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 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. Highlights ‒ A single-cell transcriptomic atlas of >1 million PBMCs from 982 donors uncovers sex-specific immune aging trajectories. ‒ Aging females show greater cellular remodeling and stronger transcriptional shifts than males. ‒ Female-specific expansions with age of cytotoxic CD8+ T effector memory cells, inflammatory monocytes, and CD4+ T helper 22 cells reflect a systemic shift toward a pro-inflammatory, self-reactive immune state. ‒ Male-specific B cell shifts reveal expansion of CD5+ clonal subpopulations linked to leukemic precursor states. Graphical Abstract