Juliana Sucharov, Gregor Bieri, Karishma J.B. Pratt, Amber R. Philp, Turan Aghayev, Shanan Sahota, Laura Remesal, Adam B. Schroer, Cedric E. Snethlage, Rebecca Chu, Zachary J. Holmes, Julien Couthouis, Saul Villeda
Changes in peripheral CD8 + T cells are a hallmark of immune aging. However, the role of aged non-infiltrating CD8 + T cells in brain aging remains to be fully defined. Here, we showed that aged circulating CD8 + T cells and their secreted factors drove hippocampal-dependent cognitive decline. Using heterochronic parabiosis and transcriptomics analysis, we observed that peripheral CD8 + T cells maintained properties intrinsic to their age. Systemic exposure of young mice to aged CD8 + T cells elicited synaptic-related hippocampal changes and impaired cognition, and inhibiting activation, but not infiltration, mitigated their pro-aging effects. Conversely, targeting aged circulating CD8 + T cells restored youthful signatures and rescued cognition. Mechanistically, we identified granzyme K (GZMK) as a secreted pro-aging CD8 + T cell-derived factor in plasma, and GZMK inhibition rescued cognition in aged animals. Together, our data identified activated aged CD8 + T cell-derived circulating factors as potential therapeutic targets to rescue cognition in old age.