2. Academic Validation
  3. Aged circulating CD8+ T cells and their secreted factors drive cognitive decline

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

  • Immunity. 2026 Jun 9;59(6):1651-1666.e8. doi: 10.1016/j.immuni.2026.04.014.
Juliana Sucharov 1,  Gregor Bieri 2,  Karishma J B Pratt 3,  Amber R Philp 2,  Turan Aghayev 2,  Shanan Sahota 2,  Laura Remesal 2,  Adam B Schroer 2,  Cedric E Snethlage 4,  Rebecca Chu 1,  Zachary J Holmes 1,  Julien Couthouis 5,  Saul A Villeda 6
Affiliations

Affiliations

  • 1 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 2 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 3 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 4 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, CA 94143, USA.
  • 5 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 6 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, San Francisco, CA 94143, USA; Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
PMID: 42140192 DOI: 10.1016/j.immuni.2026.04.014
Abstract

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.

Keywords

brain aging; cognitive decline; hippocampus; immune aging; parabiosis; peripheral immune brain cross-talk; rejuvenation.

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