THE DIFFERENTIAL REGULATION OF INSULIN-LIKE GROWTH-FACTOR (IGF) BINDING-PROTEINS BY IGF-I DURING THE LIFE-SPAN OF THE RAT

To evaluate the therapeutic potential of insulin-like growth factor-I (IGF-I) as an anabolic agent during aging, we determined its effects on IGF binding proteins (BPs) in male rats of 2, 8, 16, and 24 months of age. In control animals, a striking increase (143%) in the predominant 39-45 kDa serum IGFBP (BP-3), with little change iii serum IGF-I, accompanied the marked deceleration of growth which occurred between 2 and 8 months; the levels of IGF-I and its BPs declined by 15% and 34%, respectively, later in life. Infusion of IGF-I (1.2 mg/kd/day) for 2 weeks produced progressively larger increases in circulating IGF-I with age, from 24% to 95% between 2 and 24 months, consistent with an age-related decrease in exogenous ICF-I clearance. We attributed these results to the large increase in IGFBPs that occurred with maturation, as well as an induction of IGFBP-3 (34-68%) and a larger increase in the 30-34 kDa IGFBP (BP-2; 136-235%) following IGF-I treatment in the older (16-24 months) animals. Anabolic actions of IGF-I, which were seen only in the older rats, included modest increases in weight velocity (5.2 +/- 1.2 g/week), serum phosphorous (20%), and alkaline phosphatase (26%) compared to age-matched controls. In conclusion, differential changes in the relative levels of the different IGFBPs with IGF-I treatment in older animals appeared to profoundly influence both the half-life and tissue accessibility of exogenous IGF-I, thus modulating the potential benefits of IGF-I as an anabolic agent during aging.