Study Background

Study Design

Download an Overview of the Study Design

Download Overview and Introduction to CALERIE Slides.

Caloric restriction (CR) has been shown in several—but not all—laboratory animal models to increase life span and to delay or slow the progression of a wide variety of aging changes and age-related pathologies. The CALERIETM (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) clinical trial was the first study to focus specifically on the effects of sustained CR in humans.  CALERIETM demonstrated the feasibility of sustained human CR (for at least two years) and the favorable effects on predictors of longevity and cardiometabolic risk factors.  No previous clinical study of non-obese individuals attained the degree of CR nor the resulting sustained weight loss that was achieved in CALERIETM. Other noteworthy features of CALERIETM are the substantial size of the trial, the comprehensive physiologic, psychologic, Quality of Life (QOL) and cognitive assessments conducted, as well as the extensive collection of biological samples which include serum, plasma, urine, and biopsies from skeletal muscle (vastus lateralis) and adipose tissue (subcutaneous abdominal).  Detailed documentation about measures available in the CALERIETM database and stored specimens available for future studies is available in the  Database Documentation and Biorepository sections of this website.

These features, combined with the careful attention to detail in the collection of data, make the publicly available CALERIETM data sets and biospecimens a unique and invaluable research resource for the investigation of innumerable hypotheses about the biological mechanisms underlying the effects of CR on human aging biology and for translational research to develop strategies for promoting health span.

The CALERIETM trials were conducted in two phases. Phase 1 of CALERIETM consisted of three single-site pilot randomized controlled studies testing differing degrees of caloric restriction (20%, 25%, and 30%) in a range of age groups with BMIs between 25.0 and 30 (i.e., overweight status) for six months to one year. Data from CALERIETM Phase 1 studies informed design of the two-year CR Phase 2 study.  Papers describing the Phase 1 studies’ design and results are available via the Publications search tool.

Specific Aims

The design of the CALERIE study paper provides a detailed description of CALERIETM 2’s aims.  The following is a brief summary. 

CALERIETM 2 tested effects of a two-year randomized clinical trial (25% CR vs. Ad Libitum (AL). The longer intervention period allowed the study to distinguish long-term CR effects after weight has stabilized from the acute effects of weight loss. 

CALERIETM Phase 2’s specific primary aim was to test the hypothesis that CR in humans causes sustained metabolic adaptation as defined by: 

  • Reduction in core body temperature
  • Reduced resting metabolic rate (RMR) corrected for changes in body composition

These metabolic adaptations to CR in laboratory animals were proposed to mediate its deceleration of aging changes. The sample size was specified in advance to provide robust statistical tests of these hypotheses. 

CALERIETM Phase 2 secondary aims were to test the hypotheses that CR in humans: 

  • Reduces serum triiodothyronine (T3)
  • Reduces inflammation as reflected by plasma concentrations of tumor necrosis factor-α a (TNF-α)

Both thyroid hormones and inflammatory mediators have been suggested to mediate aging changes and CR’s effects on them in laboratory animals.  

In addition, numerous exploratory aims were pursued, including measurement of changes in

  • risk factors for cardiometabolic diseases
  • body composition and metabolism
  • circulating levels of serum hormones, multiple inflammatory mediators, and growth factors
  • indicators of mitochondrial function
  • bone mineral density
  • physical activity and physical function
  • mood, cognition, and other psychological outcomes

The study also systematically assessed participant safety outcomes.

Study Design

CALERIETM Phase 2, completed in May 2013, was a two-year three-site randomized controlled trial in young and middle-aged non-obese healthy men and women. It compared outcomes in a group assigned a target of 25% CR (i.e., a 25% reduction in energy intake below baseline levels) with outcomes in an ad libitum diet control group. 

CALERIETM Phase 2 potential participants were screened during a series of physical and psychological tests and interviews to identify healthy individuals who agreed to make the necessary commitments to participate in a two-year intensive CR-oriented lifestyle modification program.  CALERIETM participant requirements included:

  • Absence of significant health problems, including diabetes, cancer, heart and liver disease, and AIDS 
  • Absence of medication use except oral contraceptives 
  • Age from 20 to 50 (inclusive) for men and ages 20-47 (inclusive) for women
  • Body mass index (BMI) of 22-27.9 (lean to slightly overweight) 
  • No recent substantial weight loss
  • No history of eating disorders, behavioral, or psychiatric problems 
  • Use by women of an acceptable form of contraception throughout the study

220 healthy volunteers across three sites (Tufts University, Pennington Biomedical Research Center, and Washington University School of Medicine) were randomized beginning in 2007. The study Coordinating Center was at the Duke Clinical Research Institute. 

The CALERIETM intervention employed an intensive behavioral approach coupled with dietary modifications anticipated to enhance adherence to CR. Intervention staff included psychologists and nutritionists who provided individual and group counseling and utilized a centralized interactive database to monitor interventionists’ practices and participant adherence over the course of the study.  The design and methodology of the study are elucidated here.

A unique feature of the CALERIETM trial was the objective measurement of caloric intake. To accomplish this, CALERIETM used the intake balance method to calculate energy intake from the difference between changes in energy stores (assessed by dual energy X-ray absorptiometry) and total energy expenditure (TEE) assessed by the doubly-labeled water method. The CALERIETM data set includes these measures made at baseline and at intervals after the start of the study. 

Summary of Findings

Effects of the CALERIETM intervention on its primary and secondary outcomes, as well as several exploratory outcomes, are published in A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. Additional CALERIETM 2 publications are available via the search tool in Publications section of this website. The following provides a brief summary of key findings. 

In CALERIETM Phase 2, participants achieved 12% CR and sustained 10% weight loss over two years.  In regards to CALERIETM’s two primary outcomes, the intervention did not significantly affect core temperature and lowered RMR (adjusted for changes in body energy stores) only in the first year of the intervention. The intervention significantly affected both of the CALERIETM secondary outcomes, producing diminutions in circulating levels of both T3 and TNF-ɑ.  It also markedly lowered a variety of cardiometabolic risk factors. 

Caloric restriction at levels achieved in CALERIETM was safe and generally well tolerated (with the inherent limitations on conclusions from a trial of limited size). The CALERIETM intervention produced a small diminution in bone mineral density, though not in excess of expected changes based on weight. CR at levels achieved in CALERIETM Phase 2 had some positive effects and no negative effects on quality of life and psychological outcomes.

As described here, the CALERIETM intervention did not significantly affect changes in circulating levels of platelet-derived growth factor AB, transforming growth factor beta, or insulin-like growth factor 1 (IGF-1), which has been proposed to mediate a variety of aging processes, but significantly increased circulating levels of IGF-1 binding protein. It produced small transient elevation on circulating cortisol. 

Other analyses of CALERIETM findings are in progress.

CALERIETM Study Contact Information

Contact email for scientists desiring to join research related to caloric restriction or request help with statistical analyses of CALERIETM data.  We do not provide specific dietary or clinical advice about CR or other diet interventions.

Steering Committee

Ex Officio

Clifford Rosen, MD, Committee Chair
Director, Clinical and Translational Research
Senior Scientist
Maine Medical Center Research Institute

William E. Kraus, MD
Director of Clinical Translation, Duke Molecular Physiology Institute
Duke University School of Medicine
300 N. Duke Street, 51-201
Durham, NC 27701
(919) 681-6733

Carl F. Pieper, DrPH
Associate Professor
Duke Department of Biostatistics & Bioinformatics
0508 Busse Building
Durham, NC 27710
(919) 660-7525

Kim M. Huffman, MD, PhD
Associate Professor
Division of Rheumatology & Immunology
Duke Molecular Physiology Institute
Duke University School of Medicine
300 N. Duke Street, 51-202
Durham, NC 27701
(919) 668-1644

Sai Krupa Das, PhD
Scientist 1, Associate Professor
Jean Mayer, USDA, Human Nutrition Research Center on Aging
Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy
Tufts University
Boston, MA
(617) 556-3313

Corby K. Martin, PhD
Pennington Biomedical Research Center
6400 Perkins Rd.
Baton Rouge LA 70808
(225) 763-2585

Susan B. Racette, PhD
Washington University School of Medicine
St. Louis, MO

Leanne Redman, PhD
Reproductive Endocrinology and Women’s Health
Pennington Biomedical Research Center
6400 Perkins Rd.
Baton Rouge LA 70808
(225) 763-0947

James White, PhD
Assistant Professor
Division of Hematology
Duke Molecular Physiology Institute
Duke University School of Medicine
300 N. Duke Street, 51-207
Durham, NC 27701
(919) 681-6931


External Science Committee

Rozalyn M Anderson, PhD
Department of Medicine SMPH
University of Wisconsin-Madison

Daniel Belsky, PhD
Assistant Professor
Department of Epidemiology & Butler Aging Center
Columbia University Mailman School of Public Health

National Institute on Aging

Chhanda Dutta, Ph.D.
Chief, Clinical Gerontology Branch
Division of Geriatrics and Clinical Gerontology
National Institute on Aging, NIH
Gateway Building, Suite 3W-200
7201 Wisconsin Ave
Bethesda, MD 20892
Phone:  301-496-4161