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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月13日

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  • Monica E. Mesecar,
  • Megan F. Duffy,
  • Dominic J. Acri,
  • Jinhui Ding,
  • Rebekah G. Langston,
  • Syed I. Shah,
  • Mike A. Nalls,
  • Xylena Reed,
  • Sonja W. Scholz,
  • D. Thad Whitaker,
  • Pavan K. Auluck,
  • Stefano Marenco,
  • Alex R. DeCasien,
  • J. Raphael Gibbs,
  • Mark R. Cookson

摘要

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.