Aged circulating CD8+ T cells and their secreted factors drive cognitive decline.

In mice, inhibiting aged immune cells or the molecules they release results in improved cognitive function.

In aged mice, specific immune cells in the blood release a protein called granzyme K that damages the brain's protective barrier and lowers the activity of genes important for brain cell connections, leading to reduced performance in memory and object recognition tasks; removing these cells or blocking the protein restores memory function.

Inhibiting the protein granzyme K in older mice reverses memory deficits and restores normal activity of genes involved in brain cell connections.

Blocking a specific signaling pathway in aged T cells prevents cognitive decline in mice, even when those cells do not enter the brain, showing that immune activation outside the brain causes hippocampal dysfunction.

Removing aged CD8+ T cells from old mice restores synaptic gene expression, improves memory dependent on the hippocampus, and repairs blood vessel integrity without changing microglial activity, demonstrating that these cells directly contribute to age-related cognitive decline.

Old CD8+ T cells keep their aging-related gene expression patterns even when placed in a young body's environment, showing that their aging state is determined by internal cellular properties and not by signals from the rest of the body.