Glycan Biomarkers Enable Accurate Prediction of Biological Aging in Mice

A new study published in Engineering has established an absolute quantification strategy for immunoglobulin G (IgG) N-glycans linked to aging, providing a reliable method to assess biological age and explore anti-aging interventions. Researchers from Fudan University employed glycomic and transcriptomic approaches to identify key glycan markers and build a predictive model for biological aging, while also investigating the rejuvenating potential of IgG modified with youthful N-glycan signatures.

The research focused on longitudinal changes in IgG N-glycans in C57BL/6 mice across natural aging and caloric restriction (CR) models. Glycomic profiling revealed consistent age-related shifts: The bisected glycan GP3 (F(6)A2B) was significantly downregulated, whereas the digalactosylated glycan GP8 (F(6)A2G2) showed sustained upregulation from early adulthood onward. Using external standards for these two glycans, the team established precise absolute concentration measurements, which supported the development of the abGlycoAge prediction model. When applied to CR mice, the model indicated a younger biological state, with an average age reduction of 3.9 to 14.0 weeks compared to age-matched mice fed ad libitum.

To uncover the molecular basis of these glycan changes, the team performed RNA sequencing on splenic B cells. The analysis revealed that the expression of Derl3, Smarcb1, Ankrd55, Tbkbp1, and Slc38a10 was altered during aging and partially reversed by CR, suggesting these genes contribute to the regulation of GP3 and GP8 levels. Gene set enrichment analysis further confirmed perturbation of protein N-linked glycosylation pathways in aged mice, consistent with the observed glycan profile shifts.

In a preliminary therapeutic assessment, 80-week-old mice were administered IgG modified with young signature N-glycans (IgG-Ny), IgG modified with youthful N-glycans. High-dose IgG-Ny treatment alleviated multiple aging-related declines, including reduced levels of the inflammatory cytokines interleukin-6 and tumor necrosis factor-α, as well as decreased senescence-associated β-galactosidase staining in the brain, kidneys, and lungs. Low-dose IgG-Ny showed weaker or inconsistent effects across tissues, indicating dose-dependent and organ-specific responses.

This work advances glycan-based aging assessment by moving beyond relative quantification to absolute concentration measurements, which support more consistent and translatable biomarker applications. The identification of GP3 and GP8 as stable aging-associated glycans, together with the abGlycoAge model, provides a practical tool for evaluating biological aging and testing anti-aging strategies. The findings also highlight glycoengineering of IgG as a potential avenue for developing interventions to mitigate age-related physiological deterioration.