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Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype (SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-κB Essential Modulator (NEMO) was the most promising  in-silico  knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts  in-vitro . We strengthen the speculated regulator function of the NF-κB signaling pathway in the onset and maintenance of the SASP using  in-silico  and  in-vitro  approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-κB, giving access to possible therapy targets for SASP-accompanied diseases.

A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence