Age-Related Oxidative Stress Compromises Endosomal Proteostasis

SummaryA hallmark of aging is an imbalance between production and clearance of reactive oxygen species and increased levels of oxidatively damaged biomolecules. Herein, we demonstrate that splenic and nodal antigen-presenting cells purified from aging mice accumulate oxidatively modified proteins with side-chain carbonylation, advanced glycation end products, and lipid peroxidation. Furthermore, we show that the endosomal accumulation of oxidatively modified proteins interferes with the efficient processing of exogenous antigens and degradation of macroautophagy-delivered proteins. In support of a causative role for oxidized products in the inefficient immune response, a decrease in oxidative stress improved the adaptive immune response to immunizing antigens. These findings underscore a previously unrecognized negative effect of age-dependent changes in cellular proteostasis on the immune response.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Aging dendritic cells (DCs) are characterized by an oxidatively modified proteome ► Aggregates of oxidized proteins accumulate in endosomal compartments ► The oxidatively damaged proteome compromises DC antigen processing and presentation ► Antioxidant treatment partially restores DCs' priming ability only in aging mice