{
  "abstract": "Aging drives chronic disease in part through senescent cells, including macrophages, which fuel inflammation. Senescent macrophages are functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance, whereas we previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular basis of this senotype has remained undefined. Using genetic and multi-omic approaches, we show that a p53-p21-dependent program actively represses p16 and is required for senescent macrophage viability. We identify Cyclin D2 as a non-canonical downstream effector that redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming and modulates AKT1-mTORC1 signaling that sustains the SASP. Cyclin D2-p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, and can be selectively depleted by senolytic treatment. Together, these findings define a druggable p53-p21-Cyclin D2 axis that specifies macrophage senotype.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 30,
  "authors": [
    {
      "name": "G. Torres"
    },
    {
      "name": "I. A. Salladay-Perez"
    },
    {
      "name": "C. Y. Deng"
    },
    {
      "name": "I. Avila"
    },
    {
      "name": "Y. Delgado"
    },
    {
      "name": "G. Tong"
    },
    {
      "name": "J. Munoz-Estrada"
    },
    {
      "name": "L. Estrada"
    },
    {
      "name": "A. Dhingra"
    },
    {
      "name": "W. R. Armstrong"
    },
    {
      "name": "A. Singh"
    },
    {
      "name": "I. Cooper"
    },
    {
      "name": "E. Enriquez"
    },
    {
      "name": "P. Kaushal"
    },
    {
      "name": "J. Ni"
    },
    {
      "name": "K. Chowdhury"
    },
    {
      "name": "C. Pan"
    },
    {
      "name": "L. Stiles"
    },
    {
      "name": "C. Beninca"
    },
    {
      "name": "S. T. Hui"
    },
    {
      "name": "A. Krall"
    },
    {
      "name": "H. Christofk"
    },
    {
      "name": "A. J. Lusis"
    },
    {
      "name": "T. E. O'Sullivan"
    },
    {
      "name": "J. G. Meyer"
    },
    {
      "name": "R. Singh"
    },
    {
      "name": "V. A. Tornini"
    },
    {
      "name": "O. S. Shirihai"
    },
    {
      "name": "M. Bouhaddou"
    },
    {
      "affs": [
        0
      ],
      "name": "A. J. Covarrubias"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3qkszvyw5nw3y.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.22.753597",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753597v1.full",
  "id": "3qkszvyw5nw3y",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753597v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "immunology"
    ],
    [
      "openalex",
      "2737|Telomeres, Telomerase, and Senescence"
    ]
  ],
  "openalex": "W7214610432",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753597v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3qkszvyw5nw3y.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:53Z",
      "native_id": "10.64898/2026.09.22.753597",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753597v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:immunology",
      "subfield": "immunology"
    }
  ],
  "title": "The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.",
  "title_text": "The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:53Z",
  "url": "https://research.draconitic.com/paper/3qkszvyw5nw3y",
  "venue": "bioRxiv",
  "versions": []
}