OBJECTIVE: To determine whether plasma leptin and insulin concentrations are related to adiposity-associated elevations in muscle sympathetic nerve activity (MSNA) with age in healthy adult humans. DESIGN: Cross-sectional investigation of young and older adult men. SUBJECTS: Thirty healthy adult men, 16 young (25+/-1 y, mean+/-s.e.) and 14 older (61+/-1 y). MEASUREMENTS/RESULTS: The older men had higher (P<0.05) levels of body mass, BMI, total fat mass and truncal fat mass (dual energy X-ray absorptiometry) than the young men. MSNA burst frequency (microneurography) was approximately 75% higher in the older men (P<0.001). Plasma leptin concentrations were approximately 150% higher (P<0.01), whereas plasma insulin concentrations were approximately 70% higher (P<0.05) in the older subjects. MSNA was related to both total (r=0.51, P<0.01) and truncal (r=0.56, P<0.01) fat mass. Plasma leptin concentrations were related to total and truncal fat mass (both r=0.83, P<0.001), and to MSNA (r=0.49, P<0.01). Plasma insulin concentrations were related to MSNA (r=0.38, P<0.05). We used partial correlation analyses to assess whether leptin and/or insulin are potential contributors to the relation between body fat and MSNA. Adjusting for the effects of plasma leptin, but not insulin, concentrations eliminated the significant relations between MSNA and total and truncal fat mass. CONCLUSION: Our results: (1) demonstrate a positive relation between MSNA and plasma leptin concentrations in young and older healthy men; and (2) support the concept that circulating leptin concentrations may act as a humoral signal contributing to adiposity-associated elevations in MSNA with age in adult humans.