{
  "abstract": "The dorsolateral prefrontal cortex (DLPFC) underpins higher cognitive functions and is highly susceptible to age-related decline. However, a comprehensive, lifespan-resolved map of its cellular and molecular programs has been lacking. Here, we constructed the first single-nucleus transcriptomic atlas of the human DLPFC, spanning the full lifespan, profiling over 1.3 million nuclei from 284 postmortem samples ranging in age from 0-97 years. This unprecedented resource reveals three distinct transcriptomic phases: dynamic developmental remodeling, midlife stability, and late-life molecular reactivation. Non-linear modeling of age trends uncovers ten distinct trajectories, including a neuronal resilience program peaking in early adolescence and glial aging programs marked by immune activation in late adulthood. Pseudotime analyses reconstruct lineage maturation from fetal progenitors to aged states, identifying gene modules linked to neurodevelopmental and neurodegenerative disease risk. Spatial transcriptomics confirm these dynamic programs, mapping excitatory neuron modules to specific cortical layers and glial signatures to distinct gray–white matter domains. Notably, we identify circadian reprogramming in late adulthood, with loss of neuronal core clock rhythmicity and emergence of stress-adaptive glial rhythms. Together, this study provides the first anatomically resolved, cell-type–specific, and lifespan-wide reference for the human DLPFC, establishing a foundational resource for understanding brain development, aging, and disease vulnerability.",
  "abstract_shown": true,
  "affiliations": [
    "Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA",
    "Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI, USA",
    "Waisman Center, University of Wisconsin-Madison, Madison, WI, USA",
    "Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA",
    "Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA",
    "Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA",
    "Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA, USA",
    "Department of Physiology, University of California San Francisco, San Francisco, CA, USA",
    "Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA",
    "Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark",
    "Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA",
    "Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA",
    "Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA, USA",
    "Department of Neurology, University of California San Francisco, San Francisco, CA, USA",
    "Neuroscience and Biomedical Sciences Graduate Programs, University of California San Francisco, San Francisco, CA, USA",
    "Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA",
    "Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA",
    "Mental Illness Research, Education and Clinical Center VISN2, James J. Peters VA Medical Center, New York, NY, USA"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 68,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Hui Yang",
      "orcid": "0000-0003-0043-8793"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Tereza Clarence",
      "orcid": "0000-0002-0099-2797"
    },
    {
      "affs": [
        4
      ],
      "name": "Madeline R. Scott",
      "orcid": "0000-0002-2059-2256"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Xinyi Wang",
      "orcid": "0000-0001-8003-4216"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "N. M. Prashant",
      "orcid": "0000-0003-3548-5637"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Milos Pjanic",
      "orcid": "0000-0001-9746-8838"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Sanan Venkatesh",
      "orcid": "0000-0002-3094-2731"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Aram Hong",
      "orcid": "0009-0000-6083-1998"
    },
    {
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        3
      ],
      "name": "Clara Casey",
      "orcid": "0009-0002-9430-3557"
    },
    {
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      ],
      "name": "Sarah E. Murphy",
      "orcid": "0009-0005-1296-6325"
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        3
      ],
      "name": "Zhiping Shao",
      "orcid": "0009-0006-4889-6637"
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      "name": "Marcela Alvia",
      "orcid": "0000-0001-9706-1376"
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        3
      ],
      "name": "Stathis Argyriou",
      "orcid": "0009-0008-0713-6599"
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      ],
      "name": "Alexander Kawah Yu",
      "orcid": "0009-0006-3253-0745"
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    {
      "affs": [
        5,
        6
      ],
      "name": "Athan Z. Li",
      "orcid": "0009-0001-6415-0003"
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        3
      ],
      "name": "Biao Zeng"
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      "affs": [
        7,
        6
      ],
      "name": "Chenfeng He"
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    {
      "affs": [
        7,
        6
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      "name": "Chirag Gupta",
      "orcid": "0000-0002-6121-7065"
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      "name": "Christian Dillard",
      "orcid": "0000-0001-5740-7328"
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      "name": "Christian Porras",
      "orcid": "0000-0002-2621-6753"
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      ],
      "name": "Collin Spencer"
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      "affs": [
        7,
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        6
      ],
      "name": "Daifeng Wang",
      "orcid": "0000-0001-9190-3704"
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        8,
        9
      ],
      "name": "David Alan Bennett",
      "orcid": "0000-0003-3689-554X"
    },
    {
      "name": "David Burstein"
    },
    {
      "name": "Deepika Dayal Mathur",
      "orcid": "0000-0002-2591-4170"
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    {
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        9
      ],
      "name": "Fotis Tsetsos",
      "orcid": "0000-0001-5521-846X"
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        11
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      "name": "Gennadi Ryan",
      "orcid": "0000-0002-2516-121X"
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      ],
      "name": "Jennifer Monteiro Fortes",
      "orcid": "0009-0008-8520-3603"
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    {
      "affs": [
        12,
        6
      ],
      "name": "Jerome J. Choi",
      "orcid": "0009-0008-7206-5758"
    },
    {
      "affs": [
        7,
        6
      ],
      "name": "Kalpana Hanthanan Arachchilage",
      "orcid": "0000-0002-0849-9534"
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    {
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        0,
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        3
      ],
      "name": "Karen Therrien",
      "orcid": "0000-0003-3351-7260"
    },
    {
      "affs": [
        13
      ],
      "name": "Lars J. Jensen"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "Lisa Laverne Barnes",
      "orcid": "0000-0002-0072-9817"
    },
    {
      "affs": [
        14,
        15
      ],
      "name": "Logan C. Dumitrescu",
      "orcid": "0000-0002-9782-9944"
    },
    {
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        3
      ],
      "name": "Lyra Sheu"
    },
    {
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      ],
      "name": "Marios Anyfantakis",
      "orcid": "0009-0007-8773-0864"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Maxim Signaevsky",
      "orcid": "0000-0003-4495-5055"
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        13
      ],
      "name": "Mikaela Koutrouli",
      "orcid": "0000-0002-8953-3561"
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      "affs": [
        10,
        16
      ],
      "name": "Monika Ahirwar",
      "orcid": "0009-0004-7105-4206"
    },
    {
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      ],
      "name": "Nicolas Y. Masse",
      "orcid": "0000-0002-9094-1298"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Noah Cohen Kalafut",
      "orcid": "0000-0003-1421-0829"
    },
    {
      "affs": [
        2
      ],
      "name": "Pavel Katsel",
      "orcid": "0000-0001-8076-0162"
    },
    {
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        0,
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      ],
      "name": "Pengfei Dong",
      "orcid": "0000-0003-3735-5158"
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    {
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        6
      ],
      "name": "Pramod B. Chandrashekar"
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    {
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      ],
      "name": "Rachel Bercovitch",
      "orcid": "0009-0003-4446-8422"
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    {
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      ],
      "name": "Roman Kosoy",
      "orcid": "0000-0002-3080-7900"
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      "affs": [
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        6
      ],
      "name": "Saniya Khullar",
      "orcid": "0000-0002-4166-874X"
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    {
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        5,
        6
      ],
      "name": "Sayali Anil Alatkar",
      "orcid": "0000-0001-5984-461X"
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      ],
      "name": "Seon Kinrot",
      "orcid": "0000-0001-5614-0983"
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        11,
        12,
        18,
        16
      ],
      "name": "Steven M. Finkbeiner",
      "orcid": "0000-0002-3480-394X"
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        0,
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      ],
      "name": "Steven P. Kleopoulos",
      "orcid": "0000-0002-9213-9629"
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      "affs": [
        14,
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      ],
      "name": "Timothy J. Hohman",
      "orcid": "0000-0002-3377-7014"
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      "affs": [
        7,
        6
      ],
      "name": "Ting Jin"
    },
    {
      "affs": [
        10,
        16
      ],
      "name": "Vivek G. Ramaswamy"
    },
    {
      "affs": [
        6
      ],
      "name": "Xiang Huang"
    },
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      "name": "Zhenyi Wu",
      "orcid": "0009-0001-4180-7877"
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    {
      "affs": [
        19,
        20,
        3
      ],
      "name": "Nadejda M. Tsankova",
      "orcid": "0000-0002-5333-312X"
    },
    {
      "affs": [
        21
      ],
      "name": "Pavan Kumar Auluck",
      "orcid": "0000-0003-4799-7904"
    },
    {
      "affs": [
        21
      ],
      "name": "Stefano Marenco",
      "orcid": "0000-0002-2488-2365"
    },
    {
      "affs": [
        19,
        2,
        3,
        22
      ],
      "name": "Vahram H. Haroutunian",
      "orcid": "0000-0001-5860-2512"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5h7me4yjnh4fg.bib",
  "cited_by": 13,
  "doi": "10.1038/s41586-026-10271-7",
  "fulltext_url": null,
  "id": "5h7me4yjnh4fg",
  "issns": [
    "0028-0836",
    "1476-4687"
  ],
  "landing_url": "https://doi.org/10.1038/s41586-026-10271-7",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Single-cell and spatial transcriptomics"
    ]
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  "openalex": "W7214098459",
  "pdf_url": null,
  "pmcid": "PMC12632665",
  "pmid": "41282859",
  "published": "2026-09-23",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/5h7me4yjnh4fg.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:06Z",
      "native_id": "W7214098459",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41586-026-10271-7"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Single-cell and spatial transcriptomics",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Lifespan single-cell transcriptomic atlas of the human prefrontal cortex",
  "title_text": "Lifespan single-cell transcriptomic atlas of the human prefrontal cortex",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:05Z",
  "url": "https://research.draconitic.com/paper/5h7me4yjnh4fg",
  "venue": "Nature",
  "versions": []
}