AGED CD8+ T CELLS DRIVE COGNITIVE DECLINE VIA GZMK [parabiosis]

Changes in peripheral CD8+ T cells are a prominent hallmark of immune aging. While infiltrating CD8+ T cells are implicated in aging and neurodegenerative disease-related pathology in the brain, the role of aged non-infiltrating CD8+ T cells has yet to be fully defined. Here, we show that targeting activated aged peripheral CD8+ T cells rescues age-related cognitive decline. Using heterochronic parabiosis and single cell transcriptomics analysis we observed that aged peripheral CD8+ T cells maintain properties intrinsic to their age, being refractory to the effects of a young or aged systemic milieu. Systemic exposure of young mice to aged CD8+ T cells elicited synaptic-related aging transcriptional signatures in the hippocampus and impaired cognition. Inhibiting migration of aged peripheral CD8+ T cells to lymph nodes mitigated pro-aging effects on the young hippocampus. Conversely, targeting aged CD8+ T cells restored synaptic-related signatures in the aged hippocampus and ameliorated cognitive impairments. Mechanistically, we identified granzyme k (GZMK) as a secreted age-associated CD8+ T cell-derived factor that impairs cognitive function. Together, our data identify activated aged CD8+ T cells and their secreted factors as potential therapeutic targets to rescue cognition in old age. Considering the pro-aging effects observed in the hippocampus following both heterochronic parabiosis and transplantation of an aged hematopoietic system into young mice, we first assessed changes in peripheral CD8+ T cell trafficking and transcriptional responses to a young and aging systemic milieu using heterochronic parabiosis. Young (4 months) and aged (20 months) mice were surgically joined into isochronic (young-young and old-old) and heterochronic (young-old) parabiotic pairings for 28 days. To distinguish young versus aged cells in heterochronic parabionts, young CD45.1 B6/BoyJ and aged CD45.2 B6 mice were joined. We performed single cell RNA seq analysis on splenocytes of young isochronic, aged isochronic, young heterochronic and aged heterochronic parabionts after separation of CD45.1+ or CD45.2+ cells to analyze donor versus recipient immune cells.