Single-cell atlas of the human immune system reveals sex-specific dynamics of immunosenescence

Single-cell atlas of the human immune system reveals sex-specific dynamics of immunosenescence | 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 Single-cell atlas of the human immune system reveals sex-specific dynamics of immunosenescence Marta Melé, Maria Sopena-Rios, Aida Ripoll-Cladellas, Fatemeh Omidi, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6784948/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Apr, 2026 Read the published version in Nature Aging → Version 1 posted You are reading this latest preprint version Abstract Immunosenescence, or immune aging, is characterized by both changes in cell type abundance and a decline in cellular function, leading to increased susceptibility to immune-related diseases. Yet, the extent to which sex influences the dynamic composition of immune cells during immunosenescence remains unknown. Here, we use single-cell RNA sequencing in peripheral blood mononuclear cells from 982 donors to uncover the sex-specific immune aging dynamics. We reveal that aging drives sexually dimorphic compositional and transcriptional shifts, with females showing stronger immune remodeling. Female-specific shifts include the expansion of three cytotoxic CD8+ T effector memory subpopulations and inflammatory monocytes. In addition, female CD4+ central memory T cells exhibit abundance shifts in subpopulations involved in autoimmunity alongside age-associated transcriptional signatures enriched for autoimmune-related pathways. Conversely, males show an age-related expansion of a B cell subpopulation associated with an asymptomatic precursor state to chronic lymphocytic leukemia. These sex-biased, functionally distinct immune subpopulations represent sex-specific hallmarks of immune aging. Our work underscores the complexity and sexual dimorphism of immunosenescence and supports the development of sex-specific strategies to promote healthy aging. Biological sciences/Immunology/Autoimmunity Biological sciences/Immunology/Gene regulation in immune cells Biological sciences/Cell biology/Senescence scRNA-seq aging immune system immunosenescence sex females males single-cell transcriptomics Full Text Additional Declarations There is NO Competing Interest. Supplementary Tables are not available with this version Supplementary Files SupplementaryFigures.pdf Supplementary Figures Cite Share Download PDF Status: Published Journal Publication published 10 Apr, 2026 Read the published version in Nature Aging → 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-6784948","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":467100680,"identity":"06b1b243-8d97-41c3-800f-0e25075b275a","order_by":0,"name":"Marta Mel\u0026#x00E9","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyklEQVRIiWNgGAWjYDADPgbmY0QrZmwAkWwMbGkka+ExI069bvvZ5w9+MGyTY2Pv+fbwRw2DnHwDAS1mZ9ING3sYbhuz8ZzdbsxzjMHY4AAhLQfSGBt4GG4ntknkbpMGujFxAyGHmZ1/xtj4h+F2fZv8m2eSPxsY6ucTdNiNNMZmoC0JbBI8bBK8DQwJDAQdduMZ42wZg9uGbTxp5kC/SBhuIKjlfBrDxzcVt+X52Q8/A4aYjTzBEIMAAzhLgij1o2AUjIJRMAoIAABiOjvSSRgDyAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8874-6453","institution":". 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