Serum Levels of Insulin-Like Growth Factor-I (IGF-I) and IGF-Binding Protein-3 in Healthy Centenarians: Relationship with Plasma Leptin and Lipid Concentrations, Insulin Action, and Cognitive Function

It has been demonstrated that healthy centenarians have more favorable anthropometric characteristics and insulin-mediated glucose uptake than aged subjects. The plasma insulin-like-growth factor I (IGF-I) concentration may account for such differences. Three groups of subjects were studied: 1) adults (<50 yr; n = 30), 2) aged subjects (75–99 yr; n = 30), 3) centenarians (>100 yr; n = 19). In all subjects, fasting plasma IGF-I, IGF-binding protein-3 (IGFBP-3), leptin, and lipid concentrations were determined; body composition was assessed by bioimpedance analysis; and insulin-mediated glucose uptake was evaluated by euglycemic hyperinsulinemic glucose clamp. IGF-I declined with advancing age, but no differences between aged subjects and centenarians were found. IGFBP-3 showed a trend similar to IGF-I, but lower values were present in centenarians than in aged subjects. Nevertheless, centenarians had a plasma IGF-I/IGFBP-3 molar ratio greater than that in aged subjects. Centenarians had also a whole body glucose disposal (WBGD) greater than that in aged subjects, but similar to that in adults. Mini Mental State Examination (27± 2.1 vs. 18.3 ± 3.1; P < 0.02) and Instrumental Activities Daily Living (26 ± 2.6 vs. 8.4 ± 4.1; P < 0.001) scores were significantly different in aged subjects and centenarians, respectively. In centenarians, the plasma IGF-I/IGFBP-3 molar ratio correlated with the body mass index (r = −0.55; P < 0.009); the amount of body fat (r =− 0.62; P < 0.003); fat-free mass (r = 0.56; P < 0.008); fasting plasma leptin (r =− 0.63; P < 0.004), triglycerides (r =− 0.58; P < 0.01), free fatty acid (r =− 0.64; P < 0.005), and low density lipoprotein cholesterol (r = −0.59; P < 0.009) concentrations; Mini Mental State Examination (r = 0.53; P < 0.0.03); and WBGD (r = 0.64; P < 0.005). All correlations were independent of daily fat and carbohydrate intake and WBGD (P < 0.05 for all). No significant correlations between the plasma IGF-I/IGFBP-3 molar ratio and plasma total (r = 0.31; P = NS) and high density lipoprotein cholesterol (r = 0.34; P = NS) concentrations were present. The correlation between the plasma IGF-I/IGFBP-3 molar ratio and WBGD persisted after adjustment for body fat, fasting plasma insulin concentration, daily carbohydrate and fat intake, and daily physical activity (r = 0.55; P < 0.009), but not after further adjustment for plasma free fatty acid concentration (r = 0.30; P = 0.17). In conclusion, healthy centenarians have plasma IGF-I/IGFBP-3 molar ratios greater than aged subjects. A more elevated plasma IGF-I/IGFBP-3 molar ratio might improve insulin action and plasma lipid concentration in centenarians. THE PLASMA insulin-like growth factor I (IGF-I) concentration has been shown to decline with advancing age (1, 2), but also to be influenced by sex steroids (3), nutritional status (4), and liver function (5). More than 80% of plasma IGF-I circulates bound to IGF-binding protein-3 (IGFBP-3) and forms a large 150-kDa complex that cannot leave the circulation (1); thus, only the unbound form of IGF-I is considered to be biologically active (6). Recently, the IGF-I/IGFBP-3 molar ratio has been indicated to reflect the amount of unbound and biologically active IGF-I (6). Such a hypothesis is supported by the fact that excessive amounts of IGFBP-3 in serum have been associated with poor growth in uremic children despite normal/high levels of IGF-I, and GH treatment of these children improved the imbalance between IGF-I and IGFBP-3 concomitantly with increased linear growth (6, 7). Previous studies have demonstrated that healthy centenarians have better anthropometric characteristics (8) and glucometabolic profiles (9) than aged subjects and not different from those in healthy adults. As IGF-I may have a regulatory role on body composition (10), plasma lipid concentration (11), and insulin action (12), it cannot be excluded that IGF-I or the IGF-I/IGFBP-3 molar ratio affects such anthropometric and metabolic characteristics in healthy centenarians. In light of such findings, we sought answers to the following questions. 1) Is there any difference in plasma IGF-I, IGFBP-3, and/or IGF-I/IGFBP-3 molar ratio between aged subjects and centenarians? If yes, 2) is any change in plasma IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio related to body composition, plasma leptin and lipid concentrations, and insulin action in healthy centenarians? For this reasons in 79 healthy subjects with a large age range (21–106 yr), fasting plasma IGF-I and IGFBP-3, leptin, and lipid concentrations were determined, body composition was assessed by bioimpedance analysis, and insulin-mediated glucose uptake was evaluated by euglycemic hyperinsulinemic glucose clamp. Subjects and Methods Subjects Seventy-nine subjects (42 males and 37 females) with a wide age range (21–106 yr) were studied. The whole group of subjects was categorized in 3 groups: 1) adults (<50 yr; n = 30), 2) aged subjects (75–99 yr (...truncated)