Interferon-related inflammaging links epigenetic age acceleration to multimorbidity

Chronic systemic inflammation and DNA methylation changes are two major hallmarks of aging, yet their interaction is poorly known. We investigated the relation between circulating inflammatory proteome and epigenetic age acceleration as assessed by DNA methylation in four independent cohorts of different ages and health conditions. Epigenetic age scores known to predict human health span (GrimAge and PhenoAge) were more strongly associated with age-associated inflammatory proteins, frailty, and multimorbidity when compared to epigenetic age scores associated with lifespan (Horvath and Hannum). Mendelian randomization analyses showed that blood concentrations of important inflammatory cytokines associated with the interferon pathway (CXCL9, CXCL10, CCL11, and IL-18) increase with age and are causal drivers of epigenetic age acceleration and age-related diseases. Furthermore, aging was associated with dysregulation of cytokine production capacity in immune cells in response to microbial stimulation. These findings argue that the interferon pathway may represent a target for anti-aging interventions.