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Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice

Author

Listed:
  • Zhihui Zhang

    (University of Rochester)

  • Xiao Tian

    (University of Rochester)

  • J. Yuyang Lu

    (University of Rochester)

  • Kathryn Boit

    (University of Rochester)

  • Julia Ablaeva

    (University of Rochester)

  • Frances Tolibzoda Zakusilo

    (University of Rochester)

  • Stephan Emmrich

    (University of Rochester)

  • Denis Firsanov

    (University of Rochester)

  • Elena Rydkina

    (University of Rochester)

  • Seyed Ali Biashad

    (University of Rochester)

  • Quan Lu

    (University of Rochester)

  • Alexander Tyshkovskiy

    (Brigham and Women’s Hospital and Harvard Medical School
    Moscow State University)

  • Vadim N. Gladyshev

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Steve Horvath

    (University of California Los Angeles
    University of California Los Angeles)

  • Andrei Seluanov

    (University of Rochester
    University of Rochester Medical Center)

  • Vera Gorbunova

    (University of Rochester
    University of Rochester Medical Center)

Abstract

Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent—the naked mole-rat1,2. To study whether the benefits of HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.

Suggested Citation

  • Zhihui Zhang & Xiao Tian & J. Yuyang Lu & Kathryn Boit & Julia Ablaeva & Frances Tolibzoda Zakusilo & Stephan Emmrich & Denis Firsanov & Elena Rydkina & Seyed Ali Biashad & Quan Lu & Alexander Tyshkov, 2023. "Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice," Nature, Nature, vol. 621(7977), pages 196-205, September.
    • Handle: RePEc:nat:nature:v:621:y:2023:i:7977:d:10.1038_s41586-023-06463-0
    DOI: 10.1038/s41586-023-06463-0
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    Cited by:

    1. Kejun Ying & José P. Castro & Anastasia V. Shindyapina & Alexander Tyshkovskiy & Mahdi Moqri & Ludger J. E. Goeminne & Sofiya Milman & Zhengdong D. Zhang & Nir Barzilai & Vadim N. Gladyshev, 2024. "Depletion of loss-of-function germline mutations in centenarians reveals longevity genes," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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