Researchers at UCSF demonstrated that aged CD8+ T cells circulating in blood — not just those infiltrating the brain — directly drive hippocampal-dependent cognitive decline in mice. Using heterochronic parabiosis, the team showed these immune cells retain age-intrinsic properties regardless of systemic environment. Exposing young mice to aged CD8+ T cells impaired cognition and altered synaptic gene expression in the hippocampus. Crucially, inhibiting T cell activation (not brain infiltration) reversed these effects. Depleting aged CD8+ T cells or blocking their secreted factor Granzyme K (GZMK) rescued cognition in old mice. GZMK was detected in human plasma and increased with age, suggesting a translatable therapeutic target for age-related cognitive decline.
