SUMMARY The overarching goal of this project is to understand how immune cells impact the brain during aging, with the objective of restoring old brain function. The brain has long been considered an ‘immuno-privileged organ’. However, recent studies have shown that immune cells infiltrate the brain in neurodegenerative diseases such as Alzheimer’s disease and during aging. A key remaining challenge is to understand how immune cells impact the brain during aging, and could this knowledge be used to restore functionality of old brain and treat neurodegenerative diseases? The subventricular zone (SVZ) of the adult brain provides a great paradigm to address this question, as this regenerative region of the brain contains many different cell types – neural stem cells (NSCs), endothelial cells, microglia – and exhibits clear functional decline during aging. To gain a single cell understanding of the changes that occur with age in neurogenic niches, we recently performed single cell RNA-sequencing of young and old neurogenic niches in mice. This analysis revealed a striking infiltration of cytotoxic T cells only in the old neurogenic niche, which was confirmed by immunofluorescence. Surprisingly, we found that T cells from old SVZs are clonally expanded and secrete interferon g (IFNg), suggesting that they have encountered specific antigens. We also showed that T cells can impair NSC proliferation both in co-cultures and in vivo. Based on these data, our specific hypothesis is that T cell clonal expansion in old brains drives the deterioration of the neurogenic niche with age, and that preventing this T cell expansion restores function to old neurogenic regions. Probing this idea would be critical to counter the decline in brain function during aging and neurodegenerative diseases, such as Alzheimer’s disease. To test our hypothesis, we propose the following experiments: 1. To determine how T cells infiltrate neurogenic niches in old individuals; 2. To understand the functional impact of T cells on old neurogenic niches; 3. To examine the interaction between immune cells and neurogenic niches in young, old, and rejuvenated individuals. Completion of these aims will provide unique mechanistic insights into the regulation of T cell and other immune cells during aging in regenerative niches of the brain. This work should also give a fundamental understanding of the mechanistic impact of the interferon response and T cell cytotoxicity on different cell types in the brain. Knowledge from our study should pave the way for building transformative strategies, including new immunotherapies, for the restoration of a pristine tissue, which will be a critical step for improving brain function during aging and age-related diseases such as Alzheimer’s disease.

NARRATIVE As the organism ages, adult regenerative neural stem cell niches no longer produce new neurons. Adult neurogenic niches have been found to be important for aspects of learning and memory, raising the intriguing possibility that boosting the production of neurons by these niches may help preserve or enhance cognitive function with advancing age. Uncovering the immune-based mechanisms underlying the decline and rejuvenation of adult neurogenic niches during aging should give important insights into the factors that control regeneration in the normal aging nervous system as well as in age-related neurodegenerative diseases such as Alzheimer’s disease.