Calorie Restriction on Biomarkers of Longevity, Metabolic Adaptation, and Oxidative Stress in Overweight Individuals

Abstract & Commentary

By Sarah L. Berga, MD, James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, is Associate Editor for OB/GYN Clinical Alert.

Dr. Berga is a consultant for Pfizer, Organon, and is involved in research for Berlex and Health Decisions, Inc.

Synopsis: Calorie restriction in overweight humans induces metabolic changes that are associated with increased longevity in some animal models.

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.

The aim of the present study was to determine if prolonged calorie restriction in humans would impact biomarkers of aging and oxidative stress. 48 men and women with a BMI between 25 and 30 kg/m2 were randomized to one of 4 arms for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction from measured baseline energy requirements); 12.5% calorie restriction + 12.5% increase in energy expenditure by exercise); and very low-calorie diet until 15% weight reduction followed by a weight maintenance diet. Outcome variables were measured before and at 3 and 6 months into the interventions and included body composition, dehydroepiandrosterone sulfate (DHEAS), glucose, insulin, protein carbonyls, DNA damage, 24-h energy expenditure, and core body temperature. Because subjects were highly selected and well paid, adherence was high.

Associated weight changes were: controls -1.0%, calorie restriction -10.4%; calorie restriction + exercise -10.0%; and very low calorie diet -13.9%. Fasting insulin was reduced in all intervention groups while DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie and calorie + exercise groups but not in the very low-calorie diet. The reduction in 24-h energy expenditure was greater than expected on the basis of weight loss alone. DNA damage also was reduced.

The authors conclude that calorie restriction induces metabolic changes that in animals are associated with increased longevity.


Prolonged calorie restriction increases life span in rodents and other species with shorter life spans, presumably by reducing metabolism. The very act of metabolizing food creates radical oxygen species (ROS) that are then hypothesized to wreck havoc on the intracellular environment, including DNA, leading to cell death and disease states. In this study, the investigators clearly demonstrate what has been known for some time, namely that low calorie diets induce metabolic adaptations, including reduced metabolism. Whether these metabolic changes actually confer longevity in humans is another matter and one that cannot be easily addressed using customary and conventional study designs.

Although the present study was assiduously designed and conducted, this alone does not mitigate the trouble inherent in the slippery slope of interpreting the outcome data. In this study, the induction of energy deficits and weight loss reduced insulin levels. However, in other contexts associated with increased longevity, insulin resistance is associated with lower metabolism. Thus, a simple story seems elusive. Further, in humans, long-term dietary restriction carries many potential risks, including nutrient imbalance, increased cortisol secretion, and stress reactivity. Perhaps the reconciliation rests with whether the dietary restriction results in a BMI that is lower than ideal or a reduction in BMI toward ideal. Indeed, calorie restriction that results in a BMI of less than 20 has been associated with increased mortality and morbidity, especially in women.

Long story short is that calorie restriction might well be a good thing in humans with a BMI greater than ideal. The ideal for women is a BMI between 21 and 23. The ideal for men is between 20 and 22. Once ideal weight is achieved and maintained, then further reductions have the potential to cause more harm than good. This is especially true if the goal is to preserve reproductive potential, as reproductive drive is extremely sensitive to weight reductions below ideal and to nutrient imbalance. A limitation of the present study is that stress and reproductive hormones were not assessed, but based on other studies in humans, the same dictum is likely to hold. Weight reduction below the ideal may compromise fertility and reproductive outcomes in both men and women while weight reduction toward the ideal may enhance fertility and reproductive outcomes.