INTERRELATIONSHIPS BETWEEN LEPTIN RESISTANCE, BODY COMPOSITION, AND AGING IN ELDERLY WOMEN

To the Editor: It has recently been suggested that leptin resistance is a feature of aging.1 Leptin resistance may be responsible for increases in fat mass and visceral fat mass2 and in particular for the greater metabolic risk observed in old age.3 In old rats, leptin infusion failed to produce a significant change in food intake, total or visceral fat mass, or insulin sensitivity.4 Moreover, in a sample of aging rats that underwent calorie restriction, leptin activity was markedly lower than in young controls.1,5 Lower availability of leptin in the hypothalamus, impaired peripheral leptin action, or both have been proposed as mechanisms of leptin resistance across aging.6,7 In humans, leptin resistance and aging have been poorly studied, because direct measurement of leptin sensitivity appears difficult. The aim of this study was to examine, in a group of healthy women, the relationships between aging, body composition, and leptin resistance, evaluated using a surrogate index. Thirty-four healthy women aged 27 to 83 with body mass indexes (BMIs) ranging from 18.5 to 41.5 kg/m2 were studied. (More details can be obtained from the corresponding author.) The ethical committee of the University Hospital of Verona approved the study, and subjects gave informed consent. BMI and waist circumference were obtained in all participants. Total body fat mass (FM) in kg and as a percentage of body weight (FM%) and lean body mass (LBM) were measured using dual-energy X-ray absorptiometry (DXA) (Hologic QDR 4500, Waltham, MA; System Software Version 11.1). In all subjects, in the morning, after 12 hours of fasting, resting energy expenditure (REE) was evaluated using indirect calorimetry (Vmax 29N Sensormedics).8 Insulin was measured using double-antibody radioimmunoassay (Diagnostic Products Corp., Los Angeles, CA) and leptin using enzyme-linked immunosorbent assay (DBC-Diagnostic Biochem Canada Inc, London, Ontario, Canada). The ratio between REE and fasting leptin levels was used as a surrogate index of leptin resistance.9 Leptin-resistant subjects have a low REE:leptin ratio, because high leptin levels are required to maintain a normal REE. Logarithmic transformation was performed for non-normally distributed variables. Data were analyzed using univariate and multivariate analysis of variance. Pearson correlation was used to test associations between variables. Stepwise multiple regression analysis was used to evaluate the effects of independent variables on leptin resistance. Table 1 shows the main characteristics of the women, stratified according to age and BMI. FM% was significantly higher in the group of elderly normal-weight than in younger normal-weight women but significantly lower than in overweight to obese women of the same age. The young women had higher REE:leptin ratios than the elderly normal-weight subjects (Table 1), even after adjustment for LBM (180.8±16.5 vs 95.6±20.5, P<.01). Moreover, a significantly lower REE:leptin ratio was found in overweight to obese elderly subjects than in normal-weight women of the same age after adjustment for LBM (31.6±17.3 vs 95.6±20.5, P<.05). In the whole group, the REE:leptin ratio was negatively related to age (correlation coefficient (r)=−0.723, P<.001), BMI (r=−0.622, P<.001), waist circumference (r=−0.646, P<.001), FM (r=−0.648, P<.001), FM% (r=−0.835, P<.001), and insulin (r=−0.352, P<.05). In a stepwise multiple regression analysis, FM% explained 72.3% of the REE:leptin ratio variance (β coefficient −0.857) and age an additional 4% (β coefficient −0.313), independent of BMI, waist circumference, LBM, and insulin. This study suggests that leptin resistance, as evaluated according to REE:leptin ratio, increases with aging and adiposity. Experimental studies in animals have showed that leptin's action is profoundly impaired in aging rats, independent of their body fat pattern.1,4,5 Old animals kept relatively lean and insulin sensitive using calorie restriction were resistant to leptin administration.1,5 In contrast with the observations of a previous study,1 old CD-1 mice who did not become obese with aging did not develop a defect in leptin transport across the blood–brain barrier;10 moreover, leptin resistance was reversible with modest weight reduction.10 In the current study, a significant negative relationship was observed between age and REE:leptin ratio, suggesting a decline in leptin sensitivity with aging. This decline was stronger in overweight to obese older women than in normal-weight age-matched women. When a multiple regression analysis was performed, the main predictor of leptin resistance was the degree of adiposity, with age explaining approximately 4% of REE:leptin ratio variance. In conclusion, this study shows that leptin resistance increases with adiposity and age. Although leptin resistance may be partially attributed to aging per se, leptin sensitivity appears to be strictly related to adiposity, even in aged individuals. Conflict of Interest: None of the authors had a personal or financial conflict of interest related to this manuscript. This study was supported by grants from MIUR project COFIN n 2005063885_005. Author Contributions: Study concept and design: EZ, LB, OB, and MZ. Acquisition of subjects: GM, GF, and KG. Analysis and interpretation of data: EZ and VDF. Preparation of manuscript: EZ, VDF, MZ, and GM. Sponsor's Role: None.

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