AP-1 is a regulatory transcription factor of inflammaging in the murine kidney and liver

Abstract

Aging is characterized by chronic low-grade inflammation in multiple tissues, also termed “inflammaging”, which represents a significant risk factor for many aging-related chronic diseases. However, the mechanisms and regulatory networks underlying inflammaging across different tissues have not yet been fully elucidated. Here, we profiled the transcriptomes and epigenomes of the kidney and liver from young and aged mice and found that activation of the inflammatory response is a conserved signature in both tissues. Moreover, we revealed links between transcriptome changes and chromatin dynamics through integrative analysis and identified AP-1 and ETS family transcription factors (TFs) as potential regulators of inflammaging. Further in situ validation showed that c-JUN (a member of the AP-1 family) was mainly activated in aged renal and hepatic cells, while increased SPI1 (a member of the ETS family) was mostly induced by elevated infiltration of macrophages, indicating that these TFs have different mechanisms in inflammaging. Functional data demonstrated that genetic knockdown of Fos, a major member of the AP-1 family, significantly attenuated the inflammatory response in aged kidneys and livers. Taken together, our results revealed conserved signatures and regulatory TFs of inflammaging in the kidney and liver, providing novel targets for the development of anti-aging interventions.