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 da mages during the life span and a species-specific genetic program. The genetic program of aging appears to have co-evolved with the sexual m ode 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 glan d is an example of such ''antagonistic pleiotropy.'' The prostate glan d 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 p opulation, fibroblastic and smooth muscle cells are thought to produce growth factors that support the development and function of the epith elial cells. Both epithelial and stromal cells are dependent on androg ens. In this study, we have examined age-dependent expression of the a ndrogen receptor gene in the prostatic tissues of rats and dogs. Unlik e the rat, in which the prostatic growth ceases after sexual maturatio n, the dog prostate continues to grow during aging. Similar to the dog , the antagonistic pleiotropy of the prostatic growth in the human cau ses the pathological condition of benign prostatic hyperplasia (BPH), the major health problem in old men. Quantitation of the androgen rece ptor (AR) mRNA in the total prostate extracts from young and old anima ls by the reverse transcriptase-polymerase chain reaction (RT-PCR) met hod showed about a 30% decline in AR mRNA in the 24-month-old rat pros tate, 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, d evelopmental maturation during the first month of life is associated w ith an increase in AR immunoreactivity in the luminal columnar epithel ium, with a concomitant loss of immunoreactivity in the basal cells. F urthermore, with aging, there was a marked increase in the proportion of AR-negative basal cells in comparison to luminal columnar cells. Su rprisingly, in both young adult (similar to 1-year-old) and old (simil ar to 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 matu ration serves as a stop signal for the prostate growth. However, in ce rtain species, such as the dog, robust AR expression in the stromal ce lls overrides this regulatory blockage and leads to prostatic hyperpla sia in old age. (C) 1996 Wiley-Liss, Inc.