The CALERIE™ Legacy Study

Study Overview
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Brief Summary
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The purpose of the CALERIE Legacy Study is to follow up on the health and wellness of participants from phase 2 of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, which was conducted from 2007 to 2011.

Detailed Description
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The CALERIE Legacy Study is an observational follow-up study of participants from phase 2 the CALERIE trial, the first randomized controlled trial of calorie restriction (CR) in humans without obesity. The overarching goal of the CALERIE Legacy Study is to examine whether two years of CR results in sustained improvements in the biological, phenotypic, and functional hallmarks of human aging 10 to 15 years after the structured intervention. Participants will complete clinical assessments, dietary recalls, and questionnaires, and laboratory evaluations will be performed on blood and urine samples. The study also includes an optional biospecimen banking component.

Official Title
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Legacy Effects of CALERIE™, a 2-year Calorie Restriction Intervention, on Hallmarks of Healthspan and Aging

Conditions
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Calorie Restriction

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Enrolled in the CALERIE trial and started their allocated group (CR intervention or ad libitum control condition) Willing and able to attend one of the clinical sites for an in-person visit and provide informed consent Exclusion Criteria: Pregnant women Women less than 12 months postpartum Documented note from the CALERIE trial indicating that the subject should not be contacted or requested not to be contacted for future research Diagnosed active cancer or terminal illness

Ages Eligible for Study
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Minimum Age: 33 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Calorie Restriction (CR)<br>Individuals in the CR group were prescribed a 25% reduction from their baseline energy intake during the two-year CALERIE trial. | |
| Ad Libitum (AL)<br>Individuals in the AL group were asked to continue their usual dietary intake during the two-year CALERIE trial. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biological age - Klemera-Doubal Method | Biological age will be quantified by the Klemera-Doubal Method (KDM), an algorithm-based measure. Biological age is expressed in years. | 10-15 years post CALERIE trial | 
| Biological age - Homeostatic Dysregulation | Biological age will be quantified by homeostatic dysregulation, an algorithm-based measure. Biological age is expressed in years. | 10-15 years post CALERIE trial | 
| Biological age - Levine Phenotypic Age | Biological age will be quantified by Levine Phenotypic Age, an algorithm-based measure. Biological age is expressed in years. | 10-15 years post CALERIE trial | 
| Healthspan | Healthspan will be assessed by sex-specific metabolic syndrome score (MSS). MSS was developed using mean blood pressure (MBP; = [2 × diastolic blood pressure + systolic blood pressure]/3), high density lipoprotein cholesterol (HDL), triglycerides (TG), waist circumference (WC), and fasting blood glucose (FBG): Women: MSS = [45-HDL]/SDHDLW+ [TG-150]/SDTG + [WC-88]/SDWCW + [FBG-100]/SDFBG + [mean BP-100]/SDMBP Men: MSS = [40-HDL]/SDHDLW+ [TG-150]/SDTG + [WC-102]/SDWCW + [FBG-100]/SDFBG + [mean BP-100]/SDMBP This score does not have a unit. | 10-15 years post CALERIE trial | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Height | Height will be measured in cm. | 10-15 years post CALERIE trial | 
| Weight | Weight will be measured in kg. | 10-15 years post CALERIE trial | 
| Waist circumference | Weight circumference will be measured in cm. | 10-15 years post CALERIE trial | 
| Hip circumference | Hip circumference will be measured in cm. | 10-15 years post CALERIE trial | 
| Body mass index (BMI) | BMI (kg/m2) will be calculated using height and weight measurements. | 10-15 years post CALERIE trial | 
| Blood pressure | Systolic and diastolic blood pressure will be measured in mmHg. | 10-15 years post CALERIE trial | 
| Pulse rate at rest | Pulse rate will be measured in beats/min. | 10-15 years post CALERIE trial | 
| Respiration rate at rest | Respiration rate will be measured in breaths/min. | 10-15 years post CALERIE trial | 
| Fat mass | Whole-body fat mass (%) as measured by dual-energy X-ray absorptiometry. | 10-15 years post CALERIE trial | 
| Fat-free mass | Whole-body fat-free mass (%) as measured by dual-energy X-ray absorptiometry. | 10-15 years post CALERIE trial | 
| Bone mineral content | Whole-body bone mineral content (g/cm2) as measured by dual-energy X-ray absorptiometry. | 10-15 years post CALERIE trial | 
| Resting metabolic rate (RMR) | RMR will be measured in kcal/d by indirect calorimetry using a ventilated hood system. | 10-15 years post CALERIE trial | 
| Respiratory quotient (RQ) | RQ will be measured by indirect calorimetry using a ventilated hood system. This is a ratio and does not have a unit. | 10-15 years post CALERIE trial | 
| Maximal aerobic capacity (V̇O2max) | Maximal aerobic capacity (V̇O2max) will be measured in mL/kg/min using the Cornell incremental treadmill test. | 10-15 years post CALERIE trial | 
| Interleukin-6 (IL-6) | IL-6, a blood-based biomarker of aging proposed by the Targeting Aging with MEtformin (TAME) Biomarkers Workgroup, will be measured in pg/mL. | 10-15 years post CALERIE trial | 
| Insulin - TAME panel | Insulin, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in μIU/mL. | 10-15 years post CALERIE trial | 
| Insulin - 0 min (OGTT) | Insulin (μIU/mL) will be measured at 0 minutes (pre-dose) during an oral glucose tolerance test (OGTT) to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Insulin - 30 min (OGTT) | Insulin (μIU/mL) will be measured at 30 minutes post dose during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Insulin - 60 min (OGTT) | Insulin (μIU/mL) will be measured at 60 minutes post dose during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Insulin - 90 min (OGTT) | Insulin (μIU/mL) will be measured at 90 minutes post dose during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Insulin - 120 min (OGTT) | Insulin (μIU/mL) will be measured at 120 minutes post dose during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Insulin-like growth factor 1 (IGF-1) | IGF-1, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Hemoglobin A1c (HbA1c) | HbA1c, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in mmol/mol. | 10-15 years post CALERIE trial | 
| Tumor necrosis factor α receptor II (TNFRII) | TNFRII, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| High-sensitivity C-reactive protein (hsCRP) | hsCRP, a blood-based biomarker of inflammation, will be measured in μg/mL. | 10-15 years post CALERIE trial | 
| Growth/differentiation factor 15 (GDF15) | GDF15, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in pg/mL. | 10-15 years post CALERIE trial | 
| Cystatin C | Cystatin C, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in mg/L. | 10-15 years post CALERIE trial | 
| N-terminal B-type natriuretic peptide (NT-proBNP) | NT-proBNP, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in pg/mL. | 10-15 years post CALERIE trial | 
| Senescence-associated secretory phenotype (SASP) proteins | SASP proteins, blood-based biomarkers of cellular senescence, will be measured using a SASP panel. | 10-15 years post CALERIE trial | 
| Urinary Isoprostanes - iPF(2α)-III | Urinary iPF(2α)-III, a biomarker of systemic oxidative stress, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Urinary Isoprostanes - 2,3-dinor-iPF(2α)-III | Urinary 2,3-dinor-iPF(2α)-III, a biomarker of systemic oxidative stress, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Urinary Isoprostanes - iPF(2α)-VI | Urinary iPF(2α)-VI, a biomarker of systemic oxidative stress, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Urinary Isoprostanes - 8,12-iso-iPF(2α)-VI | Urinary 8,12-iso-iPF(2α)-VI, a biomarker of systemic oxidative stress, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Creatinine | Creatinine, a byproduct of routine activity in the muscle, will be measured in urine in mg/mL. | 10-15 years post CALERIE trial | 
| Dehydroepiandrosterone (DHEA) | DHEA, a blood-based steroid hormone, will be measured in μg/dL. | 10-15 years post CALERIE trial | 
| Interleukin 1 beta (IL-1b) | IL-1b, a blood-based marker of inflammation, will be measured in pg/mL. | 10-15 years post CALERIE trial | 
| Interleukin 8 (IL-8) | IL-8, a blood-based marker of inflammation, will be measured in pg/mL. | 10-15 years post CALERIE trial | 
| Tumor necrosis factor α (TNF-α) | TNF-α, a blood-based marker of inflammation, will be measured in pg/mL. | 10-15 years post CALERIE trial | 
| Insulin-like growth factor-binding protein 1 (IGFBP-1) | IGFBP-1, a blood-based transport protein, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Transforming growth factor beta 1 (TGFB1) | TGFB1, a blood-based marker of immune function, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Insulin-like growth factor-binding protein 3 (IGFBP-3) | IGFBP-3, a blood-based transport protein, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Platelet-derived growth factor-AB (PDGF-AB) | PDGF-AB, a blood-based marker of cellular function, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Intercellular Adhesion Molecule 1 (ICAM-1) | ICAM-1, a blood-based marker of inflammation, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Growth hormone | Growth hormone, a blood-based bio-marker of cellular function, will be measured in ng/mL. | 10-15 years post CALERIE trial | 
| Monocyte Chemoattractant Protein 1 (MCP1) | MCP1, a blood-based marker of inflammation, will be measured in pg/mL. | 10-15 years post CALERIE trial | 
| Leptin | Leptin, a hormonal regulator of energy balance, will be measured in pg/mL. | 10-15 years post CALERIE trial | 
| Total adiponectin | Total adiponectin, a protein hormone that regulates several metabolic processes, including glucose regulation and fatty acid oxidation, will be measured in μg/mL. | 10-15 years post CALERIE trial | 
| High molecular weight adiponectin | High molecular weight adiponectin, a protein hormone that regulates several metabolic processes, including glucose regulation and fatty acid oxidation, will be measured in μg/mL. | 10-15 years post CALERIE trial | 
| Muscle strength - Knee extension (60°) | Knee extension at 60 degrees per second will be expressed in Nm. | 10-15 years post CALERIE trial | 
| Muscle strength - Knee extension (180°) | Knee extension at 180 degrees per second will be expressed in Nm. | 10-15 years post CALERIE trial | 
| Muscle strength - Knee flexion (60°) | Knee flexion at 60 degrees per second will be expressed in Nm. | 10-15 years post CALERIE trial | 
| Muscle strength - Knee flexion (180°) | Knee flexion at 180 degrees per second will be expressed in Nm. | 10-15 years post CALERIE trial | 
| Physical functioning | Physical functioning as measured by a physical performance battery. This physical performance battery provides a composite score ranging from 0 to 12 and includes results from the balance, gait and chair stand tests. | 10-15 years post CALERIE trial | 
| Cognition | Cognition as measured by the Cambridge Neuropsychological Test Automated Battery (CANTAB). The CANTAB evaluates six main areas of cognitive function: reaction time; verbal recognition memory; intra-extra dimensional set shift; rapid visual information processing; delayed matching to sample; and spatial working memory. | 10-15 years post CALERIE trial | 
| Dietary intake- calories | Dietary intake in calories (kcals/day), as measured by multiple-pass 24-hour dietary recalls and Nutrition Data System for Research (NDSR) software. | 10-15 years post CALERIE trial | 
| Dietary intake - carbohydrates | Dietary carbohydrate as % of energy or grams will be measured by multiple-pass 24-hour dietary recalls and Nutrition Data System for Research (NDSR) software. | 10-15 years post CALERIE trial | 
| Dietary intake - proteins | Dietary proteins as % of energy or grams will be measured by multiple-pass 24-hour dietary recalls and Nutrition Data System for Research (NDSR) software. | 10-15 years post CALERIE trial | 
| Health-related quality of life | Quality of life as measured by the RAND 36-Item Short Form Survey (SF-36). The RAND SF-36 measures eight aspects of health: physical functioning, role limitations due to physical health problems, role limitations due to personal or emotional problems, energy/fatigue, emotional well-being, social functioning, bodily pain, and general health perceptions. It also includes a single item that provides an indication of perceived change in health. Each item is on a 3- or 5-point Likert scale (1-3 or 1-5). Each response is transformed to a recoded value of 0-100, and the transformed scores of the 9 subscales are averaged to derive a composite score. Higher scores indicate more favorable health states. | 10-15 years post CALERIE trial | 
| Depression status | Depression status as measured by the Beck Depression Inventory II (BDI-II). The 21-item BDI-II measures depression severity. The score range is 0-63, with higher scores indicating greater depression severity. Nineteen items are on a 4-point Likert scale (0-3). Two items are on a 7-point Likert scale, and responses are scaled to 0-3. The values are summed to calculate the total score. | 10-15 years post CALERIE trial | 
| Mood | Mood as measured by the Profile of Mood States Second Edition (POMS 2). The POMS 2 assesses six mood subscales using 65 items, each on a 5-point Likert scale (0-4): tension-anxiety (9 items, score range 0-36), depression-dejection (15 items, range 0-60), anger-hostility (12 items, range 0-48), vigor-activity (8 items, range 0-32), fatigue-inertia (7 items, range 0-28), and confusion-bewilderment (7 items, range 0-28). High vigor-activity scores reflect a good mood or emotion, and low scores in the other subscales reflect a good mood or emotion. Total mood disturbance, which is calculated by subtracting the vigor subscale score from the total subscale score (range 0-200), also will be assessed. | 10-15 years post CALERIE trial | 
| Sleep | Sleep as measured by the Pittsburgh Sleep Quality Index (PSQI). The PSQI measures sleep quality and disturbance over the course of one month using seven subscales: subjective sleep quality; sleep latency; sleep duration; habitual sleep efficiency; sleep disturbances; use of sleeping medication; and daytime dysfunction. The scoring range of each subscale is 0-3. The scoring range of the Global PSQI (the composite score of the seven subscales) is 0-21. For both the subscales and Global PSQI, higher scores indicate greater difficulties with sleeping. | 10-15 years post CALERIE trial | 
| Sexual function | Sexual function as measured by the Derogatis Interview for Sexual Functioning - Self Report (DISF-SR). Both versions of the DISF-SR (male and female) are scored from 20 to 75, with higher scores indicating higher sexual functioning. | 10-15 years post CALERIE trial | 
| Food cravings | Food cravings as measured by the Food Cravings Questionnaire-Trait (FCQ-T). The FCQ-T measures frequency and intensity of food cravings. It has 39 items on a 6-point Likert scale (1-6) and a score range of 39-234. Higher scores indicate more frequent and intense food cravings. Scores on all items are summed for a total score. | 10-15 years post CALERIE trial | 
| Dietary restraint, disinhibition, and hunger | Dietary restraint, disinhibition, and hunger as measured by the Three-Factor Eating Questionnaire (TFEQ). The 51-item TFEQ will be used to measure dietary restraint (21 items), disinhibition (16 items), and hunger (14 items). Item responses are scored as 0 or 1 and summed. Higher scores indicate higher levels of restrained eating (range 0-21), disinhibited eating (range 0-16), and predisposition to hunger (range 0-14). | 10-15 years post CALERIE trial | 
| Disordered eating | Disordered eating as measured by the Multiaxial Assessment of Eating Disorder Symptoms (MAEDS). MAEDS will be used to assess six domains of disordered eating: binge eating (range 8-56), restrictive eating (range 9-63), purgative behavior (range 7-49), fear of fatness (range 11-77), avoidance of forbidden foods (range 10-70), and depression (range 11-77). | 10-15 years post CALERIE trial | 
| Body shape perceptions | Body shapes perceptions as measured by the Body Shape Questionnaire (BSQ). Items on the BSQ are rated on a 6-point Likert-type scale. The score ranges from 34-204 points. Higher scores indicate increased concern regarding body shape. | 10-15 years post CALERIE trial | 
| Physical activity | Physical activity as measured by the 7-Day Stanford Physical Activity Recall (PAR). The PAR estimates an individual's time spent in sleep and physical activity for the 7 days prior to the interview. Energy expenditure based on time spent in sleep and physical activities can be estimated. Sub-scores of energy expenditure for each of the following activities are calculated, summed, and averaged to estimate energy expenditure as kilocalories per day: sleep, moderate physical activity, hard physical activity, and very hard physical activity. Higher scores indicate greater physical activity per day. Metabolic equivalent (MET) value for each activity is provided: 1 MET for sleep, 4 METs for moderate activity, 6 METs for hard activity, and 10 METs for very hard activity. Time spent in each activity over 7 days is multiplied by the appropriate MET value. The minimum value for each activity is zero; there is no maximum value. | 10-15 years post CALERIE trial | 
| Resilience | Resilience as measured by the 25-item Connor-Davidson Resilience Scale (CD-RISC-25). CD-RISC-25 is scored from 0 to 100, with higher scores indicating higher resilience. | 10-15 years post CALERIE trial | 
| Total cholesterol | Total cholesterol will be measured in mg/dL using a standard lipid panel. | 10-15 years post CALERIE trial | 
| High-density lipoprotein cholesterol (HDL-C) | HDL-C will be measured in mg/dL using a standard lipid panel. | 10-15 years post CALERIE trial | 
| Triglycerides | Triglycerides will be measured in mg/dL using a standard lipid panel. | 10-15 years post CALERIE trial | 
| Low-density lipoprotein cholesterol (LDL-C) | LDL-C will be calculated in mg/dL using measured values of total cholesterol, HDL-C, and triglycerides. | 10-15 years post CALERIE trial | 
| Glucose - 0 min (OGTT) | Glucose (mg/dL) will be measured at 0 minutes (pre-dose) during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Glucose - 30 min (OGTT) | Glucose (mg/dL) will be measured at 30 minutes post dose during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Glucose - 60 min (OGTT) | Glucose (mg/dL) will be measured at 60 minutes post dose during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Glucose - 90 min (OGTT) | Glucose (mg/dL) will be measured at 90 minutes post dose during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Glucose - 120 min (OGTT) | Glucose (mg/dL) will be measured at 120 minutes post dose during an OGTT to evaluate glucoregulatory response. | 10-15 years post CALERIE trial | 
| Insulin resistance | Insulin resistance will be calculated using the Homeostatic Model Assessment (HOMA) and measured values of fasting glucose (mmol/L) and fasting insulin (μ/L): (fasting glucose × fasting insulin) ∕ 22.5 | 10-15 years post CALERIE trial | 
| Beta-cell function | Beta-cell function will be calculated using HOMA-β and measures of fasting insulin (μ/L) and fasting glucose (mg/dL): HOMA-β (%) = (360 × fasting insulin) ∕ (fasting glucose - 63) | 10-15 years post CALERIE trial | 
| Triiodothyronine (T3) | T3, a blood-based marker of thyroid function, will be measured in ng/dL. | 10-15 years post CALERIE trial | 
| Thyroxine (T4) | T4, a blood-based marker of thyroid function, will be measured in ng/dL. | 10-15 years post CALERIE trial | 
| Thyroid stimulating hormone (TSH) | TSH, a blood-based marker of thyroid function, will be measured in μIU/mL. | 10-15 years post CALERIE trial | 
| Alkaline phosphatase (ALKP) | ALKP, a blood-based marker of liver function, will be measured in IU/L. | 10-15 years post CALERIE trial | 
| Alanine transaminase (ALT) | ALT, a blood-based marker of liver function, will be measured in U/L. | 10-15 years post CALERIE trial | 
| Aspartate aminotransferase (AST) | AST, a blood-based marker of liver function, will be measured in U/L. | 10-15 years post CALERIE trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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calorie restriction, dietary intervention, biological aging, behavioral data