Aging induces a distinct gene expression program in mouse islets

Abstract

The role of aging in the pathogenesis of type 2 diabetes remains poorly understood. In the past adult β-cells were assumed to undergo frequent turnover. However, we find that β-cell turnover declines to very low levels in middle-aged mice. We therefore hypothesized that aged islets could exhibit a distinct gene expression program. We compared gene expression in islets from young mice to islets from aged mice under basal conditions. Aging was associated with differential expression of many genes in islets, including mRNAs encoding for chromatin remodeling components, RNA binding proteins, and pancreatic endocrine transcription factors. We previously observed that cell cycle entry of β-cells is severely restricted by middle age, with minimal of β-cell proliferation in response to regenerative stimuli such as 50% partial pancreatectomy. To characterize the effect of age in adaptive β-cell proliferation, we measured gene expression in islets from young mice after pancreatectomy. As expected, partial pancreatectomy induced differential expression of many genes, including those encoding Reg (regenerating) proteins. Surprisingly, partial pancreatectomy also induced expression of Reg genes in islets from aged mice, which have greatly reduced capacity for adaptive β-cell proliferation. However, there was little overlap (besides the Reg genes) in between the partial pancreatectomy induced islet genes in young mice versus old mice. Thus, partial pancreatectomy does not induce the same gene expression program in young mice vs old mice. Taken together, our results reveal that aged islets exhibit a unique gene expression signature that could contribute to the limited regenerative capacity of mature β-cells.

Figure 1

Aging is associated with distinct gene expression patterns in islets. Genomic microarray mRNA expression analysis of islets in the basal state, comparing islets from young mice (1.5 months of age) versus those from old mice (14 or 19 months of age). The two pair-wise arrays comprising in this data set (N2) represented the expression sets that exhibited the least exocrine contamination. (A) Heat map of the 91 elements of the PancChip microarray that were differentially expressed 1.5-fold change (FC) or more. Red: genes with higher expression in islets from young versus old mice. Green: genes with lower expression in islets from young versus old mice. (B and C) The most differentially expressed genes in islets from young versus old mice. (B) Genes that were expressed at higher levels in young mice. (C) Genes that were expressed at lower levels in young mice.

Figure 2

Partial pancreatectomy induces cell cycle component gene expression in islets from young mice but not in old mice. Candidate qPC R mRNA expression studies of islets after 50% partial pancreatectomy versus sham-operated controls. (A) Studies performed in young mice (1.5 months). (B) Studies performed in old mice (14 months). Results expressed as fold change from control.

Figure 3

Partial pancreatectomy induces distinct gene expression patterns in islets from young mice versus old mice, except for Reg family genes. Genomic microarray mRNA expression analysis of islets after partial pancreatectomy (PPx) versus sham operated controls (Sham). (A–C) Partial pancreatectomy studies in young mice (1.5 months of age). (A) Heat map of the 115 elements of the PancChip microarray that were differentially expressed 1.5-fold or more. Red: genes with higher expression in islets after PPx. Green: genes with lower expression in islets after PPx. (B and C) The most differentially expressed genes in islets after PPx. (B) Genes that were expressed at higher levels after PPx. (C) Genes that were expressed at lower levels after PPx. (D and E) Partial pancreatectomy studies in old mice (14 months of age). (D) Heat map of the 83 elements of the PancChip microarray that were differentially expressed 1.5-fold or more. (E) Genes that were expressed at higher levels after PPx. (F and G) Overlap analysis of PPx induced genes in both young and old mice. (F) Heat map of the 10 elements of the PancChip microarray that were commonly induced 1.5-fold or more. (G) Genes that were commonly induced by PPx in both young and old mice.