Accelerated biological aging in people with Down syndrome with full and segmental trisomy 21 begins in childhood as revealed by immunoglobulin G glycosylation

Cells from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic aging marks. Causative mechanisms remain un-proven and hypotheses range from amplified chromosomal instability to actions of several supernumerary chromosome 21 genes. Plasma immunoglobulin G (IgG) glycosylation profiles are established as a reliable predictor of biological and chronological aging. We performed IgG glycan profiling of n=246 individuals with DS (208 adults and 38 children) from three European populations and compared these to age-, sex- and demography-matched general populations. We uncovered very significantly increased IgG glycosylation aging marks associated with DS. Average levels of IgG glycans without galactose (G0) and those with two galactoses (G2) as a function of age in persons with DS corresponded to levels detected in 19 years older euploid individuals. Some aging marks were significant already in children with DS. Remarkably, the IgG glycan profiles of a child with segmental duplication of only 31 genes on chromosome 21 had values similar to those of age-matched DS children, outside the normal children’s range. This is the first non-epigenetic evidence of accelerated systemic biological aging in DS, suggesting it begins very early in childhood. It points to a causative contribution of the overdose of genes in a short segment of chromosome 21, not previously linked to accelerated aging, opening a route to discovery of hitherto unrecognised mechanisms.