Protein signatures from blood plasma and urine suggest changes in vascular function and IL-12 signaling in elderly with a history of chronic diseases compared with an age-matched healthy cohort
Yu Y, Singh H, Kwon K, Tsitrin T, Petrini J, Nelson KE, Pieper R
Key processes characterizing human aging are immunosenescence and inflammaging. The capacity of the immune system to adequately respond to external perturbations (e.g., pathogens, injuries, and biochemical irritants) and to repair somatic mutations that may cause cancers or cellular senescence declines. An important goal remains to identify genetic or biochemical, predictive biomarkers for healthy aging. We recruited two cohorts in the age range 70 to 82, one afflicted by chronic illnesses (non-healthy aging, NHA) and the other in good health (healthy aging, HA). NHA criteria included major cardiovascular, neurodegenerative, and chronic pulmonary diseases, diabetes, and cancers. Quantitative analysis of forty proinflammatory cytokines in blood plasma and more than 500 proteins in urine was performed to identify candidate biomarkers for and biological pathway implications of healthy aging. Nine cytokines revealed lower quantities in blood plasma for the NHA compared with the HA groups (fold change > 1.5; p value < 0.025) including IL-12p40 and IL-12p70. We note that, sampling at two timepoints, intra-individual cytokine abundance patterns clustered in 86% of all 60 cases, indicative of person-specific, highly controlled multi-cytokine signatures in blood plasma. Twenty-three urinary proteins were differentially abundant (HA versus NHA; fold change > 1.5; p value < 0.01). Among the proteins increased in abundance in the HA cohort were glycoprotein MUC18, ephrin type-B receptor 4, matrix remodeling-associated protein 8, angiopoietin-related protein 2, K-cadherin, and plasma protease C1 inhibitor. These proteins have been linked to the extracellular matrix, cell adhesion, and vascular remodeling and repair processes. In silico network analysis identified the regulation of coagulation, antimicrobial humoral immune responses, and the IL-12 signaling pathway as enriched GO terms. To validate links of these preliminary biomarkers and IL-12 signaling with healthy aging, clinical studies using larger cohorts and functional characterization of the genes/proteins in cellular models of aging need to be conducted.