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Peer-reviewedCC BYImmunity

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

  • Juliana Sucharov1
  • Gregor Bieri2
  • Karishma J. B. Pratt3
  • Amber R. Philp2
  • Turan Aghayev2
  • Shanan Sahota2
  • Laura Remesal2
  • Adam B. Schroer2
  • Cedric E. Snethlage4
  • Rebecca Chu1
  • Zachary J. Holmes1
  • Julien Couthouis5
1 more authors
  • Saul Villeda
5 affiliations
  1. 1Department 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. 2Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA
  3. 3Department 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. 4Department 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. 5Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
Open at sourceDOICite

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.

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Cite

BibTeXRIS
BibTeX
@article{sucharov2026aged,
  title = {{Aged circulating CD8+ T cells and their secreted factors drive cognitive decline}},
  author = {Juliana Sucharov and Gregor Bieri and Karishma J. B. Pratt and Amber R. Philp and Turan Aghayev and Shanan Sahota and Laura Remesal and Adam B. Schroer and Cedric E. Snethlage and Rebecca Chu and Zachary J. Holmes and Julien Couthouis and Saul Villeda},
  journal = {Immunity},
  year = {2026},
  month = may,
  doi = {10.1016/j.immuni.2026.04.014},
  url = {https://doi.org/10.1016/j.immuni.2026.04.014},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Aged circulating CD8+ T cells and their secreted factors drive cognitive decline
AU  - Juliana Sucharov
AU  - Gregor Bieri
AU  - Karishma J. B. Pratt
AU  - Amber R. Philp
AU  - Turan Aghayev
AU  - Shanan Sahota
AU  - Laura Remesal
AU  - Adam B. Schroer
AU  - Cedric E. Snethlage
AU  - Rebecca Chu
AU  - Zachary J. Holmes
AU  - Julien Couthouis
AU  - Saul Villeda
PY  - 2026
DA  - 2026/05/14
JO  - Immunity
DO  - 10.1016/j.immuni.2026.04.014
UR  - https://doi.org/10.1016/j.immuni.2026.04.014
AB  - 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.
SN  - 1074-7613
SN  - 1097-4180
ER  -