Accelerated biological aging and underlying epigenetic modification mediated the association between obesity and asthma

BACKGROUND: The relationships among obesity, accelerated biological aging, and asthma, as well as the underlying epigenetic mechanisms, remain incompletely understood. METHODS: We conducted a prospective cohort study in the UK Biobank to evaluate whether accelerated biological aging mediates the association between obesity and incident asthma. We then performed two-sample Mendelian randomization (MR) to assess the potential causal effect of accelerated biological aging on asthma from an epigenetic perspective. Epigenetic MR and colocalization analyses were used to prioritize aging-related DNA methylation (DNAm) CpG sites associated with asthma. Finally, single-cell RNA sequencing (scRNA-seq) was applied to characterize the cell-type-specific expression patterns of CpG-mapped genes. RESULTS: In the UK Biobank cohort, KDM-BA acceleration and PhenoAge acceleration partially mediated the association between obesity and asthma, with proportions mediated of 4.0% and 12.2%, respectively. Two-sample MR further suggested that DNAm PhenoAge acceleration was associated with a higher risk of asthma (OR = 1.02; 95% CI: 1.01-1.03; P = 0.004). Epigenetic MR and colocalization analyses suggested that cg02010481 (JAZF1), cg17929770 (RSPH6A), cg19927816 (SYMPK; RSPH6A), cg08544331 (RUNX3), cg15498134 (RUNX3), and cg04389704 (FBXL19) were associated with a reduced risk of asthma, whereas cg16553500 (COL16A1), cg16351569, cg10036013 (FOXK1), cg11647481 (FOXK1), cg23776012 (KRT222), and cg08258403 were associated with an increased risk of asthma. In scRNA-seq analyses, JAZF1, SYMPK, FOXK1, and RUNX3 were differentially expressed across multiple immune cell types. CONCLUSIONS: This study demonstrates that accelerated biological aging partially mediates the association of obesity with asthma and further elucidates underlying epigenetic mechanisms linking aging to asthma.