GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE266nnn/GSE266454/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE266454GEOGSEfalseAGED CD8+ T CELLS DRIVE COGNITIVE DECLINE VIA GZMKChanges 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.2026/06/25GSE266454GSM8247194GSM8247183GSM8247195GSM8247184GSM8247192GSM8247182GSM8247193GSM8247190GSM8247191GSM8247202GSM8247189GSM8247200GSM8247201GSM8247198GSM8247187GSM8247188GSM8247199GSM8247185GSM8247196GSM8247186GSM824719724247266454Mus musculus[42140192]