N-glycosylation remodeling in aging: Biomarkers and modulators of biological age across organ systems

Aging is characterized by progressive functional decline, increased disease susceptibility, and dysregulation of cellular homeostasis. Among post-translational modifications, N-glycosylation has emerged as a key regulator of protein stability, signaling, and immune function with broad relevance to aging biology. Recent large-scale glycomic studies demonstrate that the human N-glycome undergoes consistent age-associated remodeling across plasma, immune cells, and tissues, including reduced galactosylation and sialylation, altered fucosylation, and changes in N-glycan branching. These shifts are particularly pronounced on immunoglobulin G (IgG), where Fc N-glycan profiles serve as robust biomarkers of biological age, inflammation, morbidity, and mortality risk. Beyond circulating markers, cell and tissue-specific analyses reveal that regulated changes in glycosylation directly influence receptor signaling, inflammatory tone, and organ level aging phenotypes in the cardiovascular, nervous, and immune systems. Mechanistically, age-dependent N-glycan remodeling reflects the integrated effects of transcriptional reprogramming of glycosyltransferase networks, metabolic regulation of nucleotide sugar availability, and altered spatial organization of glycosylation enzymes within the Golgi apparatus. Importantly, emerging evidence indicates that plasma N-glycosylation patterns are partially reversible through metabolic and lifestyle interventions. Together, these findings position N-glycosylation as a central and dynamic component of aging biology, linking metabolic and inflammatory states to functional outcomes across biological scales. • IgG Fc N-glycan profiles are robust biomarkers of biological age. • Caloric restriction partially reverses pro-aging plasma glycan signatures. • Altered N-glycan branching and sialylation drive subset-specific T cell aging. • Aging remodels cardiac, lung, neural, and immune N-glycans via distinct pathways.