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

Abstract

Immunosenescence, the gradual deterioration of the immune system with age, leads to an increased susceptibility to a range of diseases associated with immune dysfunction. Notably, sex is an important variable underlying how immune aging unfolds, as, for instance, autoimmunity develops with aging differently between males and females. Even though some clinical and molecular differences have been identified between male and female immunosenescence, it is not known to what extent sex affects the dynamic composition of immune cells over time. Here, we analyze a large single-cell RNA-sequencing dataset of peripheral blood mononuclear cells from a sex-balanced cohort of 982 human donors providing novel transcriptional and cellular insights into immune aging at an unprecedented resolution. We uncover that aging induces cell type-dependent and sex-specific transcriptional shifts that translate into a differential abundance of distinct immune cell subpopulations. These shifts predominantly involve translation-related genes, indicating a strong link between transcriptional and translational throughput with cell function and consequent immune cell composition. This sexual dimorphism overlaps known autoimmune disease-related genetic variants and results in the differential enrichment of functionally distinct immune populations. Specifically, we uncover that a cytotoxic CD8+ T effector memory subpopulation with an NK-like phenotype accumulates with age only in females and identify a distinct B cell subpopulation that expands with age exclusively in males, representing novel sex-specific hallmarks of immune aging. Our findings underscore the hidden complexity of immune aging and demonstrate the value of high-resolution, single-cell analyses in large population cohorts. This research paves the way for future sex-specific interventions targeting immunosenescence to ultimately promote a personalized approach to foster healthy aging.