Summary: New research clarifies how brain inflammation and aging-related cognitive decline may be connected through a cascading cellular process.
Source: Harvard
Researchers at Harvard have published a study in Cell that provides new insight into how inflammation may drive the cognitive decline associated with aging. The work points to a possible cascade of cellular events—beginning with non-neuronal cells—that ultimately affects neuronal function.
“Understanding aging is one of the most important goals in biomedicine,” said Xiaowei Zhuang, David B. Arnold Jr. Professor of Science in the department of chemistry and chemical biology, professor of physics, an HHMI investigator, and a co-author of the paper. She emphasized that the brain’s complexity—its many distinct neuronal and non-neuronal cell types and the intricate ways they interact—makes the study of aging particularly challenging.
To address this complexity, the team used MERFISH (Multiplexed Error-Robust Fluorescence In Situ Hybridization), an advanced spatial transcriptomics approach developed in the Zhuang laboratory. MERFISH can measure thousands of RNA species across intact tissue and preserve the spatial relationships between cells, allowing researchers to build detailed atlases of gene expression and cellular neighborhoods within the brain.
“MERFISH lets us track how gene expression changes not only across ages but also in specific cell types depending on their spatial context,” said Catherine Dulac, Samuel W. Morris University Professor in Molecular and Cellular Biology and an HHMI investigator, who is also a co-author. This spatial perspective enabled the researchers to see how aging affects cells in situ rather than only in isolation.
Using MERFISH combined with single-cell RNA sequencing, the team mapped molecular and spatial signatures of aging in the mouse frontal cortex and striatum. William E. Allen, a Harvard junior fellow, together with Timothy R. Blosser and Zuri A. Sullivan from the Zhuang and Dulac groups, characterized how neuronal and non-neuronal cell states shift over the mouse lifespan and how those changes distribute across distinct brain regions.
Overall, the study found that non-neuronal cells—especially glial and immune cells—undergo larger and more pronounced shifts in gene expression and cell state than neurons. Importantly, these changes were not uniform across the brain: subcortical white matter showed particularly strong alterations compared with gray matter, with oligodendrocytes, astrocytes, and microglia showing notable activation and state changes.
“Because oligodendrocytes produce myelin, support neuronal metabolism, modulate synapses, and participate in immune surveillance, their decline or activation can have widespread consequences,” Zhuang explained. If oligodendrocytes lose integrity and begin to shed myelin, Dulac noted, that can trigger downstream effects that disrupt neuronal circuits and broader brain function.
This pattern suggests a multistep process in which inflammation first affects non-neuronal cells in specific spatial niches—such as white matter—and these changes then lead to neuronal dysfunction and cognitive impairment. “Aging is ultimately linked to declines in cognition, but our data indicate that many initiating events may occur in non-neuronal populations,” Dulac said.
Identifying this sequence of cellular events creates potential opportunities for intervention. If inflammation in aging primarily targets non-neuronal cells, then reducing inflammation through lifestyle measures—such as diet, exercise, or other strategies—might mitigate aspects of brain aging and its cognitive consequences, the authors suggest. While more research is needed, the study offers a roadmap for future hypothesis-driven experiments.
The interdisciplinary collaboration behind the study has deep roots. Zhuang and Dulac began working together more than a decade ago when they combined high-resolution imaging methods to visualize synapses at unprecedented resolution. Their long-term partnership and complementary expertise in imaging and neurobiology helped make the current project possible, with junior fellow William Allen playing a key role in bringing the teams together for this investigation.
Beyond the central findings, the study highlights the power of spatially resolved single-cell transcriptomics to comprehensively profile diverse cell types and large gene sets within intact tissue. Such datasets generate rich resources for exploring aging mechanisms and guiding targeted follow-up studies into inflammation, glial activation, and neuronal vulnerability.
About this inflammation and brain aging research news
Author: Clea Simon
Source: Harvard
Contact: Clea Simon – Harvard
Image: The image is in the public domain
Original Research: Open access.
Title: “Molecular and spatial signatures of mouse brain aging at single-cell resolution” by William E. Allen et al. Cell
Abstract
Molecular and spatial signatures of mouse brain aging at single-cell resolution
Highlights
- High-resolution mapping of cellular and molecular changes in aging frontal cortex and striatum
- Aging triggers spatially dependent cell-state changes, predominantly in non-neuronal cells
- Subcortical white matter is a hotspot for aging-related glial and immune activation
- Aging-induced inflammation and LPS-driven inflammation share similarities but also show important differences
Summary
The brain’s cellular diversity and complex organization have limited systematic descriptions of how aging alters its molecular and cellular architecture, hindering understanding of the mechanisms behind functional decline. In this study, researchers constructed a detailed cell atlas of aging in mouse frontal cortex and striatum using spatially resolved single-cell transcriptomics, quantifying age-dependent changes in gene expression and spatial organization across major cell types.
They observed stronger changes in cell state, gene expression, and spatial arrangement among non-neuronal cells compared with neurons. The data reveal molecular and spatial signatures of glial and immune activation during aging, with these signatures particularly enriched in subcortical white matter. The study also identifies both shared and distinct activation patterns when comparing natural aging with experimentally induced systemic inflammation, offering critical insights into age-related brain decline and inflammatory processes.