Implications of aberrant glycosylation on age-related disease progression

Glycosylation, the enzymatic attachment of glycans to proteins, is a ubiquitous post-translational modification in eukaryotes, responsible for many essential physiological processes such as moderating protein folding, stability, trafficking, and cell-cell communication. Through N-linked and O-linked glycosylation pathways, complex glycoforms are formed that are indispensable for maintaining cellular homeostasis. Emerging evidence suggests that glycosylation patterns undergo significant alterations with aging and across a range of diseases, including cancer, diabetes mellitus, neurodegenerative disorders, hypertension, osteoporosis and cardiovascular diseases. Age-associated reductions in galactosylation and fucosylation of serum N-glycans have been recognized as biomarkers of biological aging. Additionally, hyperfucosylation of glycoproteins has been reported in age-related malignancies, while altered glycosylation patterns are associated with osteoporosis. Moreover, increased glycosylation of glial fibrillary acidic protein (GFAP) contributes to reactive astrogliosis in Alzheimer’s disease, while altered glycan profiles of α-synuclein are associated with protein aggregation in Parkinson’s disease, highlighting the role of glycoform modulation in the progression neurodegenerative disorders. Additionally, dysregulated O-GlcNAcylation pattern impairs insulin signaling and β-cell viability in metabolic disorders such as diabetes. Likewise, aberrant N- and O-glycan structures derive cancer progression and metastasis by altering cell adhesion, promoting immune evasion, and modulating extracellular matrix interactions. In cardiovascular diseases, abnormal IgG glycosylation and elevated O-GlcNAcylation of vascular proteins promote pro-inflammatory and pro-fibrotic responses. Similarly, changes in the glycosylation of osteogenic proteins, including osteopontin and alkaline phosphatase, impair bone formation and remodeling in osteoporosis. Collectively, this review aims to highlight the most commonly associated age-related disease and the connection of glycosylation in both the pathophysiology and its therapeutic aspects.