Senescent cells create an adenosine-rich niche through p16-dependent CD39 upregulation that drives A2aR-Eomes signaling in CD8+ T cells to generate a pathogenic Granzyme K+ population, which subsequently propagates systemic cellular senescence and inflammaging through PAR1-MAPK and complement activation, establishing a feed-forward loop that causally drives organismal aging and can be therapeutically reversed by targeting the adenosine-A2aR-Gzmk axis.

The causal link between the aging microenvironment and T cell aging remains elusive. Here, we demonstrate that adenosine within aging tissues actively reprograms CD8+ T cells into a pro-aging Granzyme K+ (Gzmk+) population. Mechanistically, senescent cells create an adenosine-rich niche via p16-dependent CD39 upregulation, triggering A2aR signaling to induce Gzmk+ T cell differentiation. Once released, Gzmk promotes systemic inflammaging through PAR1 and complement activation. Crucially, targeting this axis—either via genetic Gzmk ablation or pharmacological A2aR blockade—reverses multi-organ aging phenotypes and significantly extends healthy lifespan in mice. Human analysis reveals age-dependent Gzmk+ T cell accumulation in multi organs, while coffee intake (an A2aR antagonist) inversely correlates with plasma Gzmk levels. Our findings uncover how metabolic niche changes drive T cell aging and establish the adenosine-Gzmk axis as a pivotal therapeutic target for combating age-related diseases.