Olivia Zhou

All Publications

• Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition. Immunity Navarro Negredo, P., You, J., Hauptschein, M., Schroer, A. B., Richard, D. J., Abhiraman, G. C., Tsai, A. P., Sun, E. D., Notarangelo, G., Ramirez-Matias, J., Zhou, O. Y., Buckley, M. T., Malacon, K. E., Xu, L., Sucharov, J., Ramirez Lopez, E., Picton, L., Wyss-Coray, T., Saxton, R. A., Fernandes, R. A., Villeda, S. A., Garcia, K. C., Brunet, A. 2026

  Abstract

  The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.

  View details for DOI 10.1016/j.immuni.2026.01.016

  View details for PubMedID 41619730

• Spatial transcriptomic clocks reveal cell proximity effects in brain ageing. Nature Sun, E. D., Zhou, O. Y., Hauptschein, M., Rappoport, N., Xu, L., Navarro Negredo, P., Liu, L., Rando, T. A., Zou, J., Brunet, A. 2024

  Abstract

  Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions-exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell-cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

  View details for DOI 10.1038/s41586-024-08334-8

  View details for PubMedID 39695234

  View details for PubMedCentralID 6039826

• Spatiotemporal transcriptomic profiling and modeling of mouse brain at single-cell resolution reveals cell proximity effects of aging and rejuvenation. bioRxiv : the preprint server for biology Sun, E. D., Zhou, O. Y., Hauptschein, M., Rappoport, N., Xu, L., Navarro Negredo, P., Liu, L., Rando, T. A., Zou, J., Brunet, A. 2024

  Abstract

  Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain aging is complex and accompanied by many cellular changes2-20. However, the influence that aged cells have on neighboring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in aging tissues have not yet been developed. Here, we generate spatiotemporal data at single-cell resolution for the mouse brain across lifespan, and we develop the first machine learning models based on spatial transcriptomics ('spatial aging clocks') to reveal cell proximity effects during brain aging and rejuvenation. We collect a single-cell spatial transcriptomics brain atlas of 4.2 million cells from 20 distinct ages and across two rejuvenating interventions-exercise and partial reprogramming. We identify spatial and cell type-specific transcriptomic fingerprints of aging, rejuvenation, and disease, including for rare cell types. Using spatial aging clocks and deep learning models, we find that T cells, which infiltrate the brain with age, have a striking pro-aging proximity effect on neighboring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating effect on neighboring cells. By developing computational tools to identify mediators of these proximity effects, we find that pro-aging T cells trigger a local inflammatory response likely via interferon-γ whereas pro-rejuvenating neural stem cells impact the metabolism of neighboring cells possibly via growth factors (e.g. vascular endothelial growth factor) and extracellular vesicles, and we experimentally validate some of these predictions. These results suggest that rare cells can have a drastic influence on their neighbors and could be targeted to counter tissue aging. We anticipate that these spatial aging clocks will not only allow scalable assessment of the efficacy of interventions for aging and disease but also represent a new tool for studying cell-cell interactions in many spatial contexts.

  View details for DOI 10.1101/2024.07.16.603809

  View details for PubMedID 39071282

  View details for PubMedCentralID PMC11275735

• Chromatin accessibility dynamics of neurogenic niche cells reveal defects in neural stem cell adhesion and migration during aging. Nature aging Yeo, R. W., Zhou, O. Y., Zhong, B. L., Sun, E. D., Navarro Negredo, P., Nair, S., Sharmin, M., Ruetz, T. J., Wilson, M., Kundaje, A., Dunn, A. R., Brunet, A. 2023

  Abstract

  The regenerative potential of brain stem cell niches deteriorates during aging. Yet the mechanisms underlying this decline are largely unknown. Here we characterize genome-wide chromatin accessibility of neurogenic niche cells in vivo during aging. Interestingly, chromatin accessibility at adhesion and migration genes decreases with age in quiescent neural stem cells (NSCs) but increases with age in activated (proliferative) NSCs. Quiescent and activated NSCs exhibit opposing adhesion behaviors during aging: quiescent NSCs become less adhesive, whereas activated NSCs become more adhesive. Old activated NSCs also show decreased migration in vitro and diminished mobilization out of the niche for neurogenesis in vivo. Using tension sensors, we find that aging increases force-producing adhesions in activated NSCs. Inhibiting the cytoskeletal-regulating kinase ROCK reduces these adhesions, restores migration in old activated NSCs in vitro, and boosts neurogenesis in vivo. These results have implications for restoring the migratory potential of NSCs and for improving neurogenesis in the aged brain.

  View details for DOI 10.1038/s43587-023-00449-3

  View details for PubMedID 37443352

  View details for PubMedCentralID 4683085

• Seeing is believing: old clones die young. Nature aging Zhou, O. Y., Brunet, A. 2023; 3 (4): 371-373

  View details for DOI 10.1038/s43587-023-00394-1

  View details for PubMedID 37117790

  View details for PubMedCentralID 6284110

• Seeing is believing: old clones die young NATURE AGING Zhou, O. Y., Brunet, A. 2023

  View details for DOI 10.1038/s43587-023-00394-1

  View details for Web of Science ID 000955746700001

• Brain Metastases from Endometrial Cancer: Clinical Characteristics, Outcomes, and Review of the Literature. World neurosurgery Bhambhvani, H. P., Zhou, O. n., Cattle, C. n., Taiwo, R. n., Diver, E. n., Gephart, M. H. 2020

  Abstract

  Brain metastases from endometrial cancer are rare and poorly described. We aimed to estimate the proportion of brain metastases at our institution that arose from endometrial cancer, and to detail clinicopathologic features and survival outcomes.We retrospectively identified and reviewed the charts of 30 patients with brain metastases from endometrial cancer seen at Stanford Hospital from 2008 to 2018.Among all patients with brain metastases, the proportion arising from endometrial cancer was 0.84%. Median age at diagnosis was 62 (range, 39 - 79), and median overall survival (OS) was 6.8 months (range, 1.0 month - 58.2 months). Most patients harbored endometrioid histology (53.3%), and some had concurrent metastases to lung (50.0%), bone (36.7%), and liver (20.0%). Median time from endometrial cancer diagnosis to brain metastasis development was 20.8 months (range, 1.4 months - 11.2 years), and the median number of brain metastases was 2 (range, 1 - 20). Patients with non-endometrioid histologies had more brain metastases than those with endometrioid histology (6.21 versus 2.44, p = 0.029). There was no difference in OS by histology.We describe the largest cohort to date of patients with brain metastases originating from endometrial cancer. These patients represent a small fraction of all brain metastasis patients and have poor prognoses. These data enable providers caring for patients with brain metastases from endometrial cancer to appropriately counsel their patients.

  View details for DOI 10.1016/j.wneu.2020.11.087

  View details for PubMedID 33321250