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Functional Role of Aging Clock Genes Confirmed

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A new research paper was published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 24, entitled, “Mapping of the gene network that regulates glycan clock of ageing.”

Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing.

In this new study, researchers Azra Frkatović-Hodžić, Anika Mijakovac, Karlo Miškec, Arina Nostaeva, Sodbo Z. Sharapov, Arianna Landini, Toomas Haller, Erik van den Akker, Sapna Sharma, Rafael R. C. Cuadrat, Massimo Mangino, Yong Li, Toma Keser, Najda Rudman, Tamara Štambuk, Maja Pučić-Baković, Irena Trbojević-Akmačić, Ivan Gudelj, Jerko Štambuk, Tea Pribić, Barbara Radovani, Petra Tominac, Krista Fischer, Marian Beekman, Manfred Wuhrer, Christian Gieger, Matthias B. Schulze, Clemens Wittenbecher, Ozren Polasek, Caroline Hayward, James F. Wilson, Tim D. Spector, Anna Köttgen, Frano Vučković, Yurii S. Aulchenko, Aleksandar Vojta, Jasminka Krištić, Lucija Klarić, Vlatka Zoldoš, and Gordan Lauc from Genos Glycoscience Research LaboratoryUniversity of ZagrebNovosibirsk State UniversityLomonosov Moscow State UniversityUniversity of EdinburghUniversity of TartuLeiden University Medical CenterDelft University of TechnologyHelmholtz Zentrum MuenchenGerman Center for Diabetes Research (DZD)King’s College LondonGuy’s and St Thomas’ Foundation TrustUniversity of FreiburgUniversity of RijekaGerman Institute of Human Nutrition Potsdam-RehbrueckeUniversity of PotsdamHarvard T.H. Chan School of Public HealthChalmers University of TechnologyUniversity of Split School of MedicineAlgebra University CollegeJohns Hopkins Bloomberg School of Public Health, and Institute of Cytology and Genetics SB RAS performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans.

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“Here, we conducted a GWAS of IgG galactosylation phenotypes in a study that almost doubles the sample size (N=13,705) compared to previous GWAS of IgG N-glycome [33] and focused on the genes with in silico evidence for involvement in the IgG galactosylation process.”

Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system, the researchers manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.

“Further research is needed to fully elucidate [the] functional mechanism behind their role in ageing and to reveal the complete network of gene interactions regulating the complex process of IgG glycosylation.”

Reference: Frkatović-Hodžić A, Mijakovac A, Miškec K, et al. Mapping of the gene network that regulates glycan clock of ageing. Aging. 2023;15(24):14509-14552. doi: 10.18632/aging.205106

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