Reduced metabolic rate after caloric restriction-can we agree on how to normalize the data?

The extension of longevity by caloric restriction is one of the most intensively studied adaptations in the gerontology literature. Caloric restriction is the only environmental intervention that consistently decreases the biological rate of aging across a wide range of species. It remains the “gold standard” by which other anti-aging interventions are often compared. Despite the long history of research on caloric restriction (1) and the consistent pattern of responses across species, the mechanism(s) responsible for its effects remains enigmatic. The interesting study by Blanc et al. (2) provides new information on the impact of caloric restriction on energy expenditure. The authors have performed a carefully controlled study that determined the effects of caloric restriction on total daily energy expenditure and its components in male rhesus monkeys. The second objective of the study examined the statistical methods to normalize metabolic rate changes in response to caloric restriction. The first major finding noted is that 11 yr of caloric restriction ( 30% less food than controls) reduced resting metabolic rate by 13% after values were adjusted for the loss of fat-free mass (12% loss). Body composition was assessed from dual-energy x-ray absorptiometry, which provides a three-compartment (fat mass, fat-free mass, and bone mass) estimation of body composition. Total daily energy expenditure was measured from doubly labeled water, which provides a representative snapshot of free-living energy expenditure. When doubly labeled water is combined with indirect calorimetry, a breakdown of the components of daily energy expenditure (resting energy expenditure and nonbasal energy expenditure) emerges. Despite a decline in adjusted resting energy expenditure, the authors report no significant differences in adjusted total daily energy expenditure between control and calorically restricted animals. Thus, the decline in adjusted total daily energy expenditure was mainly attributed to the reduced resting energy expenditure adjusted for the loss of fat-free mass. The authors attribute the lack of significant changes in daily energy expenditure to the observed variability associated with the component of physical activity. The authors acknowledge that the lower resting energy expenditure per kilogram in response to caloric restriction is not a consistent finding, even in their own colony. The authors, however, evoke an interesting hypothesis. That is, the lower resting energy expenditure is detectable in older cohorts of rhesus monkeys. Indeed, when younger animals (yr 9) were removed from their statistical analyses, the lower resting energy expenditure is even more apparent. This raises the interesting notion of an interaction between age and resting energy expenditure in response to caloric restriction. That is, are the energetic responses different depending on which age caloric restriction is initiated? Relative to this point is a recent study (3) that showed that a larger energy imbalance is required in older subjects to change body weight when compared with younger adults. The strengths of this study include its longitudinal design (11 yr follow-up), the careful assessment of total daily energy expenditure with doubly labeled water, and a thoughtful discussion of statistical approaches to normalize metabolic rate for changes in body composition. The last point is not trivial. It has been suggested that adaptations in energy expenditure may, in part, explain the effects of dietary restriction on increasing life span (4). It has been postulated that a lower oxygen consumption may reduce the formation of reactive oxygen species, thus reducing oxidative damage and increasing life span (4). The authors point out, however, that the controversy among investigators is whether dietary restriction reduces metabolic rate, independent of changes in body size and composition. Thus, the method by which metabolic rates are statistically adjusted for changes in body composition becomes an important methodological issue. Simply put, is the decline in energy expenditure proportionally greater than the loss of fat mass and fat-free mass in response to caloric restriction? A consensus on statistical approaches to normalize metabolic rate for changes in body composition have been historically (5) and recently discussed (6–10). In brief, there are a plethora of statistical approaches that have been applied to normalize metabolic rate data for changes in body composition. It is not the intent of this editorial to present an overview of these approaches. The investigators in the present study make a strong case for the use of a regression-based approach to normalize metabolic rate data in response to caloric restriction. The authors suggest that a regressionbased approach more appropriately adjusts for the non-zero intercept between the dependent and independent variables and, thus, takes into account the true mathematical relationship between changes in the independent and dependent variables. There seems to be an emerging consensus that a regression-based approach is a more appropriate statistical approach to adjust metabolic rate data when there are concomitant changes in body composition. Of course, as in any statistical approach, underlying assumptions should be tested and met. Despite this assertion, there is a reluctance by the scientific community to normalize metabolic rate data using regression-based procedures. This may be due partially to the convenience and tradition of placing a variable in the denominator and asserting that the confounding variable is now controlled. A common example is simply dividing resting energy expenditure by the quantity of fat-free mass (i.e. resting metabolic rate/fat-free mass). This approach, however, may provide erroneous results (8). The 0013-7227/03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(1):14–15 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/jc.2002-021672