Age-associated epigenetic modifications in human DNA increase its immunogenicity

Abstract

Chronic inflammation, increased reactivity to self-antigens and incidences of cancer are hallmarks of aging.However, the underlying mechanisms are not well understood. Age-associated alterations in the DNA either due tooxidative damage, defects in DNA repair or epigenetic modifications such as methylation that lead to mutations andchanges in the expression of genes are thought to be partially responsible. Here we report that epigenetic modifications inaged DNA also increase its immunogenicity rendering it more reactive to innate immune system cells such as the dendriticcells. We observed increased upregulation of costimulatory molecules as well as enhanced secretion of IFN-α fromdendritic cells in response to DNA from aged donors as compared to DNA from young donors when it was deliveredintracellularly via Lipofectamine. Investigations into the mechanisms revealed that DNA from aged subjects is notdegraded, neither is it more damaged compared to DNA from young subjects. However, there is significantly decreasedglobal level of methylation suggesting that age-associated hypomethylation of the DNA may be the cause of its increasedimmunogenicity. Increased immunogenicity of self DNA may thus be another mechanism that may contribute to theincrease in age-associated chronic inflammation, autoimmunity and cancer. © Agrawal et al.