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Peer-reviewedCC BYnpj Aging

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

  • Monica E. Mesecar1
  • Megan F. Duffy1
  • Dominic J. Acri1
  • Jinhui Ding2
  • Rebekah G. Langston1
  • Syed I. Shah3
  • Mike A. Nalls4,3
  • Xylena Reed1,4
  • Sonja W. Scholz5,6
  • D. Thad Whitaker1
  • Pavan Kumar Auluck7
  • Stefano Marenco7
3 more authors
  • Alex R. DeCasien8
  • Jesse Raphael Gibbs2
  • Mark Cookson9,10
10 affiliations
  1. 1Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
  2. 2Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
  3. 3DataTecnica LLC, Washington, DC, USA
  4. 4Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA
  5. 5Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA
  6. 6Neurodegenerative Diseases Research Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
  7. 7Human Brain Collection Core, Division of Intramural Research, National Institute of Mental Health, NIH, Bethesda, MD, USA
  8. 8Computational and Evolutionary Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
  9. 9Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. [email protected]
  10. 10Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA. [email protected]
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Abstract

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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Cite

BibTeXRIS
BibTeX
@article{mesecar2026regionspecific,
  title = {{Region-specific transcriptional signatures of brain aging in the absence of neuropathology at the single-cell level}},
  author = {Monica E. Mesecar and Megan F. Duffy and Dominic J. Acri and Jinhui Ding and Rebekah G. Langston and Syed I. Shah and Mike A. Nalls and Xylena Reed and Sonja W. Scholz and D. Thad Whitaker and Pavan Kumar Auluck and Stefano Marenco and Alex R. DeCasien and Jesse Raphael Gibbs and Mark Cookson},
  journal = {npj Aging},
  year = {2026},
  month = may,
  doi = {10.1038/s41514-026-00391-9},
  url = {https://doi.org/10.1038/s41514-026-00391-9},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Region-specific transcriptional signatures of brain aging in the absence of neuropathology at the single-cell level
AU  - Monica E. Mesecar
AU  - Megan F. Duffy
AU  - Dominic J. Acri
AU  - Jinhui Ding
AU  - Rebekah G. Langston
AU  - Syed I. Shah
AU  - Mike A. Nalls
AU  - Xylena Reed
AU  - Sonja W. Scholz
AU  - D. Thad Whitaker
AU  - Pavan Kumar Auluck
AU  - Stefano Marenco
AU  - Alex R. DeCasien
AU  - Jesse Raphael Gibbs
AU  - Mark Cookson
PY  - 2026
DA  - 2026/05/13
JO  - npj Aging
DO  - 10.1038/s41514-026-00391-9
UR  - https://doi.org/10.1038/s41514-026-00391-9
AB  - 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.
SN  - 2731-6068
ER  -