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

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 Tyshkovskiy, Vadim N. Gladyshev, Steve Horvath, Andrei Seluanov () and Vera Gorbunova ()
Additional contact information
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
Vadim N. Gladyshev: Brigham and Women’s Hospital and Harvard Medical School
Steve Horvath: University of California Los Angeles
Andrei Seluanov: University of Rochester
Vera Gorbunova: University of Rochester

Nature, 2023, vol. 621, issue 7977, 196-205

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06463-0

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