INSULIN-LIKE GROWTH-FACTOR-I STIMULATION OF PROTEIN-SYNTHESIS IS ATTENUATED IN CEREBRAL-CORTEX OF AGING RATS

It has been postulated that brain aging and the accompanying neurodegenerative processes associated with aging result from a deterioration of mechanisms that regulate the maintenance of basic cellular processes. In the present study, it was hypothesized that decreased availability and/or diminished responsiveness of tissues to growth factors such as insulin-like growth factor-1 may be partly responsible for decreases in total protein synthesis previously observed in aging animals. Male Brown Norway rats (5-7 and 27-28 months old) were used to determine (1) whether in vivo protein synthesis in cortex, hippocampus, hypothalamus and cerebellum decreases with age and (2) whether these deficiencies are associated with age-related alterations in response to insulin-like growth factor-1, des (1-3) IGF-1 or insulin. Analysis of in vivo protein synthesis rates revealed a decline of 20% in cortex of old rats (P < 0.05) but no changes were observed in hippocampus, hypothalamus, or cerebellum. Stimulation of cortical slices in vitro with insulin-like growth factor-1, des(1-3) insulin-like growth factor-1, or insulin increased protein synthesis rates in young animals, but the response to these growth factors was blunted in old animals. Analysis of type 1 insulin-like growth factor receptor densities by quantitative autoradiography demonstrated age-related decreases in receptor levels in cerebellar cortex and dentate gyrus of the hippocampus but no changes in cortex. Regional distribution of type 1 insulin-like growth factor receptors within each of these tissues did not appear to change with age. These data indicate that (1) the capacity for protein synthesis decreases in cortical tissue with age, (2) the decline in protein synthesis appears to be associated with a decreased response to stimulation with insulin-like growth factor-1, and (3) the number and affinity of type 1 insulin-like growth factor receptors do not decrease with age. These data suggest that alterations in signal transduction through the type 1 insulin-like growth factor receptor may be a contributing factor in the decline in protein synthesis with age and thus contribute to brain aging.