CALERIE - Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy Study

Objectives

The Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy Study (CALERIE) was funded by the National Institute on Aging and tested the hypothesis that two years of sustained 25% caloric restriction reduce resting metabolic rate and core temperature indicative of metabolic adaptation. Secondary hypotheses included proposed favorable adaptations reflecting primary aging and leading to improvements in aging biomarkers and chronic diseases of aging.

Background

Aging is a complex physiological process characterized by molecular impairments of cell and organ function, increased vulnerability to disease, and eventual demise of the organism. Aging biology has been informed through studies of caloric restriction (CR), defined as a dietary intervention that reduces calorie intake while maintaining proper micronutrient and vitamin nutrition. In the mid-1930's, McCay and coworkers were the first to observe that CR extended the lifespan of rats. Now, we know CR increases median and maximum of lifespan across a wide range of species including yeast, worm, spiders, flies, fish, mice, rats and perhaps longer-lived species, including monkeys. Although it is unlikely clinical trials will conclusively determine whether CR increases median or maximal lifespan in humans, CALERIE was designed to investigate the effects of medium-term CR on human aging biology.

Conditions

Interventions/Treatment Groups

The CALERIE 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. CALERIE was conducted at three sites, Pennington Biomedical Research Center (Baton Rouge, LA), Tufts University (Boston, MA), and Washington University School of Medicine (St. Louis, MO). Duke University Clinical Research Institute served as the coordinating center. Caloric intake was objectively measured using the intake balance method; energy intake was calculated 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. In the CR arm, weight loss occurred during the first 12 months (weight loss phase), and plateaued over the next 12 months (weight maintenance phase). Additional assessments occurred at baseline, 3, 6, 12, 18 and 24 months and included psychological and physiologic assessments, blood and urine collections, and at baseline, 12, and 24 months only, adipose and skeletal muscle biopsies.

Outcomes

• Participants sustained an average of 12% CR and achieved an average weight loss of ~10% after twelve months of intervention, which was maintained up to the end of the two-year intervention. • CR was safe and did not impair the quality of life of the participants. CR improved mood, sleep, sexual function, and self-reported general health. • For primary outcomes, the intervention did not significantly affect core temperature and lowered RMR (adjusted for changes in body energy stores) only marginally and in the first year of the intervention. • Weight change and CR caused a lowering of resting metabolic rate more pronounced than that expected on the basis of body weight loss (metabolic adaptation), and a decrease in total daily energy expenditure mostly due to decreased physical activity (behavioral adaptation). • For secondary outcomes, CR led to significant and persistent inhibition of inflammation without impairing key in vivo indicators of cell-mediated immunity • While CR slightly reduced bone mineral density, this was not in excess of expected changes based on weight. • CR improved dietary restraint and self-efficacy, and biomarkers of oxidative stress (e.g. isoprostanes), liver function, and biological aging rate.

Results/Conclusions

Ongoing analyses are evaluating the impact of CR on circulating DNA methylation, RNA transcripts, metabolic intermediates and proteins in blood, fat, and skeletal muscle as well as relating these changes to the intricate biobehavioral measures.