Single-Cell Atlas of the Human Immune System Reveals Sex-Specific Dynamics of Immunosenescence

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 immune aging dynamics. We reveal that aging drives sex-specific transcriptional shifts that overlap with known autoimmune disease-related loci. These transcriptional shifts involve translation-related genes and are associated with cell type composition changes, highlighting a connection between expression throughput and cell abundance. Finally, we identify functionally distinct immune cell subpopulations that accumulate with age in one sex, such as a female-specific cytotoxic CD8+ T cell subpopulation, representing sex-specific hallmarks of immune aging. Our work underscores the complexity of immunosenescence and supports the potential for sex-specific therapies to promote healthy aging.

Note:
Funding Information: M.S.R was supported by a predoctoral “AGAUR-FI Joan Oró” fellowship from “Secretaria d’Universitats i Recerca del Departament de Recerca i Universitats de la Generaliat de Catalunya i del Fons Europeu Social Plus” (2024 FI-3 0065) . A.R.C was supported by a predoctoral fellowship “Formación Personal Investigador (FPI)” from “el Ministerio de Ciencia, Innovación y Universidades (MCIN)” and “la Agencia Estatal de Investigación (AEI)” (MCIN/AEI FPI with code PRE2019-090193). M.M. was supported by a grant PID2019-107937GA-I00 funded by MCIN/AEI/10.13039/501100011033 and a grant RYC-2017- 22249 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”. J.E.P is supported by the National Health and Medical Research Council Fellowship (APP1107599) and with the support of the Fok Family in memory of Dr. and Mrs. Wing Kan Fok. L.F. is supported by a grant from the Dutch Research Council (ZonMW-VICI 09150182010019), and a sponsored research collaboration with Biogen, Roche and Takeda. This work is co-financed by Oncode Institute, which is partly funded by the Dutch Cancer Society. This project has received funding from the European Union’s Horizon Europe research and innovation programme under grant agreement No 101057553. M.G.P.W. is supported by a NWO Vidi grant of the Dutch Research Council (VI.Vidi.223.041).

Declaration of Interests: The authors declare no competing interests

Keywords: scRNA-seq, aging, immune system, immunosenescence, sex, females, males, single-cell transcriptomics