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
  • 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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