Age-dependent expression of the androgen receptor gene in the prostate and its implication in glandular differentiation and hyperplasia

The senescence phenotype is the product of both cumulative physical damages during the life span and a species-specific genetic program. The genetic program of aging appears to have co-evolved with the sexual mode of reproduction. The same developmental processes that prepare the animal for maximum vitality and reproductive competence during young adulthood, if allowed to continue, can be detrimental during old age. Androgen receptor- mediated development and growth of the prostate gland is an example of such 'antagonistic pleiotropy.' The prostate gland is composed of two major groups of cells: the epithelial and stromal. Among the epithelial type, the columnar cells on the luminal surface produce the prostatic secretions, and the basal cells are presumed to serve as progenitors of the columnar cells. Within the stromal cell population, fibroblastic and smooth muscle cells are thought to produce growth factors that support the development and function of the epithelial cells. Both epithelial and stromal cells are dependent on androgens. In this study, we have examined age-dependent expression of the androgen receptor gene in the prostatic tissues of rats and dogs. Unlike the rat, in which the prostatic growth ceases after sexual maturation, the dog prostate continues to grow during aging. Similar to the dog, the antagonistic pleiotropy of the prostatic growth in the human causes the pathological condition of benign prostatic hyperplasia (BPH), the major health problem in old men. Quantitation of the androgen receptor (AR) mRNA in the total prostate extracts from young and old animals by the reverse transcriptase- polymerase chain reaction (RT-PCR) method showed about a 30% decline in AR mRNA in the 24-month-old rat prostate, as compared to the prostate of 3- month-old young adult animals. However, no significant difference in AR mRNA contents between 1-year-old and 10-year-old dog prostates was observed. In situ immunostaining for the androgen receptor protein revealed that in the case of rat, developmental maturation during the first month of life is associated with an increase in AR immunoreactivity in the luminal columnar epithelium, with a concomitant loss of immunoreactivity in the basal cells. Furthermore, with aging, there was a marked increase in the proportion of AR- negative basal cells in comparison to luminal columnar cells. Surprisingly, in both young adult (~1-year-old) and old (~10-year-old) dogs, most of the AR immunoreactivity was localized in the fibroblastic stromal cells rather than in the epithelial cells. Based on these observations and the existing literature, we propose that normally, in most mammalian species, an age- dependent decline in the conversion of basal to columnar epithelial cells after sexual maturation serves as a stop signal for the prostate growth. However, in certain species, such as the dog, robust AR expression in the stromal cells overrides this regulatory blockage and leads to prostatic hyperplasia in old age.