A central challenge in longevity research is determining whether an intervention can meaningfully influence how an individual ages. Waiting to observe its effect on lifespan would require a lifetime, making longevity itself an impractical research outcome. Scientists must therefore rely on biomarkers that provide earlier, measurable indications of the biological processes underlying ageing.
Among the most promising candidates are molecular biomarkers, particularly proteins and their post-translational modifications. Although a protein’s amino acid sequence generally remains unchanged throughout life, subsequent modifications can alter its structure, stability and function. One of the most common and biologically significant is glycosylation, the attachment of carbohydrate structures known as glycans to proteins or lipids. Glycans influence numerous molecular properties, while their final structures are shaped by a complex interplay of genetic and epigenetic factors. Consequently, the complete set of glycans within a cell, tissue or individual, i.e. the glycome, is highly dynamic, varying both between individuals and within the same person over time (https://pubmed.ncbi.nlm.nih.gov/39383621/).
The biological importance of glycosylation has long been recognised. The ABO blood group system, discovered by Karl Landsteiner in 1901, provides a landmark example (https://www.nobelprize.org/prizes/medicine/1930/landsteiner/facts/). ABO antigens are carbohydrate structures on red blood cells whose glycosylation determines blood group and transfusion compatibility, demonstrating how small differences in glycans can have major clinical consequences.
Despite their importance, glycans are difficult to analyse because of their structural complexity. Different structures may occupy the same glycosylation site and vary in composition, linkages, branching and chemical modifications. Unlike DNA, glycans cannot be amplified, so their characterisation requires multiple processing steps and sophisticated technologies. High-throughput glycomics now enables thousands of samples to be analysed through increasingly automated workflows. However, current methods remain largely focused on N-glycosylation and still face challenges in standardisation and reproducibility (https://www.nature.com/articles/s41589-026-02217-x).
Glycans play key roles in cell recognition and immune regulation. A well-characterised example is immunoglobulin G (IgG), the most abundant antibody in human blood. IgG carries N-linked glycans at Asn297 in its Fc region, where they influence receptor interactions and the antibody’s pro- or anti-inflammatory activity. This glycosylation profile changes markedly with age (Journal of Experimental Medicine), with increases in agalactosylated glycans, decreases in digalactosylated glycans (https://pubmed.ncbi.nlm.nih.gov/3367097/; https://doi.org/10.1093/gerona/glt190) and reduced sialylation (https://pubmed.ncbi.nlm.nih.gov/26840264/; https://pubmed.ncbi.nlm.nih.gov/42435950/). Similar changes occur in inflammatory and autoimmune diseases, suggesting that age-related remodelling may shift IgG towards a more pro-inflammatory state and supporting its potential as an ageing biomarker (https://pubmed.ncbi.nlm.nih.gov/19126970/; https://doi.org/10.1093/gerona/glt190).
While chronological age records the time since birth, biological age reflects the body’s condition and functional capacity. The GlycanAge index, based on three IgG glycan traits, has been reported to explain approximately 58% of the variation in chronological age. After adjustment for age and sex, it was also associated with body mass index, waist circumference, triglycerides and blood glucose (https://pubmed.ncbi.nlm.nih.gov/24325898/). Because these indicators are linked to age-related disease, glycan-derived age may capture aspects of health, inflammation and biological ageing beyond the passage of time. Glycan biomarkers could therefore help assess biological age and monitor responses to lifestyle changes as preventive measures or treatments.
Projects such as the Human Glycome Project and GlySign aim to translate this research into clinical practice by developing standards, generating large datasets and validating biomarkers. Although technological and regulatory challenges remain, glycans offer a dynamic source of information closely connected to immunity, inflammation, lifestyle and age-related disease. Glycan-based biomarkers may ultimately allow researchers to detect the effects of longevity interventions much earlier, making the glycome a valuable tool for understanding, measuring and potentially improving how we age.
“How old would you be if you didn’t know how old you was?” – Satchel Paige