Background: Abdominal adiposity and fat mass increase with aging, and as does insulin resistance which is frequently associated with hyperleptinemia and leptin resistance. Serum leptin may predict risk of metabolic syndrome and mortality among older adults.

Objectives: The objectives of the present study were to evaluate the relationship of serum leptin with risk of metabolic syndrome and mortality and to examine these associations in relation to the measures of body adiposity and proinflammatory cytokines. The influence of leptin receptor (I/D) gene polymorphism on diabetes as a contributing cause of mortality was also examined. Gender specific serum leptin cut off values as a biomarker for the risk of metabolic syndrome were determined.

Design: The Health, Aging and Body Composition (HABC) study is a prospective cohort of 3,075 older adults aged 70 to 79 years. Body composition, demographic information, biochemical variables including, markers of systemic inflammation, and genetic variation were assessed in detail.

Results: Women in quintile 2, 3, 4 and 5 of serum leptin were at significantly lower risk for metabolic syndrome as compared to those in quintile 1 after controlling for confounders. Serum leptin was independently associated with risk of metabolic syndrome after sequentially adjusting for demographic variables (p<0.0001), fat depots (p=.0024), and proinflammatory cytokines (p=.0098) in women. Among men, the association between serum leptin and risk of metabolic syndrome was explained by body adiposity. Women in quartile 2 and 3 of serum leptin were at lower risk than women in quintile 1 for all-cause mortality and mortality from cardiovascular disease independent of body fat and proinflammatory cytokines. Additionally, elevated level of serum leptin was associated with increased risk for diabetes as a contributing cause of mortality for both genders after sequentially adjusting for potential confounders, body fat and proinflammatory cytokines. Significant interaction was found between leptin receptor genotype and total percent fat (p=0.008) in association with diabetes as a contributing cause of mortality among women. The cut off serum leptin level that suggests the possible risk of metabolic syndrome was determined to be 6.45 ng/ml with 60% sensitivity and 63% specificity among men and 18.25 ng/ml with 55% sensitivity and 62% specificity among women.

Conclusion: Elevated levels of serum leptin may be associated with increased risk of metabolic syndrome and risk of diabetes as a contributing cause of mortality among older women. However, intermediary levels of serum leptin may lower the risk of all-cause mortality and mortality from CVD, suggesting a paradoxical association of serum leptin with cardiovascular risk factors and mortality from CVD among older women