High-throughput N-glycan analysis in aging and inflammaging: State of the art and future directions

As the global population ages at an unprecedented rate, the prevalence of age-related diseases is increasing, making inflammaging - a phenomenon characterized by a chronic, low-grade inflammatory state that follows aging - a significant concern. Understanding the mechanisms of inflammaging and its impact on health is critical for developing strategies to improve the quality of life and manage health in the aging population. Despite their crucial roles in various biological processes, including immune response modulation, N-glycans, oligosaccharides covalently attached to many proteins, are often overlooked in clinical and research studies. This repeated oversight is largely due to their inherent complexity and the complexity of the analysis methods. High-throughput N-glycan analysis has emerged as a transformative tool in N-glycosylation research, enabling cost- and time-effective, detailed, and large-scale examination of N-glycan profiles. This paper is the first to explore the application of high-throughput N-glycomics techniques to investigate the complex interplay between N-glycosylation and the immune system in aging. Technological advancements have significantly improved Nglycan detection and characterization, providing insights into age-related changes in Nglycosylation. Key findings highlight consistent shifts in immunoglobulin G (IgG) and plasma/serum glycoprotein glycosylation with age, with a pronounced rise in agalactosylated structures bound to IgG that also affect the composition of the total plasma N-glycome. These N-glycan modifications seem to be strongly associated with inflammaging and have been identified as valuable biomarkers for biological age, predictors of disease risk, and proxy biomarkers for monitoring intervention efficacy at the individual level. Despite current challenges related to data complexity and methodological limitations, ongoing technological innovations and interdisciplinary research are expected tofurther advance our knowledge of glycan biology, improve diagnostic and therapeutic strategies, and promote healthier aging. The integration of glycomics with other omics approaches holds promise for a more comprehensive understanding of the aging immune system, paving the way for personalized medicine and targeted interventions to mitigate inflammaging. In conclusion, this paper underscores the transformative impact of high-throughput Nglycan analysis in aging and inflammaging.