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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\u201330 years) and 7 aged (60\u201385 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.<\/jats:p>","DOI":"10.1038\/s41514-026-00391-9","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T08:08:02Z","timestamp":1778659682000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Region-specific transcriptional signatures of brain aging in the absence of neuropathology at the single-cell level"],"prefix":"10.1038","volume":"12","author":[{"given":"Monica E.","family":"Mesecar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan F.","family":"Duffy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic J.","family":"Acri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekah G.","family":"Langston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed I.","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mike A.","family":"Nalls","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xylena","family":"Reed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja W.","family":"Scholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Thad Whitaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavan K.","family":"Auluck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Marenco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex R.","family":"DeCasien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Raphael Gibbs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Cookson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"391_CR1","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/s41582-019-0244-7","volume":"15","author":"Y Hou","year":"2019","unstructured":"Hou, Y. et al. 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