Distinct cell-types in the prostate share an aging signature suggestive of metabolic reprogramming

Abstract

Age is a significant risk factor for disease of the prostate. However, the mechanisms by which age increases disease risk have not been well described. We previously reported age-related changes within the inflammatory and luminal compartments of the mouse prostate. Old mouse prostates exhibit an expansion of the population of Trop2+ luminal progenitor cells and a reduction in the frequency and functional capacity of Trop2- luminal cells, indicating that different cell-types have distinct responses to aging. Whether distinct cell-types in the prostate share a common signature of aging has not been established. We transcriptionally profiled four distinct cell-types in young adult and old mouse prostates: stromal, basal, Trop2+ luminal progenitor and Trop2- luminal cells. Motif analysis of genes upregulated in old prostate cell-types pointed to transcriptional regulators of inflammatory and hypoxia-related signaling. Glutathione metabolism and the antioxidant response emerged as a common signature of aging across prostatic lineages. Expression of genes implicated in mouse prostate aging, including the antioxidant response gene Hmox1, correlates with age of diagnosis in primary prostate tumors from the TCGA cohort. These findings reveal a common signature shared by distinct cell-types in the old prostate reflective of age-associated metabolic reprogramming.

Keywords: Prostate; basal; hypoxia; inflammation; luminal; metabolism; stromal.

Figure 1

Age-related transcriptional changes in prostate stromal cells. (A) Heatmap of significantly differentially expressed genes in 3- and 24-month-old prostate stromal cells. Only genes greater than 1.5-fold enriched in either direction with a p-value < 0.05 are included. (B) Gene set enrichment analysis indicates significant enrichment for inflammatory response and interferon gamma hallmarks in the old prostate stromal signature. NES: normalized enrichment score. (C, D) KEGG pathway analysis reveals significantly enriched pathways in 24-month-old (C) or 3-month-old (D) stromal cell signatures. (E) Volcano plot reveals significantly altered genes based on -log (FDR) and log (fold change). FDR: false discovery rate. (F) Motif analysis reveals transcription factors with binding motif enrichment in the old prostate stromal signature. NES: normalized enrichment score.

Figure 2

Age-related transcriptional changes in prostate basal cells. (A) Heatmap of significantly differentially expressed genes in 3- and 24-month-old prostate basal cells showing genes greater than 1.5-fold enriched in either direction with a p-value < 0.05. (B) Motif analysis reveals potential transcriptional regulators of the old prostate basal cell signature. NES: normalized enrichment score. (C) Volcano plot reveals significantly altered genes based on -log (FDR) and log (fold change). FDR: false discovery rate. (D, E) KEGG pathway analysis reveals significantly enriched pathways in 24-month-old (D) or 3-month-old (E) basal cell signatures.

Figure 3

Age-related transcriptional changes in distinct luminal cell subsets. (A) Principal component analysis of gene signatures of Trop2+ and Trop2- luminal subsets from 3 and 24-month-old mouse prostates. (B, C) Volcano plots reveal significantly altered genes based on -log (FDR) and log (fold change) in Trop2+ (B) and Trop2- (C) luminal cells. FDR: false discovery rate. (D, E) Gene Ontology (GO) terms enriched in old Trop2+ (D) and Trop2- (E) luminal cell signatures. (F, G) Motif analysis reveals potential transcriptional regulators of the old Trop2+ (F) and Trop2- (G) luminal cell signatures. NES: normalized enrichment score.

Figure 4

Shared aging signatures and metabolic genes across three distinct epithelial cell subsets. (A) Venn diagram comparing genes that are significantly upregulated in old epithelial cells. (B-D) Heatmaps reveal metabolic genes that are differentially expressed between 3- and 24-month-old basal cells (B), Trop2+ luminal cells (C) and Trop2- luminal cells (D).

Figure 5

Genes associated with aging mouse prostate correlate with age in primary prostate cancer. A. Violin plots of mRNA expression in TCGA cohort of primary prostate cancer comparing the bottom and top quartiles by age of diagnosis. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001. B. Plots revealing relative mRNA expression of Hmox1 with Egr2, Rar1, Irf4, Hmgcr and Srebf2 in TCGA primary prostate cancer specimens. Spearman correlation coefficients and p-values are shown. Note: 5-11 points with very high expression lie outside of the range of plots in order to better demonstrate correlations in B.