Notch/NF-κB crosstalk signaling controls SASP gene expression during brain aging

Brain aging is associated with chronic, low-grade inflammation known as inflammaging, which is largely driven by senescent glial cells secreting pro-inflammatory factors termed as senescence-associated secretory phenotype (SASP). In humans, the release of SASP factors in the brain is linked with an increased risk for the development of neurodegenerative disorders; thus, elucidating the underlying molecular mechanisms is essential for understanding the pathophysiology of brain aging. Both NF-κB and Notch signaling are known to regulate SASP expression; however, their mode of interaction in brain inflammaging is poorly understood. Here, we demonstrate that brain aging is broadly associated with NF-κB activation but Notch suppression using different transgenic mouse models. Astrocytic NF-κB activation in young mice was able to mimic premature SASP formation but repressed Notch signaling in parallel. Bioinformatic analyses further identified conserved crosstalk sites within SASP genes co-occupied by Notch/RBPJ and NF-κB transcription factors in vivo, allowing specific combinatorial regulation. Importantly, selective physical interactions enable that activated Notch can act as a negative modulator of NF-κB signaling at different molecular levels. Consistently, pharmacological activation of Notch in primary astrocytes significantly reduced NF-κB-driven SASP gene expression. Together, these findings identify Notch-NF-κB crosstalk as a potential therapeutic target to mitigate brain inflammaging.