Absolute Quantification of Aging-Associated Glycans in IgG for Biological Age Prediction: Insights from Glycomics and Transcriptomics

Abstract

Immunoglobulin G (IgG) N-glycans have been identified as associated with aging; however, previous studies predominantly quantified changes based on the relative percentages of each glycan within the total glycan pool, neglecting the absolute concentration changes of individual glycans. Additionally, relative quantification can limit practical applications, as these often require absolute concentration measurements for consistent and interpretable biomarker values. In this study, we introduce a novel strategy for discovering aging-associated IgG glycans and establishing a prediction model based on their absolute concentration alteration. We employed a glycome quantification technology to identify the alteration in IgG glycan amount in natural aging and anti-aging (caloric restriction) models, discovering aging-related glycans. The glycomics analysis revealed key features: downregulation of bisected glycan GP3 (F(6)A2B) and upregulation of digalactosylated glycan GP8 (F(6)A2G2). These glycan changes showed significant fold changes from an early stage. Using external standards of these two glycans, we subsequently measured the absolute concentrations of them, allowing us to establish a predictive model, abGlycoAge, for biological aging. The abGlycoAge index suggested a younger state under caloric restriction, with an average age reduction of 3.9-14 weeks. Additionally, we performed RNA sequencing on splenic B cells of mice, suggesting Derl3, Smarcb1, Ankrd55, Tbkbp1 and Slc38a10 could contribute to the alteration of GP3 and GP8 in aging. This analysis enhances our understanding of glycan alterations, accounts for individual variability, and aids in designing effective anti-aging strategies. These findings highlight the crucial roles of the GP3 and GP8 as potential biomarkers for aging and health.