Female-specific biological aging is associated with asthma.

<bold>Introduction:</bold> Asthma is distinctly sexually dimorphic. Young males report higher asthma rates than females. This reverses at puberty, where females present increased incidence, reduced therapeutic effectiveness and worse asthma symptoms. The exact cause remains unknown. Biological DNA methylation (DNAm) clocks correlate with worse outcomes in chronic diseases such as asthma. The proinflammatory cytokine interleukin (IL)6 accelerates DNAm aging (DNAge) and promotes asthma symptoms. As such, we aimed to characterise the relationship between sex and DNAge clocks in asthma. <bold>Methods:</bold> Nasal brushings from the paediatric ALLIANCE cohort (n=46F/74M;asthma=73;avg age=11yr; range=3-20yr) were collected and DNAm analysed by Illumina EPIC array. DNAge was calculated using the established skinHorvath clock. The association between DNAge and sex, symptom severity, and frequency of inhaled corticosteroid (ICS) use was analysed. The relative methylation of the IL6 promoter region was also stratified by sex according to DNAge. <bold>Results:</bold> Highly symptomatic females have accelerated DNAge compared to (p=0.03), which is reinforced post-puberty (p=0.01). DNAge-accelerated females report increased asthma symptom frequency compared to normal, and DNAge-decelerated females, and all male groups (p<0.0001), despite equivalent ICS use. IL6 DNAm was reduced in DNAge-accelerated females compared to DNAge-decelerated females and both male groups (p=0.01). <bold>Conclusions:</bold> Our study identifies a DNAge accelerated asthmatic female sub-cohort that is highly symptomatic despite a similar frequency of ICS use compared to male counterparts. We present that the IL6 molecular pathway may drive this phenomenon, with further studies required to confirm a molecular mechanism.