The CALERIE™ Legacy Study

Recruiting

• Conditions: Calorie Restriction

• Registration Number: NCT05651620
• Lead Sponsor: Tufts University

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2022-09-01
• Study First Submitted QC: 2022-12-06
• Study First Posted: 2022-12-15
• Study Start: 2023-04-06
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-20
• Last Update Posted: 2024-03-22
• Primary Completion: 2025-12-31
• Study Completion: 2026-01-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 216

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

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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

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Biological age - Klemera-Doubal Method	10-15 years post CALERIE trial	Biological age will be quantified by the Klemera-Doubal Method (KDM), an algorithm-based measure. Biological age is expressed in years.
Biological age - Homeostatic Dysregulation	10-15 years post CALERIE trial	Biological age will be quantified by homeostatic dysregulation, an algorithm-based measure. Biological age is expressed in years.
Healthspan	10-15 years post CALERIE trial	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.
Biological age - Levine Phenotypic Age	10-15 years post CALERIE trial	Biological age will be quantified by Levine Phenotypic Age, an algorithm-based measure. Biological age is expressed in years.

Secondary Outcome Measures

Name	Time	Method
Phosphorus (P)	10-15 years post CALERIE trial	Phosphorus, a blood-based mineral, will be measured in mg/dL.
Sodium (Na+)	10-15 years post CALERIE trial	Sodium, an electrolyte that reflects the body's fluid balance, will be measured in meq/L.
Waist circumference	10-15 years post CALERIE trial	Weight circumference will be measured in cm.
Hip circumference	10-15 years post CALERIE trial	Hip circumference will be measured in cm.
Blood pressure	10-15 years post CALERIE trial	Systolic and diastolic blood pressure will be measured in mmHg.
Pulse rate at rest	10-15 years post CALERIE trial	Pulse rate will be measured in beats/min.
Fat mass	10-15 years post CALERIE trial	Whole-body fat mass (%) as measured by dual-energy X-ray absorptiometry.
Insulin - 90 min (OGTT)	10-15 years post CALERIE trial	Insulin (μIU/mL) will be measured at 90 minutes post dose during an OGTT to evaluate glucoregulatory response.
Insulin - 120 min (OGTT)	10-15 years post CALERIE trial	Insulin (μIU/mL) will be measured at 120 minutes post dose during an OGTT to evaluate glucoregulatory response.
Hemoglobin A1c (HbA1c)	10-15 years post CALERIE trial	HbA1c, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in mmol/mol.
Resting metabolic rate (RMR)	10-15 years post CALERIE trial	RMR will be measured in kcal/d by indirect calorimetry using a ventilated hood system.
Insulin-like growth factor 1 (IGF-1)	10-15 years post CALERIE trial	IGF-1, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in ng/mL.
Growth/differentiation factor 15 (GDF15)	10-15 years post CALERIE trial	GDF15, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in pg/mL.
Monocyte Chemoattractant Protein 1 (MCP1)	10-15 years post CALERIE trial	MCP1, a blood-based marker of inflammation, will be measured in pg/mL.
Dietary intake- calories	10-15 years post CALERIE trial	Dietary intake in calories (kcals/day), as measured by multiple-pass 24-hour dietary recalls and Nutrition Data System for Research (NDSR) software.
Dietary intake - carbohydrates	10-15 years post CALERIE trial	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.
Weight	10-15 years post CALERIE trial	Weight will be measured in kg.
Body mass index (BMI)	10-15 years post CALERIE trial	BMI (kg/m2) will be calculated using height and weight measurements.
Respiration rate at rest	10-15 years post CALERIE trial	Respiration rate will be measured in breaths/min.
Fat-free mass	10-15 years post CALERIE trial	Whole-body fat-free mass (%) as measured by dual-energy X-ray absorptiometry.
Maximal aerobic capacity (V̇O2max)	10-15 years post CALERIE trial	Maximal aerobic capacity (V̇O2max) will be measured in mL/kg/min using the Cornell incremental treadmill test.
Insulin - TAME panel	10-15 years post CALERIE trial	Insulin, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in μIU/mL.
Insulin - 0 min (OGTT)	10-15 years post CALERIE trial	Insulin (μIU/mL) will be measured at 0 minutes (pre-dose) during an oral glucose tolerance test (OGTT) to evaluate glucoregulatory response.
Insulin - 30 min (OGTT)	10-15 years post CALERIE trial	Insulin (μIU/mL) will be measured at 30 minutes post dose during an OGTT to evaluate glucoregulatory response.
High-sensitivity C-reactive protein (hsCRP)	10-15 years post CALERIE trial	hsCRP, a blood-based biomarker of inflammation, will be measured in μg/mL.
Interleukin 8 (IL-8)	10-15 years post CALERIE trial	IL-8, a blood-based marker of inflammation, will be measured in pg/mL.
Insulin-like growth factor-binding protein 1 (IGFBP-1)	10-15 years post CALERIE trial	IGFBP-1, a blood-based transport protein, will be measured in ng/mL.
Respiratory quotient (RQ)	10-15 years post CALERIE trial	RQ will be measured by indirect calorimetry using a ventilated hood system. This is a ratio and does not have a unit.
Cystatin C	10-15 years post CALERIE trial	Cystatin C, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in mg/L.
Senescence-associated secretory phenotype (SASP) proteins	10-15 years post CALERIE trial	SASP proteins, blood-based biomarkers of cellular senescence, will be measured using a SASP panel.
Urinary Isoprostanes - iPF(2α)-III	10-15 years post CALERIE trial	Urinary iPF(2α)-III, a biomarker of systemic oxidative stress, will be measured in ng/mL.
Urinary Isoprostanes - iPF(2α)-VI	10-15 years post CALERIE trial	Urinary iPF(2α)-VI, a biomarker of systemic oxidative stress, will be measured in ng/mL.
Interleukin 1 beta (IL-1b)	10-15 years post CALERIE trial	IL-1b, a blood-based marker of inflammation, will be measured in pg/mL.
Leptin	10-15 years post CALERIE trial	Leptin, a hormonal regulator of energy balance, will be measured in pg/mL.
Total adiponectin	10-15 years post CALERIE trial	Total adiponectin, a protein hormone that regulates several metabolic processes, including glucose regulation and fatty acid oxidation, will be measured in μg/mL.
Handgrip Strength	10-15 years post CALERIE trial	Handgrip strength will be measured via a hand dynamometer and expressed in kg.
Cognition	10-15 years post CALERIE trial	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.
Dietary restraint, disinhibition, and hunger	10-15 years post CALERIE trial	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).
Total cholesterol	10-15 years post CALERIE trial	Total cholesterol will be measured in mg/dL using a standard lipid panel.
Glucose - 30 min (OGTT)	10-15 years post CALERIE trial	Glucose (mg/dL) will be measured at 30 minutes post dose during an OGTT to evaluate glucoregulatory response.
Triiodothyronine (T3)	10-15 years post CALERIE trial	T3, a blood-based marker of thyroid function, will be measured in ng/dL.
Alanine transaminase (ALT)	10-15 years post CALERIE trial	ALT, a blood-based marker of liver function, will be measured in U/L.
Total Proteins	10-15 years post CALERIE trial	Total proteins is a measurement sum of albumin and globulin. Total proteins is indicative of blood vessel and immune system function. It will be measured in g/dL.
Bilirubin	10-15 years post CALERIE trial	Bilirubin, a blood-based marker of liver function, will be measured in mg/dL.
Height	10-15 years post CALERIE trial	Height will be measured in cm.
Bone mineral content	10-15 years post CALERIE trial	Whole-body bone mineral content (g/cm2) as measured by dual-energy X-ray absorptiometry.
Interleukin-6 (IL-6)	10-15 years post CALERIE trial	IL-6, a blood-based biomarker of aging proposed by the Targeting Aging with MEtformin (TAME) Biomarkers Workgroup, will be measured in pg/mL.
Insulin - 60 min (OGTT)	10-15 years post CALERIE trial	Insulin (μIU/mL) will be measured at 60 minutes post dose during an OGTT to evaluate glucoregulatory response.
Tumor necrosis factor α receptor II (TNFRII)	10-15 years post CALERIE trial	TNFRII, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in ng/mL.
Creatinine	10-15 years post CALERIE trial	Creatinine, a byproduct of routine activity in the muscle, will be measured in urine in mg/mL.
Dehydroepiandrosterone (DHEA)	10-15 years post CALERIE trial	DHEA, a blood-based steroid hormone, will be measured in μg/dL.
Tumor necrosis factor α (TNF-α)	10-15 years post CALERIE trial	TNF-α, a blood-based marker of inflammation, will be measured in pg/mL.
Insulin-like growth factor-binding protein 3 (IGFBP-3)	10-15 years post CALERIE trial	IGFBP-3, a blood-based transport protein, will be measured in ng/mL.
Muscle strength - Knee flexion (60°)	10-15 years post CALERIE trial	Knee flexion at 60 degrees per second will be expressed in Nm.
Physical functioning	10-15 years post CALERIE trial	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.
Dietary intake - proteins	10-15 years post CALERIE trial	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.
Depression status	10-15 years post CALERIE trial	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.
N-terminal B-type natriuretic peptide (NT-proBNP)	10-15 years post CALERIE trial	NT-proBNP, a blood-based biomarker of aging proposed by the TAME Biomarkers Workgroup, will be measured in pg/mL.
Urinary Isoprostanes - 2,3-dinor-iPF(2α)-III	10-15 years post CALERIE trial	Urinary 2,3-dinor-iPF(2α)-III, a biomarker of systemic oxidative stress, will be measured in ng/mL.
Urinary Isoprostanes - 8,12-iso-iPF(2α)-VI	10-15 years post CALERIE trial	Urinary 8,12-iso-iPF(2α)-VI, a biomarker of systemic oxidative stress, will be measured in ng/mL.
Platelet-derived growth factor-AB (PDGF-AB)	10-15 years post CALERIE trial	PDGF-AB, a blood-based marker of cellular function, will be measured in ng/mL.
Growth hormone	10-15 years post CALERIE trial	Growth hormone, a blood-based bio-marker of cellular function, will be measured in ng/mL.
High molecular weight adiponectin	10-15 years post CALERIE trial	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.
Muscle strength - Knee extension (180°)	10-15 years post CALERIE trial	Knee extension at 180 degrees per second will be expressed in Nm.
Muscle strength - Knee flexion (180°)	10-15 years post CALERIE trial	Knee flexion at 180 degrees per second will be expressed in Nm.
Health-related quality of life	10-15 years post CALERIE trial	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.
Transforming growth factor beta 1 (TGFB1)	10-15 years post CALERIE trial	TGFB1, a blood-based marker of immune function, will be measured in ng/mL.
Intercellular Adhesion Molecule 1 (ICAM-1)	10-15 years post CALERIE trial	ICAM-1, a blood-based marker of inflammation, will be measured in ng/mL.
Muscle strength - Knee extension (60°)	10-15 years post CALERIE trial	Knee extension at 60 degrees per second will be expressed in Nm.
Sexual function	10-15 years post CALERIE trial	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.
Body shape perceptions	10-15 years post CALERIE trial	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.
Insulin resistance	10-15 years post CALERIE trial	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
Beta-cell function	10-15 years post CALERIE trial	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)
Potassium (K+)	10-15 years post CALERIE trial	Potassium, an electrolyte that reflects the body's fluid balance, will be measured in meq/L.
Mood	10-15 years post CALERIE trial	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.
High-density lipoprotein cholesterol (HDL-C)	10-15 years post CALERIE trial	HDL-C will be measured in mg/dL using a standard lipid panel.
Low-density lipoprotein cholesterol (LDL-C)	10-15 years post CALERIE trial	LDL-C will be calculated in mg/dL using measured values of total cholesterol, HDL-C, and triglycerides.
Glucose - 0 min (OGTT)	10-15 years post CALERIE trial	Glucose (mg/dL) will be measured at 0 minutes (pre-dose) during an OGTT to evaluate glucoregulatory response.
Sleep	10-15 years post CALERIE trial	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.
Food cravings	10-15 years post CALERIE trial	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.
Disordered eating	10-15 years post CALERIE trial	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).
Physical activity	10-15 years post CALERIE trial	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.
Glucose - 60 min (OGTT)	10-15 years post CALERIE trial	Glucose (mg/dL) will be measured at 60 minutes post dose during an OGTT to evaluate glucoregulatory response.
Glucose - 120 min (OGTT)	10-15 years post CALERIE trial	Glucose (mg/dL) will be measured at 120 minutes post dose during an OGTT to evaluate glucoregulatory response.
Thyroid stimulating hormone (TSH)	10-15 years post CALERIE trial	TSH, a blood-based marker of thyroid function, will be measured in μIU/mL.
Albumin	10-15 years post CALERIE trial	Albumin, a blood-based marker of liver and kidney function, will be measured in g/dL.
Albumin/Globulin (A/G) ratio	10-15 years post CALERIE trial	A/G ratio is a blood-based marker used to monitor nutritional status and immune system, kidney, and liver function. This marker is a ratio, and therefore does not have units.
Resilience	10-15 years post CALERIE trial	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.
Triglycerides	10-15 years post CALERIE trial	Triglycerides will be measured in mg/dL using a standard lipid panel.
Glucose - 90 min (OGTT)	10-15 years post CALERIE trial	Glucose (mg/dL) will be measured at 90 minutes post dose during an OGTT to evaluate glucoregulatory response.
Thyroxine (T4)	10-15 years post CALERIE trial	T4, a blood-based marker of thyroid function, will be measured in ng/dL.
Alkaline phosphatase (ALKP)	10-15 years post CALERIE trial	ALKP, a blood-based marker of liver function, will be measured in IU/L.
Aspartate aminotransferase (AST)	10-15 years post CALERIE trial	AST, a blood-based marker of liver function, will be measured in U/L.
Blood Urea Nitrogen (BUN)	10-15 years post CALERIE trial	BUN, a blood-based marker of kidney function, will be measured in mg/dL.
Uric Acid	10-15 years post CALERIE trial	Uric acid, a blood-based marker of purine metabolism, will be measured in mg/dL.
Calcium (Ca)	10-15 years post CALERIE trial	Calcium, a blood-based mineral, will be measured in mg/dL.
Creatine Phosphokinase (CPK)	10-15 years post CALERIE trial	CPK, an enzyme marker of energy homeostasis, will be measured in U/L.
Lactate Dehydrogenase (LDH)	10-15 years post CALERIE trial	LDH, an enzyme marker of liver function, will be measured in U/L.
Globulin	10-15 years post CALERIE trial	Globulin, a blood-based marker of liver function, will be measured in g/dL.
Magnesium (Mg)	10-15 years post CALERIE trial	Magnesium, a blood-based mineral, will be measured in meq/L.
Apoprotein A1	10-15 years post CALERIE trial	Apoprotein A1, a blood-based marker of lipid metabolism, will be measured in mg/dL.
Chloride (Cl-)	10-15 years post CALERIE trial	Chloride, an electrolyte that reflects the body's fluid balance, will be measured in meq/L.
Apoprotein B	10-15 years post CALERIE trial	Apoprotein B, a blood-based marker of lipid metabolism, will be measured in mg/dL.

Trial Locations

Locations (3)

Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University; 🇺🇸 Boston, Massachusetts, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Pennington Biomedical Research Center; 🇺🇸 Baton Rouge, Louisiana, United States