The Effects of Aging on the Molecular and Cellular Composition of the Prostate Microenvironment

Advancing age is associated with substantial increases in the incidence rates of common diseases affecting the prostate including benign prostatic hyperplasia (BPH) and prostate carcinoma. However, to date, there is no established molecular explanation for the age-dependent increases in these pathologies. The prostate is comprised of a functional secretory epithelium supported by a spectrum of cell types and structural elements comprising the stroma. As reciprocal interactions between epithelium and stromal constituents are essential for normal organogenesis and serve to maintain normal functions, discordance within the stromal could permit or promote disease processes. In this study we sought to identify aging-associated alterations in the mouse prostate that could influence pathology. We quantitated transcript levels in microdissected periglandular stroma from young (4 month-old) and old (20-24 month-old) C57BL/6 mice, and identified a significant change in the expression of 1259 genes (p<0.05). These included increases in transcripts encoding genes associated with inflammation (e.g., Ccl8, Ccl12), genotoxic/ oxidative stress (e.g., Apod, Serpinb5) and paracrine-acting proteins (e.g., Cyr61). The expression of several collagen genes (e.g., Col1a1 and Col3a1) exhibited age associated declines. By immunofluorescence and electron microscopy we determined that the aged prostate contains an abundant disorganized collagen matrix and a significant increase in inflammatory infiltrates comprised of macrophages, T cells and, to a lesser extent, B cells. These findings demonstrated that during normal aging the prostate stroma exhibits phenotypic and molecular characteristics plausibly contributing to the striking age associated pathologies affecting the prostate through oxidative stress and inflammatory cell damage. Custom Agilent 44K whole mouse genome expression oligonucleotide microarrays as well as custom mouse cDNA microarrays were used to measure transcript levels in microdissected periglandular stroma from young (4 month-old) and old (20-24 month-old) C57BL/6 mice. All samples were laser-capture microdissected and total RNA isolated and amplified prior to hybridization against a reference pool of normal adult mouse tissues.