Epigenetic attenuation of interferon signaling is associated with aging-related improvements in systemic lupus erythematosus

In the general population, aging is associated with an increase in systemic inflammation and chronic disease burden. However, in systemic lupus erythematosus (SLE), older age is uniquely associated with a decrease in disease activity, suggesting a distinct relationship between aging and inflammation. Using a multiomic approach, we compared aging-related changes in the peripheral blood immune profiles of 287 patients with SLE and 928 healthy controls. In patients with SLE, aging correlated with lower expression of interferon (IFN)–stimulated genes (ISGs) across multiple cell types, decreased plasma IFN-α2, and differential genome methylation. Both patients with SLE and controls demonstrated age-related declines in naïve T cells, but only patients with SLE exhibited increases in CD56 dim natural killer cells with older age. Of the genes both down-regulated and hypermethylated with older age, ISGs were disproportionately represented, suggesting a role for epigenetic silencing. Altogether, we found that patients with SLE exhibit unique aging-related decreases in IFN signaling that correlate with improved disease activity.