Sex-specific trajectories of nonlinear immune aging at single cell level

Sex-specific trajectories of nonlinear immune aging at single cell level | 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 Sex-specific trajectories of nonlinear immune aging at single cell level Jacques Behmoaras, Harry Park, Nina Le Bert, Antonio Bertoletti, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8944546/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Despite the female predominance in age- and immune-associated diseases, the pathways underlying sex difference in healthy immune aging remain incompletely understood. Here, we present a multi-ethnic single-cell transcriptomic atlas of healthy human immune aging (35% Asian), comprising 3.8 million peripheral blood mononuclear cells (PBMCs) from 1,828 individuals aged 19–97 years. Prominent peaks of differential gene expression around 40 (mainly CD4 T cells) and after 60 (mainly CD8 T cells) years of age were accompanied by age-dependent decline in RNA/protein homeostasis and inflammatory PBMC polarization with sex-dependent kinetics. While females displayed sustained CD8 T cell immunometabolism and late-life senescence signatures in CD4 T, NK, and B cells, males exhibited early-life fluctuations in CD4 T cell immunometabolism associated with hypomethylation of SSH3 at chromosome 11q13. Deep learning-based biological age clocks stratified for sex outperformed sex-combined models, learning from transcriptional immune trajectories. We thus unravel a nonlinear PBMC aging whereby targeting sex-specific pathways can allow precision geromedicine. Biological sciences/Immunology/Lymphocytes Health sciences/Biomarkers/Predictive markers Biological sciences/Systems biology/Population dynamics Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTables.xlsx Supp Tables pbmcagingsuppfiguresv5.pdf Supp Figures Cite Share Download PDF Status: Under Review 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-8944546","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":598192331,"identity":"66690488-0323-495b-8c3a-04889d45fe3b","order_by":0,"name":"Jacques 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