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

Immunosenescence, the progressive aging of the immune system, is characterized by changes in immune cell composition and function that increase susceptibility to disease. However, how biological sex shapes immune aging at the cellular level remains poorly understood. Here, we analyze single-cell RNA sequencing data from the peripheral blood mononuclear cells of 982 female and male donors across adulthood. We find that aging drives sexually dimorphic compositional and transcriptional changes, with female individuals exhibiting stronger immune remodeling. Female-specific changes include the expansion of cytotoxic CD8⁺ effector memory T cell subsets and inflammatory monocytes, and age-related shifts in the CD4⁺ central memory T cell populations involved in autoimmunity. In contrast, a subset of male participants shows an age-associated expansion of a B cell population linked to an asymptomatic precursor state of chronic lymphocytic leukemia. Together, these findings reveal sex-specific hallmarks of immunosenescence and highlight the importance of incorporating biological sex into strategies aimed at promoting healthy immune aging.