Work

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

Year: 2026

Type: article

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.

Source: Immunity

DOI: 10.1016/j.immuni.2026.04.014

Authors: Juliana Sucharov, Gregor Bieri, Karishma J.B. Pratt, Amber R. Philp, Turan Aghayev, Shanan Sahota, Laura Remesal, Adam B. Schroer, Cedric E. Snethlage, Rebecca Chu, Zachary J. Holmes, Julien Couthouis, Saul A. Villeda

Institutions: University of California, San Francisco, Stanford Medicine, Stanford University

Language: English

Topic: Neuroinflammation and Neurodegeneration Mechanisms

Subfield: Neurology

Field: Neuroscience

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $10,400

Funders: Hevolution Foundation, National Science Foundation, Multiple Sclerosis Foundation, Simons Foundation, American Federation for Aging Research, Larry L. Hillblom Foundation, Barbara and Gerson Bakar Foundation, National Institutes of Health, University of California, San Francisco, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases

Awards: Investigating the role of the exercise blood factor Gpld1 in restoring brain vasculature function and cognition in aging, Investigating the role of platelets and platelet-derived factors in rejuvenation of the aged hippocampus, G4756830717, G6823137524, Diabetes Research Center, Systemic Mechanisms of Brain Rejuvenation, Predoctoral Training in Biomedical Sciences, The Role of Peripheral Aged CD8+ T Cells in Hippocampal-Dependent Cognitive Decline

OpenAlex ID: W7161143821

FWCI: 16.32

Cites: 59

Cited by: 7

Related to: 10