Investigating the role of IL6 exposure on biological aging in the context of asthma

Background: Interleukin (IL)-6 is a prominent pro-inflammatory cytokine driving chronic pathological processes in asthma. IL-6 is acutely increased during viral infection episodes and is higher in asthmatics. Notably, young asthmatic males report more frequent viral infections compared to their female counterparts, potentially driving sexually dimorphic asthma patterns. IL-6 is associated with accelerated biological aging in multiple diseases; however, this relationship in asthma remains unknown. As such, repeated IL-6 exposure during multiple viral infections may alter biological aging rates. We aimed to establish whether IL-6 is associated with sex-specific aging in asthma and to generate a respiratory cell model to explore IL-6, biological aging and sex in asthma. Methods: DNA methylation from nasal brushings of the paediatric ALLIANCE cohort (n=120, mean age=11yr, range=3–20yr) was processed and analysed by Illumina EPIC array using R (v4.5.1). Uniform manifold approximation and projection mapping (UMAP) was leveraged to generate an intracohort DNAm age (DNAge), which was analysed in relation to DNAm levels in the IL-6 promoter region. To establish an appropriate model for repeated IL-6 exposure, specific IL-6-responsive genes ( SOCS3 and CHI3L1 ) were assessed using a two-dimensional time (4,6,8,24,48hr) and dose (0.5, 1, 10, 50, 100 ng/ml) matrix in a bronchial epithelial cell line (BEAS-2B). Gene expression was analysed via real-time quantitative polymerase chain reaction. Results: DNAge-accelerated asthmatic females exhibited reduced methylation of the IL-6 promoter compared to DNAge-decelerated asthmatic females (p