Region-specific transcriptional signatures of brain aging in the absence of neuropathology at the single-cell level

May 13, 2026npj aging

Unique gene activity patterns in different brain areas during normal aging at the single-cell level

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Abstract

Over 8000 age-associated genes were identified from over 150,000 nuclei analyzed across four brain regions.

Normal brain aging may involve distinct molecular events that differ by brain region and cell type.
Differential expression analyses revealed that most age-related gene associations are specific to particular regions and cell types.
Functional enrichment analyses highlighted several aging-related processes, including metabolism, inflammation, and cellular senescence.
The findings indicate that different cell types exhibit unique transcriptional aging profiles, contributing to our understanding of neurodegenerative disease risk.

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As age is a significant risk factor for multiple neurodegenerative diseases, investigating normal brain aging may help identify molecular events contributing to increased disease risk over time. Single-nucleus RNA sequencing (snRNA-seq) enables analysis of gene expression changes within specific cell-types, offering insights into the molecular mechanisms underlying aging. However, most brain aging snRNA-seq datasets use age-matched controls from studies focused on pathology and sample cortical regions. Therefore, there is a need to investigate non-pathological aging within brain regions vulnerable to age-related diseases. We report a snRNA-seq study of 6 young (20-30 years) and 7 aged (60-85 years) individuals encompassing four different brain regions: the entorhinal cortex, middle temporal gyrus, subventricular zone, and putamen. We captured over 150,000 nuclei representing 10 broad cell-types. Region- and cell-type-specific differential expression analyses identified over 8000 age-associated genes. Notably, within a given cell-type, most of these associations were region-specific. Functional enrichment analyses of gene sets for each cell-type-region subgroup reflected multiple hallmarks of aging, including: proteostasis, interactions with cytokines, vesicular trafficking, metabolism, inflammation, metal ion homeostasis, and cellular senescence. Overall, our findings suggest that unique cell-types exhibit distinct transcriptional aging profiles both at the cell-type level and across different brain regions.

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Region-specific transcriptional signatures of brain aging in the absence of neuropathology at the single-cell level

Abstract

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