To examine the hypothesis that a lower level of physical activity influences the age-related decline in insulin-like growth factor-I (IGF-I), we measured serum concentrations in healthy nonobese younger and older men, characterized for maximal aerobic capacity (VO2 max) and energy expended in leisure time physical activity. To examine the independent influence of physical activity on IGF-I relative to other lifestyle variables, we also determined fat-free weight, percent body fat, body fat distribution (waist to hip and waist to thigh ratios), and habitual caloric intake in our population. IGF-I was 33% lower (P less than 0.01) in older men than in younger men, inversely related to percent body fat (r = -0.55) and indices of upper body fat distribution (waist to hip ratio, r = -0.45; waist to thigh ratio, r = -0.47), and positively related to VO2 max (r = 0.64) and leisure time physical activity (r = 0.45; P less than 0.01). IGF-I was not related to fat-free weight or daily caloric intake. After controlling for the effects of age by multiple regression analysis, VO2 max (r = 0.29) and leisure time physical activity (r = 0.24) were the sole factors independently related to IGF-I (P less than 0.05). Our results suggest that multiple factors contribute to the age-related decline in IGF-I. Lower levels of IGF-I in aging men are related at least in part to diminished physical activity.