Abstract
The pro- or anti-inflammatory activities of immunoglobulins G (IgGs) are controlled by the structure of the glycan N-linked to Asn297 of their heavy chain. The age-associated low grade inflammation (inflammaging) is associated with increased plasmatic levels of agalactosylated IgGs terminating with N-acetylglucosamine (IgG-G0) whose biogenesis has not been fully explained. Although the biosynthesis of glycans is in general mediated by glycosyltransferases associated with internal cell membranes, the extracellular glycosylation of circulating glycoproteins mediated by plasmatic glycosyltransferases has been recently demonstrated. In this study we have investigated the relationship between plasmatic glycosyltransferases, IgG glycosylation and inflammatory and aging markers. In cohorts of individuals ranging from infancy to centenarians we determined the activity of plasmatic β4 galactosyltransferase(s) (B4GALTs) and of α2,6-sialyltransferase ST6GAL1, the glycosylation of IgG, the GlycoAge test (a glycosylation-based marker of aging) and the plasma level of inflammatory and liver damage markers. Our results show that: 1) plasmatic B4GALTs activity is a new marker of aging, showing a linear increase throughout the whole age range. 2) plasmatic ST6GAL1 was high only in children and in people above 80, showing a quadratic relationship with age. 3) Neither plasmatic glycosyltransferase correlated with markers of liver damage. 4) plasmatic ST6GAL1 showed a positive association with acute phase proteins in offspring of short lived parents, but not in centenarians or in their offspring. 5) Although the glycosylation of IgGs was not correlated with the level of the two plasmatic glycosyltransferases, it showed progressive age-associated changes consistent with a shift toward a pro-inflammatory glycotype.
Highlights
Aging has been recently proposed as a continuation of developmental growth [1] and is characterized by a chronic, low grade, asymptomatic process, defined as “inflammaging” [2,3,4,5], whose individual level is related to biological age and risk of age-related diseases
3) Neither plasmatic glycosyltransferase correlated with markers of liver damage. 4) plasmatic ST6GAL1 showed a positive association with acute phase proteins in offspring of short lived parents, but not in centenarians or in their offspring
The level of ST6GAL1 and B4GALTs was measured in the plasma of individuals of both gender belonging to six age groups: children, young, middle aged, old, oldest old and centenarians
Summary
Aging has been recently proposed as a continuation of developmental growth [1] and is characterized by a chronic, low grade, asymptomatic process, defined as “inflammaging” [2,3,4,5], whose individual level is related to biological age and risk of age-related diseases. A good example is provided by the asparagine-linked (N-linked) sugar chain attached to Asn297 of IgG which, according to the presence or absence of specific terminal sugars, modulate the proor anti inflammatory properties of the antibody [9, 10]. It is known since the ’80s that the blood of rheumatoid arthritis patients contains IgG molecules with sugar chains lacking sialic acid and galactose and terminating with N-acetylglucosamine (GlcNAc), which are referred to as IgG-G0 [11]. The GlycoAge test is a widely recognized glycosidic marker of biological age [13,14,15,16], based on the relative abundance, in plasmatic glycoproteins, of two N-glycan species (an agalactosylated core fucosylated biantennary and a bigalactosylated, core fucosylated biantennary), as detected by DNA sequencer-aided fluorophore assisted carbohydrate electrophoresis (DSA-FACE) [17]
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