Single-cell analyses of global cohorts outline determinants of immune aging and link the ratio of GZMK+ to GZMB+ Tem cells to health trajectories.

Human immune aging is heterogeneous, with immune responses becoming increasingly variable over the lifespan. Here, we integrated seven large-scale public single-cell peripheral blood mononuclear cell (PBMC) datasets and a newly generated cohort, encompassing 2,609 ostensibly healthy individuals across diverse ages, ancestries, and biological sexes. We identified both conserved and cohort-associated age-associated remodeling across 59 immune populations, together with sex- and ancestry-dependent immune differences. CD8+ T cells emerged as major drivers of aging heterogeneity, with the GZMK+/GZMB+ effector memory ratio distinguishing healthy and pathology-associated aging trajectories. This ratio reflected immune remodeling driven by chronic viral exposure, including CMV, and disease-associated immune dysregulation, with the dominant driver varying across populations. Proteomic profiling across four cohorts revealed a Tem GZMB+ plasma signature associated with inflammaging, poor self-reported health, all-cause mortality, and increased risk of immune-related, metabolic, and cardiovascular diseases. Together, these findings define clinically relevant immune determinants for monitoring and guiding healthy aging interventions.