Brain Atlas Maps Epigenetic Changes Linked to Aging in Mice

Large-scale single-cell atlas from Salk and collaborators charts how DNA methylation, chromatin architecture, and gene activity shift across aging brain regions and cell types

By Curie | Biotech Reporter

March 13, 2026 — Scientists at the Salk Institute and collaborating institutions have built what they describe as the most comprehensive single-cell epigenetic atlas of the aging mouse brain, creating a new reference map for how brain cells change over time at the molecular level.

According to the team's paper in Cell, the atlas spans eight brain regions and 36 cell types, with more than 200,000 single cells profiled across methylation and chromatin-conformation assays, plus nearly 900,000 cells analyzed with spatial transcriptomics.

That scale matters because brain aging isn't uniform. Different regions and cell types age at different speeds and in different ways, which may help explain why neurodegenerative diseases can start in one part of a neural circuit and then spread into broader dysfunction.

"The brain is so interconnected, with different regions controlling different functions and aging at different speeds at the cell type level," Margarita Behrens, PhD, research professor at Salk and co-corresponding author, said in institute-linked coverage. "We can see how interconnected the brain is in conditions like Parkinson's, where the death of one group of neurons spirals into an entire circuit malfunctioning and then the tremors and cognitive effects we see in patients. So, the importance of having a cell type-specific understanding of aging will bring more granular knowledge that will expand therapeutic possibilities."

The researchers report that the atlas captures region- and cell-type-specific shifts in DNA methylation, genome organization, and transcriptional activity, including evidence of transposon demethylation and remodeling of topologically associating domains (TADs) — large structural units of chromatin that help organize the genome in 3D space.

According to Joseph Ecker, PhD, Salk professor, Howard Hughes Medical Institute investigator, and co-corresponding author, the atlas is designed as a framework tool for the field, not just a one-off dataset. The data are available via Amazon Web Services and the Gene Expression Omnibus, with the goal of helping researchers interpret human brain datasets, including those tied to NIH BRAIN Initiative efforts.

The team generated methylation data from more than 132,000 brain cells and joint methylation–chromatin conformation data from over 72,000 cells in aging mice. First author Qiurui Zeng emphasized the importance of spatial context, noting that location-level resolution helps identify which microenvironments and regional circuits appear most vulnerable with age.

"What makes this work innovative is, above all, its spatial dimension," Zeng said. "Spatial resolution reveals which regions and local microenvironments are most vulnerable to aging, how cell-type composition shifts across brain areas over time, and how neighboring cells may influence one another's aging trajectories."

Why this matters beyond basic biology: neurodegenerative disorders affect more than 57 million people globally, and incidence is expected to double every 20 years, according to estimates cited in the paper. This atlas doesn't deliver a therapy, but it delivers a high-resolution map of where to look for mechanisms that might eventually become therapeutic targets.

That's not flashy. It is foundational.