DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden, Helmholtz Zentrum München at the University Hospital, German Center for Diabetes Research (DZD e.V.), Dresden, Germany; Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, German Center for Diabetes Reseach (DZD e.V.), Dresden, Germany
DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
Anastasia Tsakmaki
Diabetes Research Group, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, United Kingdom
S Neda Mousavy Gharavy
Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology, and Metabolism, Imperial College London, London, United Kingdom; Consortium for Islet Cell Biology and Diabetes, Department of Medicine, Imperial College London, London, United Kingdom
Priyanka Murawala
DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
Judith Konantz
DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
Sarah Birke
DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
Centre for Endocrinology, Diabetes, and Metabolism, University of Birmingham, Edgbaston, United Kingdom; Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, United Kingdom
Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology, and Metabolism, Imperial College London, London, United Kingdom; Consortium for Islet Cell Biology and Diabetes, Department of Medicine, Imperial College London, London, United Kingdom
DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden, Helmholtz Zentrum München at the University Hospital, German Center for Diabetes Research (DZD e.V.), Dresden, Germany; Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, German Center for Diabetes Reseach (DZD e.V.), Dresden, Germany
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 tnfα-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 signalinghi 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.
