SummaryWe recently reported that N‐glycosylation changes during human aging. To further investigate the molecular basis determining these alterations, the aging process in mice was studied. N‐glycan profiling of mouse serum glycoproteins in different age groups of healthy C57BL/6 mice showed substantial age‐related changes in three major N‐glycan structures: under‐galactosylated biantennary (NGA2F), biantennary (NA2), and core α‐1,6‐fucosylated ‐β‐galactosylated biantennary structures (NA2F). Mice defective in klotho gene expression (kl/kl), which have a shortened lifespan, displayed a similar but accelerated trend. Interestingly, the opposite trend was observed in slow‐aging Snell Dwarf mice (dw/dw) and in mice fed a calorically restricted diet. We also discovered that increased expression and activity of α‐1,6‐fucosyltransferase (FUT8) in the liver are strongly linked to the age‐related changes in glycosylation and that this increased FUT8 and fucosylation influence IGF‐1 signaling. These data demonstrate that the glycosylation machinery in liver cells is significantly affected during aging and that age‐related increased FUT8 activity could influence the aging process by altering the sensitivity of the IGF‐1R signaling pathway.