Clinical Briefs: Hungry, but Alive—Calorie Restriction

With Comments from Russell H. Greenfield, MD. Dr. Greenfield is Medical Director, Carolinas Integrative Health, Carolinas HealthCare System, Charlotte, NC, and Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC.

Source: Heilbronn LK, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: A randomized controlled trial. JAMA 2006;295:1539-1548.

Goal: To determine the effects of prolonged significant calorie restriction, with or without exercise, in overweight subjects over six months.

Design: Randomized controlled trial.

Subjects: Sedentary men (< 50 years) and women (< 45 years) with a body mass index (BMI) between 25 and 30 kg/m2 (n = 48).

Methods: Subjects had total energy expenditure assessed at baseline and were then randomized into one of four groups: weight maintenance group (control), 25% calorie restriction (CR), 12.5% calorie restriction plus structured exercise (CRE), and very low-calorie diet (890 kcal/d) until 15% reduction in weight followed by a weight maintenance diet. Food was provided to all participants in accordance with specified menus assigned to each group. Subjects made mid-week calls to report energy intake and attended weekly group meetings. Weight was determined weekly following a 12-hour fast, and metabolic tests were performed at baseline, three and six months.

Results: In all three intervention groups fasting insulin levels dropped significantly at six months, as did energy expenditure compared with baseline. Subjects in the CR and CRE groups showed reduced core body temperature at trial's end, but no significant changes occurred in dehydroepiandrosterone sulfate (DHEAS) or fasting glucose levels in any group. Plasma T3 levels were decreased in all three intervention groups at trial's end. DNA damage was reduced from baseline in the intervention groups, but not in aggregate when compared to the control group. No association was found between DNA damage and changes in body weight, fat mass, or energy expenditure.

Conclusion: Prolonged calorie restriction in overweight humans results in: 1) a reversal in two of three previously reported biomarkers of longevity (fasting insulin level and core body temperature, but not DHEAS levels), 2) a larger than expected decrease in energy expenditure (metabolic adaptation) associated with lower thyroid hormone levels, and 3) a reduction in DNA damage.

Study strengths: Compliance and participant retention rates; methods employed for determining energy requirements.

Study weakness: Small sample size.

Of note: Theories regarding the anti-aging benefits of calorie restriction abound, and include decreased energy expenditure with consequent reduction in generation of reactive oxygen species (ROS), modulation of insulin sensitivity, decreased inflammation, and neuroendocrine effects; the oxidative stress theory of aging posits that long-term accumulation of ROS results in disease development, including cancer; subjects received significant monetary compensation for participation in the trial; group allocation was balanced for sex and two categories of BMI (25-27.9 and 28-30 kg/m2) at screening; save for the very low-calorie diet, all diets were based on American Heart Association recommendations; cognitive behavioral techniques were employed to promote adherence to diet and exercise regimens; subjects in all four groups lost weight (range 1.0-13.9%); no significant changes occurred in any group with respect to spontaneous physical activity; 24-hour energy expenditure data were also compared to data from 865 subjects with comparable baseline characteristics previously studied in a similar metabolic chamber (energy expenditure was again found to be lower in the intervention groups at three and six months); the authors believe no changes in DHEAS levels were found due to insufficient study duration; the results suggest that energy deficit rather than calorie restriction results in decreased energy expenditure; the metabolic adaptation occurred within the first three months of the study.

We knew that: Chronic calorie restriction has been shown to increase lifespan in animal studies; total energy expenditure is comprised of resting energy expenditure, nonresting energy expenditure, and the thermic effect of eating; some data suggest calorie restriction lessens energy expenditure beyond what would be expected metabolically, but the evidence is conflicting; ROS are byproducts of energy metabolism; the Baltimore Longitudinal Study of Aging showed that men with lower plasma insulin levels and oral temperatures, as well as higher DHEAS levels, live longer; fasting glucose level is not consistently altered through calorie restriction; the thermic effect of food accounts for but 10% of daily energy expenditure; recent data suggest that calorie restriction may slow age-related changes in diastolic cardiac function (Meyer, et al. Long-term caloric restriction ameliorates the decline in diastolic function in humans. J Am Coll Cardiol 2006;47:398-402.).

Clinical import: The results of this study, phase 1 of the Comprehensive Assessment of the Long Term Effects of Reducing Intake of Energy (CALERIE) trial, are certainly compelling, but the authors are quick to point out that trials of longer duration must be performed to determine whether the impacts of calorie restriction are sustained and positively impact the human aging process. The current environment underscores the importance of such data. As noted in an accompanying editorial and presented in another article in the same edition of JAMA, more than 65% of adults are overweight or obese, and 17% of children in the United States are overweight. Some of these same children are developing adult-type diseases at an alarming rate. In addition, consumers can consult with a plethora of "anti-aging" doctors (the alternative to aging does not appeal to this writer…) purveying all manner of therapeutic intervention. Certainly the focus needs to be on healthy aging to promote, as others have coined, long healthspan as well as lifespan. Some of our patients may be drawn to the idea of significant calorie restriction after learning of this trial. As health care providers we should advise that the data are preliminary, while promoting an open discussion regarding healthy dietary and lifestyle choices.

What to do with this article: Keep a hard copy in your file cabinet.