Unique human beta-cell senescence-associated secretory phenotype (SASP) reveal conserved signaling pathways and heterogeneous factors

The aging of pancreatic beta-cells may undermine their ability to compensate for insulin resistance, leading to the development of type 2 diabetes (T2D). Aging beta-cells acquire markers of cellular senescence and develop a senescence-associated secretory phenotype (SASP) that can lead to senescence and dysfunction of neighboring cells through paracrine actions, contributing to beta-cell failure. Herein, we defined the beta-cell SASP signature based on unbiased proteomic analysis of conditioned media of cells obtained from human senescent beta-cells. These experiments revealed that the beta-cell SASP is enriched for factors associated with inflammation, cellular stress response, and extracellular matrix remodeling across species. After FACS-sorting, beta-Gal-positive and negative primary beta-cells were plated in 96-well plates and incubated in serum-free islet media to generate conditioned media. Conditioned media were analyzed using SomaScan at the Genomics Proteomics Core at Beth Israel Deaconess Medical Center.