AP-1 complex activation is a conserved signature of immune system aging and a potential regulator of inflammaging in human and mice

Increased inflammation with age (i.e., inflammaging) is a hallmark of aging conserved in human and mice, but the underlying mechanisms are poorly understood, partially because a systematic comparative study of mouse and human immune system aging is lacking. We uncovered epigenomic/transcriptomic signatures of aging in spleen and peripheral blood lymphocytes from young (3 months) and old (18 months) mice in two strains: C57BL/6J (long-lived) and NZO/HILtJ (short-lived) and compared these to the aging signatures of human peripheral blood cells. The most predominant and conserved genomic signature of aging in human and mice tissues studied here was the epigenetic activation of several AP-1 complex members (Fos, Fosl2, Junb, Jund). Footprinting analyses showed that these transcription factors ‘bind’ more frequently with age and target pro-inflammatory and effector molecules, including the pro-inflammatory Il6. Analysis of single cell RNA-seq data from the mouse aging cell atlas (Tabula Muris Senis) revealed that AP-1 activation with age is a common feature across all immune cell types within spleens, yet macrophages express these molecules more often than other cells. Functional assays confirmed that spleen cells from older animals have increased c-JUN protein binding and increased IL6 production upon myeloid cell activation using poly(I:C) via TLR3. Western blot data revealed that c-JUN activation with age is not post-transcriptional since its phosphorylation levels were similar between young and old mice. Together, these data established that Jun and Fos families in the AP-1 complex are transcriptionally activated with age and target pro-inflammatory molecules and aging-related increases in the binding of these proteins likely modulate increased inflammation with age.