Abstract

Chronological age is an imperfect tool for assessing healthspan and risk for diseases. As a result, biological markers of age become important components of personalized medicine. One of such markers, the plasma glycome, and especially Immunoglobulin G (IgG) $N$-glycosylation, is gaining attention due to its dynamic nature and involvement of genetics, environment, and lifestyle. In this review, we summarize current knowledge about the role of glycomic biological age markers (“Glycan Age”) in health and disease. Aging causes the progressive reduction in the levels of IgG galactosylation and sialylation with changes in fucosylation and bisection. Moreover, these structural changes do not only reflect the physiological decline, but also impact immune cell activity by changing the affinity for activating and inhibitory $Fc\gamma$ receptors and cause the shift from anti-inflammatory towards pro-inflammatory status resulting in sterile systemic low-level inflammation, called “inflammaging.” As a marker clinically, premature glycan aging becomes a strong predictor of disease outcomes in various disease categories. Glycan aging tends to occur several years prior to the onset of clinical symptoms in autoimmunity, heart diseases, metabolic syndromes, neurodegenerative conditions, and cancers, and works as an independent predictor of overall mortality. Importantly, glycan aging is a very manipulable clock; changes in endocrine status (perimenopause), lifestyle modifications, and therapies of longevity have been shown to effectively reverse this biological clock. Finally, it would be necessary to overcome the technical issues related to standardization and integrate glycomics into multi-omics clocks using machine learning approaches.

• 1.   Fares S, Wehrle CJ, Hong H, Sun K, Jiao C, Zhang M, et al. Emerging and Clinically Accepted Biomarkers for Hepatocellular Carcinoma. Cancers. 2024;16(8):1453. doi:10.3390/cancers16081453.
• 2.   Abeltino A, Hatem D, Serantoni C, Riente A, De Giulio MM, De Spirito M, et al. Unraveling the Gut Microbiota: Implications for Precision Nutrition and Personalized Medicine. Nutrients. 2024;16(22):3806. doi:10.3390/ nu16223806.
• 3.   Tan GSQ, Miller L, Wade S, Ilomäki J, Lukose D, Rong J, et al. Association Discovery Approach in Healthcare Big Data to Identify Drug Safety and Drug Repurposing Signals. Clin Pharmacol Ther. 2026;119(1):228-240. doi:10.1002/cpt.70080.
• 4.   Wu Y, Zhang Z, Chen L, Sun S. Immunoglobulin G glycosylation and its alterations in agingrelated diseases. Acta Biochim Biophys Sin. 2024;56(8):1221-1233. doi:10.3724/ abbs.2024137.
• 5.   Vinicki M, Pribić T, Vučković F, Frkatović- Hodžić A, Plaza-Andrades I, Tinahones F, et al. Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome. GeroScience. 2024;47(6). doi:10.1007/s11357-024-01349-z.
• 6.   Bu M, Li Z, Jones EE, Lubaba U, Liu X, Li H. Immunoglobulin G in aging and cancer. Front Immunol. 2026;17:1854902. doi:10.3389/ fimmu.2026.1854902.
• 7.   Gupta P, Sághy T, Bollmann M, Jin T, Ohlsson C, Carlsten H, et al. Local Immune Activation and Age Impact on Humoral Immunity in Mice, with a Focus on IgG Sialylation. Vaccines. 2024;12(5):479. doi:10.3390/vaccines12050479.
• 8.   Krištić J, Lauc G. The importance of IgG glycosylation—What did we learn after analyzing over 100,000 individuals. Immunological Reviews. 2024;328:143-170. doi:10.1111/imr.13407.
• 9.   Lyu YX, Fu Q, Wilczok D, Ying K, King A, Antebi A, et al. Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity. Aging. 2024;16. doi:10.18632/aging.206135.
• 10.   Mijakovac A, Lauc G, et al. The Immunoglobulin G Glycome: A Modifiable Biomarker and Functional Effector of Aging, Disease, and Mortality. medRxiv [Preprint]. 2026. doi:10.11 01/2026.01.15.26341250.
• 11.   Sun W, Jian X, Zhang J, Meng X, Wang H, Zheng D, et al. The Causality between Human Immunoglobulin G (IgG) N-Glycosylation and Aging: A Mendelian Randomization Study. Molecules. 2024;29(6):1281. doi:10.3390/ molecules29061281.
• 12.   Šimunić-Briški N, et al. Regular moderate physical exercise decreases Glycan Age index of biological age and reduces inflammatory potential of Immunoglobulin. Glycoconj J. 2024;41:67–76. doi:10.1007/s10719-024- 10145-w.
• 13.   Krištić J, Lauc G. Combining blood biochemistry and glycan ages for an even more prognostic biological age. medRxiv [Preprint]. 2025. doi:10.1101/2025.09.14.25335700.
• 14.   Chi Longevity. Your Real Age Explained: Five Biological Clocks of Health. Chi Longevity Educational Series. 2026 Mar [cited 2026 Jul 17]. Available from: https://chilongevity. com/education/your-real-age-explained-thefive-biological-clocks-of-health.
• 15.   Zhao H, et al. Absolute Quantification of Aging-Associated Glycans in IgG for Biological Age Prediction: Insights from Glycomics and Transcriptomics. bioRxiv [Preprint]. 2025. doi:10.1101/2025.04.12.548901.
• 16.   Rapčan B, Song M, Frkatović-Hodžić A, Pribić T, Vuk J, Beletić A, et al. Glycan clock of ageing— analytical precision and time-dependent interand intra-individual variability. GeroScience. 2024;46(5):5781–5796. doi:10.1007/s11357-024- 01124-0.
• 17.   Juan CG, et al. In Silico Network Perturbation Reveals Hierarchical Roles of DNA Repair and Glycosylation Linking Exercise to Human Ageing Clock. medRxiv [Preprint]. 2026. doi:1 0.1101/2026.02.01.26345311.
• 18.   Gilroy R, Lauc G. Glycoproteins and longevity: an interview with Professor Gordan Lauc. Expert Opin Ther Targets. 2024;28(6):487–489. doi:10.1080/14728222.2024.2351299.

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