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Previous studies indicate that insulin-like growth factor-1 is an important neurotrophic agent and that decreases in brain concentrations of IGF-1 and the type 1 IGF receptor have an important role in the age-related decline in memory, neuronal function and possibly dendritic architecture. In this study, we assessed the effects of age and IGF-1 replacement on local cerebral glucose utilization (LCGU). Three groups of male Brown-Norway rats (7, 18 and 28 months of age) were implanted with Alzet minipumps and either saline or IGF-1 (50ng/0.5 microliter/hour) was infused into the lateral ventricle for 28 days. On day 28, LCGU was measured by infusion of 2-[(14)C]deoxyglucose during the dark phase of the light/dark cycle. Results indicate that glucose utilization significantly decreased with age throughout the brain including the anterior cingulate, sensorimotor and retrosplenial cortex, CA1, CA3 and dentate gyrus of hippocampus and several regions of the hypothalamus. Administration of IGF-1 to aged animals increased rates of LCGU in the anterior cingulate of the cortex (14.2%), CA1 region of the hippocampus (11.0%) and the arcuate nucleus of the hypothalamus (12.0%). Our results indicate that although glucose utilization decreases with age throughout the brain, the effects of IGF-1 infusion are manifest only in specific brain regions. Since IGF-1 has been shown to reverse the age-related decrease in memory, these results suggest that despite the wide distribution of the type 1 IGF receptor the actions of IGF-1 on glucose utilization are highly localized. Additionally, the close association between glucose utilization and excitatory amino acid activity suggests that IGF-1 may act on specific neural pathways to increase glutamate activity in brain regions associated with learning and memory.

Several reports have demonstrated that cerebral blood flow decreases with age and may contribute to neurodegenerative changes found in aging animals and man. Because GH and insulin-like growth factor 1 (IGF-1) decrease with age and have an important role in vascular maintenance and remodeling, we hypothesized that the decrease in cerebral blood flow is associated with a rarefaction of cerebral blood vessels resulting from a decline in GH and IGF-1. Measurements of vascular density (number of vessels/cortical surface area) in both Brown-Norway and Fisher 344/Brown-Norway rats were made at 5, 13, and 29 months of age using chronic cranial window chambers that allowed viewing of the cortical surface and its corresponding vasculature. Correlations were made with plasma levels of IGF-1. In Brown-Norway rats, arteriolar density decreased from 15.53 +/- 1.08 to 9.49 +/- 0.62 endpoints/mm2 in 7- and 29-month-old animals, respectively (P < 0.05). A decline was observed also in arteriolar anastomoses [3.05 +/- 0.21 to 1.42 +/- 0.24 connections/mm2 in 7- and 29-month-old animals (P < 0.05)]. Venular density did not decrease with age. Similar changes were observed in Fisher 344/Brown-Norway rats. The number of cortical surface arterioles was correlated with plasma IGF-1 levels at the time of vascular mapping (r = 0.772, P < 0.05), and injection of bovine GH (0.25 mg/kg, s.c., twice daily for 35 days) to 30-month-old animals increased both plasma IGF-1 and the number of cortical arterioles. These data indicate that: 1) vascular density on the surface of the cortex decreases with age; 2) vascular density is correlated with plasma levels of IGF-1; and 3) injection of GH increases cortical vascular density in older animals. We conclude that GH and IGF-1 have an important role in the decline in vascular density with age and suggest that decreases in vascular density may have important implications for the age-related decline in cerebral blood flow and brain function.