Transcriptional activation of Jun and Fos members of the AP-1 complex is a conserved signature of immune aging that contributes to inflammaging. Aging Cell. 2023;22(4):e13792.
JGM, JMG, SS1, Animals, Humans, Mice, Aging, Interleukin-6, Mice, Inbred C57BL, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, Transcriptional Activation
Aging Cell. 2023;22(4):e13792.
This study was made possible by the generous financial support of the American Federation for Aging Research (AFAR), the National Institute of General Medical Sciences (NIGMS) under award number GM124922 (to D.U.), and National Institutes of Health (NIH) grants R01 AG052608, R01 AI142086, UH2 AG056925 (to J.B.), P30 AG038070 (The Jackson Laboratory's Nathan Shock Center of Excellence for the Basic Biology of Aging) (to R.K.), National Cancer Institute P30CA034196 and The PDX R&D Core (The Jackson Laboratory) (to M.H). Opinions, interpre- tations, conclusions, and recommendations are solely the responsibil- ity of the authors and do not necessarily represent the official views of the National Institutes of Health (NIH).
Diverse mouse strains have different health and life spans, mimicking the diversity among humans. To capture conserved aging signatures, we studied long-lived C57BL/6J and short-lived NZO/HILtJ mouse strains by profiling transcriptomes and epigenomes of immune cells from peripheral blood and the spleen from young and old mice. Transcriptional activation of the AP-1 transcription factor complex, particularly Fos, Junb, and Jun genes, was the most significant and conserved aging signature across tissues and strains. ATAC-seq data analyses showed that the chromatin around these genes was more accessible with age and there were significantly more binding sites for these TFs with age across all studied tissues, targeting pro-inflammatory molecules including Il6. Age-related increases in binding sites of JUN and FOS factors were also conserved in human peripheral blood ATAC-seq data. Single-cell RNA-seq data from the mouse aging cell atlas Tabula Muris Senis showed that the expression of these genes increased with age in B, T, NK cells, and macrophages, with macrophages from old mice expressing these molecules more abundantly than other cells. Functional data showed that upon myeloid cell activation via poly(I:C), the levels of JUN protein and its binding activity increased more significantly in spleen cells from old compared to young mice. In addition, upon activation, old cells produced more IL6 compared to young cells. In sum, we showed that the aging-related transcriptional activation of Jun and Fos family members in AP-1 complex is conserved across immune tissues and long- and short-living mouse strains, possibly contributing to increased inflammation with age.