Blight or benefit: how cellular neighbors shape the aging brain

Much like plants in a thriving forest, certain cells in the brain create a nurturing environment, enhancing the health and resilience of their neighbors, while others promote stress and damage, akin to a noxious weed in an ecosystem.

A new study published in Nature on December 18, 2024, reveals these interactions playing out across the lifespan. It suggests local cellular interactions may profoundly influence brain aging — and offers fresh insights into how we might slow or even reverse the process.

“What was exciting to us was finding that some cells have a pro-aging effect on neighboring cells while others appear to have a rejuvenating effect on their neighbors,” said Anne Brunet, the Michele and Timothy Barakett Endowed Professor in Stanford’s Department of Genetics and co–senior investigator of the new study.

Specifically, Brunet said, “We were surprised to discover that neural stem cells, which we’ve studied for a long, long time, had a rejuvenating effect on the cells around them. In the future we want to understand the role of neural stem cells in providing a beneficial environment for resilience within the brain.”

Brunet collaborated with James Zou, an associate professor of biomedical data science at Stanford, to conduct the study, which was spearheaded by graduate student, Eric Sun.

Brunet’s lab, a leader in brain aging and neural stem cell biology, provided the biological expertise and experimental framework. Zou’s team brought cutting-edge AI techniques to analyze the data, while Sun, with a background in physics and quantitative analysis, acted as the bridge between these two worlds.

The research was supported by a Catalyst Award from the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute.

These findings open new avenues of research, including examining how rejuvenating interventions like exercise and reprogramming factors promote brain health, potentially by enhancing the brain's natural resilience and repair mechanisms. Such insights may suggest new strategies to combat neurodegeneration and cognitive decline. The findings may also help scientists understand how diseases such as Alzheimer’s disease change the way cells interact and drive brain aging.

Cells that age — and rejuvenate — the brain

The research team set out to tackle a fundamental question: How do cells in their native environment influence one another during the aging process? Previous studies have focused on individual cells in isolation, overlooking the critical context of their "neighborhoods" — the cells surrounding them. By preserving and analyzing these spatial relationships, the team aimed to uncover whether interactions between different cell types either drive or mitigate aging in the brain.

Their investigation revealed a striking finding: Out of the 18 different cell types the researchers identified, two rare cell types had powerful but opposing effects on nearby cells. T cells, immune cells that infiltrate the aging brain, have a distinctly pro-inflammatory, pro-aging effect on neighboring cells that may be driven by interferon-γ, a signaling molecule that drives inflammation. On the other hand, they found that neural stem cells, though rare, demonstrate a powerful rejuvenating effect, even on nearby cells outside the neural lineage. During brain development, neural stem cells mature into the major cell types in the brain; in adults, they can also give rise to new neurons and are important for maintenance and repair of the nervous system. Beyond their well-established ability to generate healthy new neurons, the new study suggests NSCs may help create a supportive environment for brain cells.

These findings are important, says Zou, “because they highlight how cellular interactions — not just the intrinsic properties of individual cells — shape the aging process.”

Building a map and models

At the heart of this research are three key innovations by the research team: a spatial single-cell atlas of gene activity in the mouse brain across its lifespan and two advanced computational tools, each essential for piecing together how cells influence one another as they age.

To map the complex neighborhoods of the brain, the researchers created a spatial single-cell transcriptomic atlas of the mouse brain, capturing gene expression data from 2.3 million cells across 20 stages of life, equivalent to human ages 20 to 95. Unlike traditional methods that separate complex tissues, like the brain, into a collection of many disconnected cells, this experimental approach preserved the spatial relationships between cells, allowing the team to study how their spatial proximity shapes aging.

The atlas laid the groundwork for the first computational tool — a spatial aging clock. The clocks are machine-learning models designed to predict the biological age of individual cells based on their gene expression.

“For the first time, we can use aging clocks as a tool to discover new biology,” says Sun, instead of just using them to estimate biological age.

The second tool, built using graph neural networks, provided a powerful way to model these cell-to-cell interactions. By creating a kind of in silico brain, the researchers could simulate what happens when specific cell types are added, removed, or altered. This allowed them to explore potential interventions that would be nearly impossible to test in a living brain.

“This computational tool allows us to simulate what happens when we perturb individuals cell in the brain, which is something we can’t really test experimentally at scale,” says Zou.

To ensure the broader scientific community can build on their findings, Sun has made their tools and code publicly available, providing a valuable resource for studying cellular interactions across various tissues and organisms.

Implications and future directions

The study offers major insights into the drivers of aging, as well as rejuvenating factors that could help restore resilience and vitality to the aging brain. “Different cells respond differently to rejuvenating interventions,” explains Brunet. “Brain aging is exceptionally complex, so future therapies will need to be tailored not only to tissues but also to the specific cell types within those tissues.”

By demonstrating how spatial context and proximity influence cellular aging, the research builds on longstanding theories about the role of immune and senescent cells in the aging process. Looking ahead, the team hopes to move from observation to causation. “If we prevent T cells from releasing their pro-aging factors or enhance the effects of neural stem cells, how does that change the tissue over time?” asks Brunet.

While the study focused on mice, the team also hopes to extend their approach to human tissues. “We’re working to make these tools broadly applicable to other tissues and biological processes,” adds Sun.

STUDY DETAILS

Sun et al. “Spatial transcriptomic clocks reveal cell proximity effects in brain aging.” Nature, published online December 18, 2024. doi: 10.1038/s41586-024-08334-8

Study Authors:

Study authors include Eric D. Sun, Olivia Y. Zhou, Max Hauptschein, Nimrod Rappoport, Lucy Xu, Paloma Navarro Negredo, Ling Liu, Thomas A. Rando, James Zou, and Anne Brunet.

Funding Acknowledgements

The research was supported by the the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute, the Stanford Knight-Hennessy Scholars Program, the National Institutes of Health (P01AG036695, R01AG071711), a National Science Foundation (Graduate Research Fellowship, CAREER award 1942926), P.D. Soros Fellowship for New Americans, Silicon Valley Foundation, Chan Zuckerberg Biohub–San Francisco Investigator program, Chan Zuckerberg Initiative, the Milky Way Research Foundation, the Simons Foundation, and a generous gift from M. and T. Barakett.

Competing Interests

Brunet is a scientific advisory board member of Calico.