A feed-forward loop between niche adenosine and Gzmk⁺ CD8 T cells propagates systemic inflammaging

Guo, L., Zheng, R., Zhan, Q., Yu, X., Zhang, Q., Yao, J., Tan, X., Li, X., Zhang, O., Liu, P., Wang, C., Yao, Y., Ma, R., Wu, X., Wang, C., Zhou, H., Sun, Y., Xiong, K., Li, L., Xu, H., Jin, J., Wu, Y., Liu, T., Wang, Z., Liu, Y., Wang, Z.-y., Cao, W.

china medical university · biorxiv

Paper

Abstract

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.

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Research summary

The paper claims that targeting the adenosine-Gzmk axis can reverse multi-organ aging phenotypes and extend healthy lifespan in mice. This research addresses the mechanisms of T cell aging and proposes a therapeutic target for age-related diseases, which is central to longevity research.

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