cholesterol, body temperature, and oxidative damage to DNA. She noted that there is still much to learn about the impact of diet and calories on longevity. Dr. Bernard also updated her listeners on studies of telomeres, the chromosome end segments whose degradation has been tied to various aspects of physical decline. Researchers have found a link between living to 100 and inheriting a type of enzyme that rebuilds telomeres, she said. Other research has linked telomere decay and stress. “One could postulate that reducing stress can help retain telomeres” and contribute to healthy aging, she said. CfA