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

Abstract

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.

COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status

“…Similarly, the mean age of COVID-19-positive patients was 56, whereas the control population was generally younger (mean: 33 years old). Nonetheless, although aging is associated with increased systemic inflammation, comparisons to prior studies on the effect of aging on the plasma/ whole-blood metabolome in humans (74,75) and animal models (52,54,56) does not suggest that the observations reported here are due to aging alone. In addition, the patients with COVID-19 in this study had significant disease, by definition, because they were all inpatients; future studies will investigate patients with milder disease and asymptomatic infected patients.…”

“…Therefore, activating this pathway may allow SARS-CoV-2 to evade immunity. Moreover, dysregulated tryptophan metabolism is seen in inflammation (51) and aging, resulting in decreased NAD synthesis in older animals (52) and humans, an observation suggesting nicotinamide riboside as a dietary supplement (53); this provides a potential metabolic explanation for the severity of COVID-19 in older subjects. It is worth noting that proinflammatory signaling favors proteolysis and amino acid catabolism (represented herein by increased acetyl-methionine and hydroxyproline and altered levels of free amino acids), which can be antagonized, in part, by antiinflammatory cytokines (e.g., IL-37) (54) or inflammasome inhibitors (55).…”

COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status

“…Therefore, activation of this pathway may be a mechanism by which SARS-CoV-2 promotes immune evasion. Moreover, dysregulated tryptophan metabolism is seen in inflammation (49) and aging, resulting in decreased NAD synthesis in older animals (50) and humans, an observation that supports an industry providing nicotinamide riboside as a dietary supplement (51); this suggests a potential metabolic explanation for the increased severity of COVID-19 in older subjects. In this context, it is worth noting that pro-inflammatory signaling favors proteolysis and amino acid catabolism (represented herein by increased acetyl-methionine and hydroxyproline, and altered levels of free amino acids), which can be antagonized, in part, by anti-inflammatory cytokines (e.g., IL-37)(52) or inflammasome inhibitors (53).…”

Influences of circulatory factors on intervertebral disc aging phenotype

“…Young (Y, aged 4 months) and old (O, aged 18 months) wildtype C57BL/6 male mice were obtained from the NIA-aged rodent colony for parabiosis and three mouse pairs were generated: young-young (Y-Y), young-old (Y-O), and old-old (O-O). Parabiosis surgery was performed as described in the Einstein Health Span Core [43,44]. In brief, an incision was made from lateral aspect of the elbow to the knee to separate the skin from the fascia layer, this allowed for fusion of the skin as well as part of the peritoneum, in order to increase the area for blood exchange.…”