Increased Hyaluronan by Naked Mole-rat Has2 Improves Healthspan in Mice

Overview

Journal Nature

Specialty Science

Date 2023 Aug 23

PMID 37612507

Authors

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

Vera Gorbunova

Affiliations

Soon will be listed here.

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-rat. 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.

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References

Seluanov A, Hine C, Azpurua J, Feigenson M, Bozzella M, Mao Z . Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc Natl Acad Sci U S A. 2009; 106(46):19352-7. PMC: 2780760. DOI: 10.1073/pnas.0905252106. View

Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J . High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013; 499(7458):346-9. PMC: 3720720. DOI: 10.1038/nature12234. View

Buffenstein R . Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species. J Comp Physiol B. 2008; 178(4):439-45. DOI: 10.1007/s00360-007-0237-5. View

Fennouri A, Przybylski C, Pastoriza-Gallego M, Bacri L, Auvray L, Daniel R . Single molecule detection of glycosaminoglycan hyaluronic acid oligosaccharides and depolymerization enzyme activity using a protein nanopore. ACS Nano. 2012; 6(11):9672-8. DOI: 10.1021/nn3031047. View

Jiang D, Liang J, Noble P . Hyaluronan as an immune regulator in human diseases. Physiol Rev. 2011; 91(1):221-64. PMC: 3051404. DOI: 10.1152/physrev.00052.2009. View

Wu M, Cao M, He Y, Liu Y, Yang C, Du Y . A novel role of low molecular weight hyaluronan in breast cancer metastasis. FASEB J. 2015; 29(4):1290-8. DOI: 10.1096/fj.14-259978. View

Zhang G, Lu R, Wu M, Liu Y, He Y, Xu J . Colorectal cancer-associated ~ 6 kDa hyaluronan serves as a novel biomarker for cancer progression and metastasis. FEBS J. 2019; 286(16):3148-3163. DOI: 10.1111/febs.14859. View

Ruppert S, Hawn T, Arrigoni A, Wight T, Bollyky P . Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation. Immunol Res. 2014; 58(2-3):186-92. PMC: 4106675. DOI: 10.1007/s12026-014-8495-2. View

Strachan R, Smith P, Gardner D . Hyaluronate in rheumatology and orthopaedics: is there a role?. Ann Rheum Dis. 1990; 49(11):949-52. PMC: 1004274. DOI: 10.1136/ard.49.11.949. View

10.

Muto J, Yamasaki K, Taylor K, Gallo R . Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the septic response to LPS. Mol Immunol. 2009; 47(2-3):449-56. PMC: 2787860. DOI: 10.1016/j.molimm.2009.08.026. View

11.

Soltes L, Mendichi R, Kogan G, Schiller J, Stankovska M, Arnhold J . Degradative action of reactive oxygen species on hyaluronan. Biomacromolecules. 2006; 7(3):659-68. DOI: 10.1021/bm050867v. View

12.

Takasugi M, Firsanov D, Tombline G, Ning H, Ablaeva J, Seluanov A . Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nat Commun. 2020; 11(1):2376. PMC: 7217962. DOI: 10.1038/s41467-020-16050-w. View

13.

Garantziotis S, Savani R . Hyaluronan biology: A complex balancing act of structure, function, location and context. Matrix Biol. 2019; 78-79:1-10. PMC: 6774756. DOI: 10.1016/j.matbio.2019.02.002. View

14.

Ferrucci L, Fabbri E . Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018; 15(9):505-522. PMC: 6146930. DOI: 10.1038/s41569-018-0064-2. View

15.

Ward J . Lymphomas and leukemias in mice. Exp Toxicol Pathol. 2006; 57(5-6):377-81. DOI: 10.1016/j.etp.2006.01.007. View

16.

Horvath S, Haghani A, Macoretta N, Ablaeva J, Zoller J, Li C . DNA methylation clocks tick in naked mole rats but queens age more slowly than nonbreeders. Nat Aging. 2022; 2(1):46-59. PMC: 8975251. DOI: 10.1038/s43587-021-00152-1. View

17.

Mozhui K, Lu A, Li C, Haghani A, Sandoval-Sierra J, Wu Y . Genetic loci and metabolic states associated with murine epigenetic aging. Elife. 2022; 11. PMC: 9049972. DOI: 10.7554/eLife.75244. View

18.

Shiotsuki H, Yoshimi K, Shimo Y, Funayama M, Takamatsu Y, Ikeda K . A rotarod test for evaluation of motor skill learning. J Neurosci Methods. 2010; 189(2):180-5. DOI: 10.1016/j.jneumeth.2010.03.026. View

19.

Maddatu T, Grubb S, Bult C, Bogue M . Mouse Phenome Database (MPD). Nucleic Acids Res. 2011; 40(Database issue):D887-94. PMC: 3245053. DOI: 10.1093/nar/gkr1061. View

20.

Chen H, Zhou X, Shoumura S, Emura S, Bunai Y . Age- and gender-dependent changes in three-dimensional microstructure of cortical and trabecular bone at the human femoral neck. Osteoporos Int. 2009; 21(4):627-36. DOI: 10.1007/s00198-009-0993-z. View