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Identification of novel plasma glycosylation-associated markers of aging.

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.

SUBMITTER: Catera M

PROVIDER: S-EPMC4884931 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:(This section will be revisited in good time prior to publication, for final approval) Research within the field of functional genomics provides a more profound understanding of living organisms, by elucidating the interaction between genes and gene products. This is of increasing importance in many fields, and especially within cancer research. With the use of microarray technology, the gene expression of a vast number of genes can be measured simultaneously. This allows us insight into tumor biology, and an opportunity to obtain knowledge of diagnostic and prognostic value, as well as hints towards the causes of cancer. In this study the gene expression in a selection of human neuroendocrine (NE) and non-neuroendocrine tumor cell lines were compared. Both qualitative and quantitative methods were applied to get an insight into the NE tumor biology. NE cells are found in practically every organ and tissue in the body and are assigned to synthesize peptide hormones and take up amino acids and transform these into biogenic amines by carboxylation. NE tumors arise after malignant transformation of neuroendocrine cells and are usually highly differentiated and have a low growth rate, which makes this a high prevalence tumor type. These rather rare tumors characteristically express NE markers, such as chromogranin A, and contains characteristic dense-secretory core granules. By using cDNA microarray analysis, the gene expression profiles of various NE tumor cell lines (e. g. carcinoid, neuroblastoma, medullary thyroid carcinoma and endocrine pancreatic tumor) were compared with those of non-NE tumor cells. As a reference the commercially available Universal human RNA reference (Stratagene) was used. Verification of the results were done by real time RT-PCR analysis after the NE nature of the cell lines was stated by immunohistochemical, electron microscopic and light microscopic examinations. A large number of genes were differentially expressed in NE cell lines vs. the non-NE cell lines, and were found to be of interest in NE tumor biology. Some of these genes were previously known in NE tumor biology, whereas the vast majority of the specified genes are novel in the context of NE tumor biology. Genes with little previous information were also identified and thought to be an asset in the search of new NE markers. A feasible prospective of the study would be expansion with additional samples cell lines and a more thorough verification with real time RT-PCR analysis. This would enhance the credibility and thus the utility of the findings. Future studies on the biological functions of the candidate genes and the mechanisms of their regulation, will hopefully enable suggestions of new NE markers of prognostic or diagnostic value, and eventually new drug targets. Keywords: neuroendocrine, neuroendocrine markers, gene expression profiling, cDNA microarray

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Identification of novel plasma glycosylation-associated markers of aging.

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