Inflammatory Signaling Reduces Pancreatic Islet Cell Replication in Aging

Aging is marked by rising chronic inflammation and a decline in many aspects of tissue maintenance, such as stem cell activity, and willingness of somatic cells to replicate. Chronic inflammation appears to disrupt regenerative processes, but there are many distinct mechanisms involved, varying by tissue type, and present understanding is far from complete. Researchers here investigate one narrow slice of the problem in the pancreas in zebrafish, finding that beta cells, important to metabolic function due to their control of insulin, reproduce less readily in old individuals due to greater inflammation.

A hallmark of aging is the reduction in cellular renewal and proliferation across different tissues and organs. The insulin producing beta cells, which reside in the islets of Langerhans, provide a good model to study regulators of cellular aging. Whereas young beta-cell are highly proliferative and increase rapidly in number from the prenatal phase until early stages of development in mammals, beta-cell proliferation becomes dramatically reduced in adults.

Previous studies have indicated that both extrinsic factors, such as the vasculature, and intrinsic factors, such as chromatin modifications, may influence the age-related changes in beta-cells. For example, rejuvenating the beta-cell environment by implanting old islets in younger animals is sufficient to restore the proliferative potential of the aged beta-cells. In addition, transcriptome and methylome studies revealed age-dependent DNA methylation changes at cell-cycle regulators, which may contribute to the quiescence of aging beta-cell.

To identify signals that change in beta-cells during organismal aging, we used the zebrafish as a model. We first characterized the rate of beta-cell proliferation in juvenile, younger, and older adults, and found that proliferation declines with advancing age. We performed transcriptomics of beta-cells from younger and older animals, which identified an upregulation of genes involved in inflammation, including NF-kB signaling. The analysis of inflammatory signaling with single-cell resolution confirmed that NF-kB signaling was activated in a heterogeneous manner at the level of individual beta-cells. Notably, beta-cells with higher levels of NF-kB signaling exhibit a more pronounced proliferative decline compared to their neighbors with lower activity.



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