ALTERATIONS IN INSULIN-LIKE GROWTH-FACTOR-I GENE AND PROTEIN EXPRESSION AND TYPE-1 INSULIN-LIKE-GROWTH-FACTOR RECEPTORS IN THE BRAINS OF AGING RATS

Ageing in mammals is characterized by a decline in plasma levels of in sulin-like growth factor-1 that appears to contribute to both structur al and functional changes in a number of tissues. Although insulin-lik e growth factor-1 has been shown to provide trophic support for neuron s and administration of insulin-like growth factor-1 to ageing animals reverses some aspects of brain ageing, age-related changes in insulin -like growth factor-1 or type 1 insulin-like growth factor receptors i n brain have not been well documented. In this series of studies, insu lin-like growth factor-1 messenger RNA and protein concentrations, and type 1 insulin-like growth factor receptor levels were analysed in yo ung (three to four- and 10-12-month-old), middle-aged (19-20-month-old ) and old (29-32-month-old) Fisher 344xBrown Norway rats. Localization of insulin-like growth factor-1 messenger RNA throughout the lifespan revealed that expression was greatest in arteries, arterioles, and ar teriolar anastomoses with greater than 80% of these vessels producing insulin-like growth factor-1 messenger RNA. High levels of expression were also noted in the meninges. No age-related changes were detected by either in situ hybridization or quantitative dot blot analysis of c ortical tissue. However, analysis of insulin-like growth factor-1 prot ein levels in cortex analysed after saline perfusion indicated a 36.5% decrease between 11 and 32 months-of-age (P<0.05). Similarly, analysi s of type 1 insulin-like growth factor receptor messenger RNA revealed no changes with age but levels of type 1 insulin-like growth factor r eceptors indicated a substantial decrease with age (31% in hippocampus and 20.8 and 27.3% in cortical layers II/III and V/VI, respectively). Our results indicate that (i) vasculature and meninges are an importa nt source of insulin-like growth factor-1 for the brain and that expre ssion continues throughout life, (ii) there are no changes in insulin- like growth factor-1 gene expression with age but insulin-like growth factor-1 protein levels decrease suggesting that translational deficie ncies or deficits in the transport of insulin-like growth Factor-1 thr ough the blood-brain barrier contribute to the decline in brain insuli n-like growth factor-1 with age, and (iii) type 1 insulin-like growth factor receptor messenger RNA is unchanged with age but type 1 insulin -like growth factor receptors decrease in several brain regions. We co nclude that significant perturbations occur in the insulin-like growth factor-1 axis with age. Since other studies suggest that i.c.v. admin istration of insulin-like growth factor-1 reverses functional and cogn itive deficiencies with age, alterations within the insulin-like growt h factor-1 axis may be an important contributing factor in brain agein g. (C) 1998 IBRO. Published by Elsevier Science Ltd.