{
  "abstract": "Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice. Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promoting leanness and glycemic control in both sexes. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a significantly greater molecular impact in the liver, muscle, and brown adipose tissue of female mice than males, there was a stronger gene enrichment with phenotypic traits in male mice. Further, we found that phenotypic changes are associated with a multi-tissue downregulation of the longevity associated PI3K-Akt signaling pathway. Val-R reduces frailty in both sexes and extends the lifespan of male by 23%, but does not extend female lifespan, corresponding with a male-specific downregulation of PI3K-Akt signaling. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA",
    "Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA",
    "William S. Middleton Memorial Veterans Hospital, Madison, WI, USA",
    "University of Wisconsin-Madison",
    "Department for Health, University of Bath, Bath, UK",
    "Department of Biological Sciences, Wayne State University, Detroit, MI, USA",
    "Institute of Environmental Health Sciences, Integrative Biosciences Center, Wayne State University, Detroit, MI, USA",
    "Wayne State University",
    "New York University",
    "New York University College of Dentistry, New York, NY, USA",
    "Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI, USA",
    "Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA",
    "Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA",
    "St. John Fisher University",
    "George M. O'Brien Center of Research Excellence, Department of Urology, University of Wisconsin, Madison, WI, USA",
    "Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, Madison, WI, USA",
    "Department of Pharmaceutical Sciences, St. John Fisher University, Rochester, NY, USA",
    "University of Wisconsin-Madison Comprehensive Diabetes Center, Madison, WI, USA",
    "Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI, USA. dlamming@medicine.wisc.edu",
    "Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA. dlamming@medicine.wisc.edu",
    "Endocrinology and Reproductive Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA. dlamming@medicine.wisc.edu",
    "Graduate Program in Cellular and Molecular Biology, University of Wisconsin-Madison, Madison, WI, USA. dlamming@medicine.wisc.edu",
    "University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI, USA. dlamming@medicine.wisc.edu",
    "University of Wisconsin-Madison Comprehensive Diabetes Center, Madison, WI, USA. dlamming@medicine.wisc.edu",
    "William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. dlamming@medicine.wisc.edu",
    "Wisconsin Nathan Shock Center of Excellence in the Basic Biology of Aging, Madison, WI, USA. dlamming@medicine.wisc.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 24,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Mariah F. Calubag",
      "orcid": "0000-0003-4843-3668"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Ismail Ademi",
      "orcid": "0009-0001-5773-0069"
    },
    {
      "affs": [
        4,
        0,
        2,
        3
      ],
      "name": "Cara L. Green",
      "orcid": "0000-0002-2293-9364"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Dulmalika N. H. Manchanayake"
    },
    {
      "affs": [
        5,
        6,
        7
      ],
      "name": "Hashan S. M. Jayarathne"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Ryan N. Marshall"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Sandra M. Le"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Penelope Lialios"
    },
    {
      "affs": [
        0,
        2,
        8
      ],
      "name": "Lucia E. Breuer"
    },
    {
      "affs": [
        9,
        3
      ],
      "name": "Shoshana Yakar"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Reji Babygirija"
    },
    {
      "affs": [
        10,
        0,
        2,
        3
      ],
      "name": "Michelle M. Sonsalla",
      "orcid": "0000-0001-8493-1416"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Isaac Grunow"
    },
    {
      "affs": [
        0,
        2,
        3
      ],
      "name": "Chung-Yang Yeh"
    },
    {
      "affs": [
        0,
        11,
        2,
        3
      ],
      "name": "Yang Liu",
      "orcid": "0000-0002-5472-6080"
    },
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Bailey A. Knopf"
    },
    {
      "affs": [
        12,
        13
      ],
      "name": "Sarah Yandell"
    },
    {
      "affs": [
        12,
        7
      ],
      "name": "Charles I. Opara",
      "orcid": "0009-0008-8189-972X"
    },
    {
      "affs": [
        14,
        15,
        3
      ],
      "name": "William A. Ricke"
    },
    {
      "affs": [
        16,
        14
      ],
      "name": "Teresa T. Liu",
      "orcid": "0000-0002-0879-2394"
    },
    {
      "affs": [
        12
      ],
      "name": "Mark P. Keller"
    },
    {
      "affs": [
        12,
        17,
        15
      ],
      "name": "Alan D. Attie"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Marianna Sadagurski",
      "orcid": "0000-0002-8203-4612"
    },
    {
      "affs": [
        18,
        19,
        20,
        21,
        22,
        23,
        24,
        25
      ],
      "name": "Dudley W. Lamming",
      "orcid": "0000-0002-0079-4467"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/34v6q9mr2epam.bib",
  "cited_by": 9,
  "doi": "10.1038/s43587-026-01169-0",
  "fulltext_url": null,
  "id": "34v6q9mr2epam",
  "issns": [
    "2662-8465"
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  "landing_url": "https://doi.org/10.1038/s43587-026-01169-0",
  "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": [
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      "openalex",
      "1302|Genetics, Aging, and Longevity in Model Organisms"
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  "pdf_url": "https://www.nature.com/articles/s43587-026-01169-0.pdf",
  "pmcid": "PMC12424762",
  "pmid": "40950235",
  "published": "2026-07-24",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/34v6q9mr2epam.ris",
  "sources": [
    {
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      "url": "https://doi.org/10.1038/s43587-026-01169-0"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1302|Genetics, Aging, and Longevity in Model Organisms",
      "subfield": "cell-biology"
    }
  ],
  "title": "Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice",
  "title_text": "Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T13:20:43Z",
  "url": "https://research.draconitic.com/paper/34v6q9mr2epam",
  "venue": "Nature Aging",
  "versions": []
}