Glycosylation is a key structural modification of immunoglobulin G (IgG) that modulates its effector functions and has multiple roles in balancing inflammation. Altered IgG glycosylation has been reported in many diseases, often years before clinical manifestation, suggesting its causal role and biomarker potential. Here, we analyzed IgG glycome composition in 20,405 individuals from 42 different studies processed at the Genos Glycoscience Research Laboratory between 2008 and 2025. Across nearly all diseases, specific IgG glycome profiles reflected accelerated biological aging. Accelerated glycan aging was strongly associated with increased risk of all-cause mortality, independent of established clinical risk factors and potential confounders. Moreover, interventions known to reduce mortality risk, including hormone replacement therapy, therapeutic plasma exchange and caloric restriction, were associated with reversal of glycan aging. Given their role in modulating low-grade systemic inflammation, IgG glycans may represent a functional link between chronic inflammation, aging, disease susceptibility and all-cause mortality.

G.L. is founder and shareowner of Genos and GlycanAge, biotech companies that specialize in glycan analysis and have several patents in the field. A.M., F.V., A.F.H., B.R., H.D., B.R.T., F.L., A.C., I.G., N.S.B., G.J., J.S., I.W., J.K., T.P., M.H., M.P.B., I.T.A., T.S., J.S., M.M.K., M.F. and A.C. are employees of Genos. T.D.S. is a co-founder of ZOE Ltd. JH has received consulting and/or advisory board fees from AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Hospira, Index Pharmaceuticals, Janssen, Johnson & Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB; speakers fees from AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma; and research grant support from Janssen, Merck Sharp & Dohme and Takeda.

This work was supported by the Human Glycome Project. Equipment and products from GlycanAge, Waters and New England Biolabs, Inc. were used for this research. IgG glycome analysis was supported through the following Horizon Europe grants: GlycanSwitch (contract no. 101071386), SYNHEALTH (contract no. 101159018) and AttractAdria (contract no. 101216942). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Wellcome Leap Dynamic Resilience Programme (co-funded by Temasek Trust), Zoe Ltd, the National Institute for Health and Care Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guys and St Thomas NHS Foundation Trust in partnership with Kings College London. CM is funded by the Chronic Disease Research Foundation (CDRF) and by the Italian Ministry of Education and Research (MUR): Dipartimenti di Eccellenza Program 2023-2027. The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), a Royal Society URF to J.F.W., the MRC Human Genetics Unit quinquennial programme QTL in Health and Disease, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). The GCKD study was and is supported by the BMBF (FKZ 01ER 0804, 01ER 0818, 01ER 0819, 01ER 0820 and 01ER 0821) and the KfH Foundation for Preventive Medicine. Unregistered grants to support the study were provided by corporate sponsors (listed at https://gckd.org). We are grateful for the willingness of the patients to participate in the GCKD study. The enormous effort of the study personnel of the various regional centers is highly appreciated. We thank the large number of nephrologists who provide routine care for the patients and collaborate with the GCKD study. The work of U.T.S. and A.K. was funded by German Research Foundation (DFG) project ID 431984000 (SFB 1453). The PRECISESADS studies received funding from the IMI 2 JU for the 3TR project (grant number 831434). The JU receives support from the EU Horizon 2020 research and innovation programme and EFPIA.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This research integrates data from a total of 20,045 participants originating from multiple independent studies, both cross-sectional and prospective, encompassing healthy individuals and patients with a range of diseases. Participants were recruited across diverse international sites, ensuring broad demographic and clinical representation. In all studies, IgG N-glycome profiling was performed using standardized UHPLC, LC-MS or CGE methodologies, analyzing either total IgG or subclass-specific Fc glycopeptides according to the respective study protocols. Each study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the relevant institutional or national ethics committees, with all participants providing written informed consent prior to enrolment. For glycomic datasets that have been previously published, the corresponding PMID references are provided in the Supplementary Table 1, and detailed descriptions of the study design, recruitment, and analytical procedures can be found in their original publications. In addition to these published datasets, several unpublished glycomic datasets were included in the present study to expand coverage and improve population diversity. The descriptions of these studies are provided below. Heart Failure The heart failure (HF) study consisted of 191 patients with heart failure and 95 control subjects, all recruited at University Hospital Dubrava, Zagreb, Croatia. The heart failure group had a mean age of 65 years, including 135 men (71%) and 55 women (29%). Clinical severity was distributed across New York Heart Association (NYHA) functional classes I-IV, with most patients in class II (58%) and class III (23%). Based on left ventricular ejection fraction (LVEF) (mean 39%), patients were classified as Heart Failure with Reduced Ejection Fraction (HFrEF) (n=103, 54%), (Heart Failure with Mildly Reduced Ejection Fraction) HFmrEF (n=33, 17%), and Heart Failure with Preserved Ejection Fraction (HFpEF) (n=51, 27%). Circulating N-terminal pro-B-type Natriuretic Peptide (NT-proBNP) levels were markedly elevated (mean ~4047 pg/mL). The control group included 95 individuals (mean age 64 years), comprising 58 men (61%) and 37 women (39%), without clinical heart failure. Plasma IgG was isolated and analyzed for N-glycan composition using UHPLC under the same experimental conditions as for the other studies. The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of University Hospital Dubrava. German Chronic Kidney Disease The German Chronic Kidney Disease (GCKD) study is a well described48,49 and ongoing multi-center prospective cohort study that recruited 5,217 participants with chronic kidney disease from 169 nephrology practices as well as nine university clinics across Germany. To be eligible, patients had to have an eGFR of 30-60 mL/min/1.73m2 or >60 mL/min/1.73m2 with excess albuminuria. Clinical endpoints are being prospectively collected in a standardized manner, with ongoing follow-up based on hospital discharge summaries and death certificates, capturing both kidney-related events and mortality. N-glycomic analysis was performed using UHPLC using the same experimental conditions as described for the other studies. The gathered data was used to examine the association of IgG glycans with prevalent diabetes mellitus (either type 1 or type 2 diabetes mellitus; N=1868 / 35.8 %; DM1 study), cardiovascular disease (defined as prevalent coronary heart disease, history of stroke or prevalent peripheral arterial disease; N=1591 / 30.5%; CVD1 study) and all-cause mortality. The GCKD study is registered as a national clinical study (DRKS 00003971) and was approved by local ethics review boards of all participating institutions. The study adheres to the principles set out in the Declaration of Helsinki PRECISESADS The PRECISESADS cohort included a total of 854 serum samples provided by collaborators from the 3TR consortium. 542 originated from cross-sectional collections and 59 from an inception cohort, while 263 samples represented healthy control subjects. After quality control, 92 healthy control samples and 88 rheumatoid arthritis (RA3), 128 Sjoegrens disease (SjD1) and 87 systemic sclerosis (SSc) samples were included in the analysis. All data were fully anonymized prior to transfer, and available metadata included only age, sex, and diagnostic category. The samples were previously characterized according to clinical diagnosis and stratified into molecular clusters as described in the PRECISESADS study. Plasma IgG was isolated and analyzed for N-glycan composition using UHPLC under the same experimental conditions as for the other studies. The study adhered to the standards set by International Conference on Harmonization and Good Clinical Practice (ICH-GCP), and to the ethical principles that have their origin in the Declaration of Helsinki (2013). Each patient signed an informed consent prior to study inclusion. The Ethical Review Boards of the participating institutions approved the protocol. EZE-DZHK The EZE-DZHK cohort represents a cross-sectional, multi-disease study encompassing a spectrum of chronic inflammatory conditions, established at the Christian-Albrechts-University of Kiel (CAU), Germany, within the framework of the broader SYSCID (Systems Medicine of Chronic Inflammatory Diseases) initiative. This cohort was designed to capture shared and disease-specific molecular features across immune-mediated disorders and includes patients sampled at a single clinical time point under standardized conditions. The study population comprised a total of 871 individuals, including patients diagnosed with five distinct chronic inflammatory diseases (EZE): systemic lupus erythematosus, ulcerative colitis, Crohns disease, rheumatoid arthritis, and psoriatic arthritis, as well as a control group consisting of individuals with cardiovascular, non-inflammatory conditions (DZHK). After quality control, a total of 609 samples were retained for downstream analyses. The final dataset included 197 control samples, 52 SLE samples (SLE4 study), 71 UC samples (UC4 study), 99 CD samples (CD4 study), 87 RA samples (RA2 study) and 103 PsA samples (PsA1 study). Total plasma IgG was isolated using standardized purification protocols to ensure comparability across disease groups. Subsequent characterization of IgG N-glycosylation was performed at the subclass level, employing subclass-specific Fc glycopeptide analysis following tryptic digestion. Glycopeptides were analyzed using LC-MS as described in the subsequent section. All study procedures were conducted in accordance with the ethical principles outlined by the SYSCID consortium and adhered to relevant institutional and regulatory guidelines governing human subject research. The study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of the Christian-Albrechts-Universitaet zu Kiel (A 124/14). Hormone replacement therapy To evaluate the effect of HRT on IgG glycans, female patients from the Newson Clinic who initiated HRT at the time of recruitment were selected. Patients were started on oestrogen in combination with progesterone, testosterone or both (Supplementary Table 8). The analysis included 19 women, followed for up to 15 months (mean follow-up = 10.1 months). The mean age at baseline was 52.6 years (sd = 4.15). Participants underwent repeated measurements during the study period: five women had two measurements, eleven had three measurements, and three had four measurements. Detailed information about the study characteristics can be found in Supplementary Table 8 and Supplementary Table 9. At each time point the dried blood spots were collected for the IgG N-glycome measurements that were performed using UHPLC under the same experimental conditions as for the other studies. The study protocol was approved by the Genos ethic committee and all participants signed the written consent.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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TwinsUK: The data used in this study are held by the Department of Twin Research at Kings College London. The data can be released to bona fide researchers using our normal procedures overseen by the Wellcome Trust and its guidelines as part of our core funding (https://twinsuk.ac.uk/resources-for-researchers/access-our-data/). ORCADES: There is neither Research Ethics Committee approval, nor consent from individual participants, to permit open release of the individual level research data underlying this study. The datasets analysed during the current study are therefore available via managed access from vikinged.ac.uk, following approval by the Viking Genes Data Access Committee and in line with the consent given by participants. Each approved project is subject to a data or materials transfer agreement (D/MTA) or commercial contract. HT study: The raw data are available on the PRIDE archive (http://www.ebi.ac.uk/pride) under the identifier: PXD015684. Data from the other studies is available from the corresponding authors upon request.

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