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The pancreatic islet, a cellular community harboring the insulin-producing beta-cells, is known to undergo age-related alterations. However, only a handful of signals associated with aging have been identified. By comparing beta-cells from younger and older zebrafish, here we show that the aging islets exhibit signs of chronic inflammation. These include recruitment of tnfalpha-expressing macrophages and the activation of NF-kB signaling in beta-cells. Using a transgenic reporter, we show that NF-kB activity is undetectable in juvenile beta-cells, whereas cells from older fish exhibit heterogeneous NF-kB activity. We link this heterogeneity to differences in gene expression and proliferation. Beta-cells with high NF-kB signaling proliferate significantly less compared to their neighbors with low activity. The NF-kB signaling(hi) cells also exhibit premature upregulation of socs2, an age-related gene that inhibits beta-cell proliferation. Together, our results show that NF-kB activity marks the asynchronous decline in beta-cell proliferation with advancing age.

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*Aging Animals Animals, Genetically Modified *Cell Proliferation Cells, Cultured Gene Expression Profiling Inflammation/immunology/metabolism/*pathology Inflammation Mediators/*metabolism Insulin-Secreting Cells/immunology/metabolism/*pathology NF-kappa B/genetics/*metabolism Signal Transduction Single-Cell Analysis Transcriptional Activation Zebrafish/immunology/*physiology *Diabetes *Inflammation *NF-kB *beta-cells *cell biology *pancreas *zebrafish