Gene expression by the anterior pituitary gland: effects of age and caloric restriction

Abstract

Biological aging is associated with functional deficits at the cellular, organ, and system levels. The pituitary gland, the central organ of the neuroendocrine system, has been shown to play an important role in the aging process. To gain a better understanding of its functional changes with aging, we compared the gene expression profiles of the anterior pituitary of young and old Brown Norway rats, focusing on the major pituitary hormone genes. We also explored the effects of caloric restriction, an intervention shown to delay or inhibit age-associated pathologic and biologic changes in a number of systems and organisms, on the expression of these genes. Of the total of 1176 genes arrayed on each of the six membranes per group that we used, 542 (46%) were detectable in the anterior pituitary of young and old rats. Significance analysis of microarrays (SAM) of these 542 detectable genes revealed 28 genes that changed significantly with age, among which 24 decreased and 4 increased. Among the five major hormone genes on the membrane, growth hormone (GH) and prolactin decreased with age, the glycoprotein hormone common α subunit gene increased, and follicle-stimulating hormone-β subunit (FSH-β) and thyrotropin-β (TSH-β) subunit did not change. Among these genes, the three found to change by array analysis were confirmed to do so by Northern blot analysis. For the two genes among the five that were not selected (i.e. did not change) by array analysis, TSH-β also showed no significant change by Northern blot; but the other, FSH-β, showed significant increase. Thus, of the five genes checked by Northern blot analysis, the results were consistent with the array data in four cases. Short-term caloric restriction (5 weeks) of young adult animals resulted in 19 genes being significantly down-regulated, while no significantly up-regulated genes were identified. Among the genes that were down-regulated were GH, gonadotropin releasing hormone receptor (GnRH-R), three cytochrome c oxidase subunits and two heat shock proteins. With long-term (21 month) caloric restriction, about 30% of the genes that changed with aging (8/28) were prevented from doing so, and none of the age-related changes was enhanced with long-term caloric restriction. The genes that showed most significant rescue were neuropeptide Y, GnRH-R, DNA-binding protein inhibitor Id-3, and nerve growth factor-induced protein I-B. These results indicate that long-term caloric restriction can partially prevent some of the age-related changes in gene expression in the anterior pituitary of Brown Norway rats, suggesting a benefit of this regimen to be the slowing of the aging process. The fact that fewer than 30% genes derived benefit also suggests that the effect of caloric restriction is rather limit, which is consistent with the thesis that caloric restriction may slow, but not prevent, the aging process.