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.; 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.

doi:10.64898/2026.03.18.712515

bioRxiv · 10.64898/2026.03.18.712515

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.·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.

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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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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., 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.. 2026-03-20. A feed-forward loop between niche adenosine and Gzmk⁺ CD8 T cells propagates systemic inflammaging. https://doi.org/10.64898/2026.03.18.712515

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