Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline.

Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon-myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration 1-6 , but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages-important representatives of the innate immune system-are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging 7 . Similarly, in the aging central nervous system (CNS), microglial cells promote damage of myelinated axons and synapses 8-20 . Here we examine the role of cytotoxic CD8 + T lymphocytes, a type of adaptive immune cells previously identified as amplifiers of axonal perturbation in various models of genetically mediated CNS diseases 21 but understudied in the aging CNS 22-25 . We show that accumulation of CD8 + T cells drives axon degeneration in the normal aging mouse CNS and contributes to age-related cognitive and motor decline. We characterize CD8 + T-cell population heterogeneity in the adult and aged mouse brain by single-cell transcriptomics and identify aging-related changes. Mechanistically, we provide evidence that CD8 + T cells drive axon degeneration in a T-cell receptor- and granzyme B-dependent manner. Cytotoxic neural damage is further aggravated by systemic inflammation in aged but not adult mice. We also find increased densities of T cells in white matter autopsy material from older humans. Our results suggest that targeting CD8 + CNS-associated T cells in older adults might mitigate aging-related decline of brain structure and function.