Parabiosis Incompletely Reverses Aging-Induced Metabolic Changes and Oxidant Stress in Mouse Red Blood Cells

Mature red blood cells (RBCs) not only account for ~83% of the total host cells in the human body, but they are also exposed to all body tissues during their circulation in the bloodstream. In addition, RBCs are devoid of de novo protein synthesis capacity and, as such, they represent a perfect model to investigate system-wide alterations of cellular metabolism in the context of aging and age-related oxidant stress without the confounding factor of gene expression. In the present study, we employed ultra-high-pressure liquid chromatography coupled with mass spectrometry (UHPLC-MS)-based metabolomics and proteomics to investigate RBC metabolism across age in male mice (6, 15, and 25 months old). We report that RBCs from aging mice face a progressive decline in the capacity to cope with oxidant stress through the glutathione/NADPH-dependent antioxidant systems. Oxidant stress to tryptophan and purines was accompanied by declines in late glycolysis and methyl-group donors, a potential compensatory mechanism to repair oxidatively damaged proteins. Moreover, heterochronic parabiosis experiments demonstrated that the young environment only partially rescued the alterations in one-carbon metabolism in old mice, although it had minimal to no impact on glutathione homeostasis, the pentose phosphate pathway, and oxidation of purines and tryptophan, which were instead aggravated in old heterochronic parabionts.