The Immunoglobulin G Glycome: A Modifiable Biomarker and Functional Effector of Aging, Disease, and Mortality

The Immunoglobulin G Glycome: A Modifiable Biomarker and Functional Effector of Aging, Disease, and Mortality | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Immunoglobulin G Glycome: A Modifiable Biomarker and Functional Effector of Aging, Disease, and Mortality Gordan Lauc, Anika Mijakovac, Elena Butz, Frano Vuckovic, Azra Frkatović-Hodžić, and 55 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9488315/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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. Health sciences/Biomarkers/Predictive markers Biological sciences/Biochemistry/Glycobiology Health sciences/Medical research/Biomarkers IgG glycome alternative glycosylation aging glycan age disease mortality biomarker inflammation Full Text Additional Declarations Yes there is potential Competing Interest. 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; speaker’s 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. Supplementary Files SupplementaryTablesfinal.xlsx Supplementary Tables Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9488315","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":627276959,"identity":"bb038701-e3ee-4cea-8d4f-a5f5618e447c","order_by":0,"name":"Gordan 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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 \u0026 Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp \u0026 Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB; speaker’s fees from AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson \u0026 Johnson, Merck Sharp \u0026 Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma; and research grant support from Janssen, Merck Sharp \u0026 Dohme and Takeda.","formattedTitle":"The Immunoglobulin G Glycome: A Modifiable Biomarker and Functional Effector of Aging, Disease, and Mortality","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"IgG glycome, alternative glycosylation, aging, glycan age, disease, mortality, biomarker, inflammation","lastPublishedDoi":"10.21203/rs.3.rs-9488315/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9488315/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"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.","manuscriptTitle":"The Immunoglobulin G Glycome: A Modifiable Biomarker and Functional Effector of Aging, Disease, and Mortality","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-23 11:21:11","doi":"10.21203/rs.3.rs-9488315/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"066094dd-8054-49bd-a661-59a672e173b6","owner":[],"postedDate":"April 23rd, 2026","published":true,"recentEditorialEvents":[{"type":"transferred","content":"Nature Communications","date":"2026-05-12T13:22:39+00:00","index":"","fulltext":""},{"type":"decision","content":"Reject before peer review","date":"2026-05-12T12:06:59+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":66764987,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":66764988,"name":"Biological sciences/Biochemistry/Glycobiology"},{"id":66764989,"name":"Health sciences/Medical research/Biomarkers"}],"tags":[],"updatedAt":"2026-05-12T13:53:31+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-23 11:21:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9488315","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9488315","identity":"rs-9488315","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}