Associations between markers of cellular ageing and of inflammation in bipolar disorders: Identification of IL-16 as an indicator of "inflamm-ageing"

BACKGROUND: Bipolar disorder (BD) has been associated with biomarkers of ageing and of inflammation with little information about associations between markers. METHOD: Using blood samples of 139 individuals with BD, we generated Horvath, Hannum, EN, GrimAge and PhenoAge epigenetic ages and used a latent profile analysis to construct subgroups of individuals based on their profile of epigenetic age accelerations. In blood samples, we measured telomere length (TL), mitochondrial DNA copy number (mtDNAcn), and 29 markers of inflammation of which 18 were analyzed. RESULTS: Univariate analyses showed higher levels of IL-16, IL-7, IL-10, IL-1RA, IL-12-IL-23p40, TNF-alpha, TNF-R1, ICAM-1, VCAM-1 and HLA-E in the epigenetically older group, and negative correlations between mtDNAcn and TNF-alpha, IP-10, VCAM-1 and IL-6R and one positive correlation between TL and IL-15. After Bonferroni correction, the associations between the epigenetically older group, IL-16 and HLA-E remained significant (p < 0.001). After adjustment for confounding variables, multivariate analyses confirmed an association between the epigenetically older group and higher levels of IL-16 (p = 0.001). Analyses of methylation of the IL-16 gene (26 sites) suggested that a lower methylation of cg20700699, located in an enhancer region, was associated with a higher level of IL-16 in the blood (p < 0.001). CONCLUSIONS: This study identified that an epigenetically older subgroup of individuals with BD were characterized by higher IL-16 blood levels. IL-16 may act as a central mediator linking immune activation, chronic inflammation, and accelerated biological ageing. If replicated, these results might support the concept of "inflamm-ageing" in BD.