1. SUMMARY
An important aspect of age-related research is to find proteins in human blood that can be used to track physiological processes of aging. Here, we have used a multiplexed affinity proteomics approach to search for the presence of age-associated protein levels in human body fluids. First, serum samples from 156 subjects aged 50-92 years were explored using a comprehensive bead array assay including 7,258 antibodies. We identified 16 age-associated profiles (adjusted P < 0.05) and followed up on the most significantly age-associated profiles in eight additional study sets (n = 4,044 individuals) analyzing both serum and plasma. Meta-analysis highlighted a consistent increase with age (P = 5.37 × 10−6) for variants of histidine-rich glycoprotein (HRG), which we confirmed by antibody validation assays and genome wide association studies. Higher levels of HRG, which is a plasma glycoprotein produced by the liver, also increased the risk of mortality during about 8.5 years follow-up (interquartile range = 7.7-9.3) after blood sampling at a hazard ratio = 1.25 per standard deviation (P = 6.45 × 10−5). Our multi-cohort affinity proteomics analysis found that blood levels of the multi-purpose HRG variants were associated with age and all-cause mortality. This combination suggests that elevated HRG levels could serve as an accessible molecular indicator for biological aging.