Decreases in growth hormone receptor signal transduction contribute to the decline in insulin-like growth factor I gene expression with age.

Several investigations have clearly indicated that plasma concentrations of insulin-like growth factor I (IGF-I) decrease with age and contribute to the decrease in tissue function that is characteristic of aging animals and man. Plasma IGF-I is regulated by GH released from the pituitary gland, and although data demonstrate a decline in GH secretion with age, GH receptor (GHR) density in liver tissue has been reported to increase. In this study, the effects of aging on GHR signal transduction were assessed in hepatic tissue to determine whether alterations in the response to GH contribute to the decline in IGF-I. Liver slices from female C57BL/6 mice (10, 17, and 31 months old) were prepared in medium and stimulated with GH. Basal GHR binding increased more than 2-fold in 31-month-old animals compared to that in either 10- or 17-month-old animals (P < 0.01), whereas the Ka values were similar in the three age groups. However, GH (2 nM)-induced IGF-I gene expression decreased dramatically with age (P < 0.01). In 10-month-old animals, GH-induced phosphorylation of the GHR complex was maximal 10 min after the addition of hormone, whereas GH-induced MAP kinase activity was maximal at 15 min. GH-induced JAK2 kinase and GHR complex phosphorylation as well as MAP kinase activity were significantly lower in 31-month-old animals than in either the 10- or 17-month-old groups (P < 0.05). The results of this study demonstrate that GH induces phosphorylation of JAK2 and the GHR complex, activates MAP kinase, and increases the expression of IGF-I messenger RNA in liver. In 17-month-old animals, decreases in IGF-I gene expression were evident that were not directly associated with diminished GHR complex phosphorylation or MAP kinase activity. By 31 months, there was a decrease in IGF-I gene expression that was associated with a marked decline in JAK2 and GHR complex phosphorylation. These data suggest that the signal transduction pathway for GH is impaired with age and that these changes may contribute to the decline in IGF-I gene expression.