Faulkes, Christopher G.Eykyn, Thomas R.Miljkovic, Jan Lj.Gilbert, James D.Charles, Rebecca L.Prag, Hiran A.Patel, NikaylaHart, Daniel WilliamMurphy, Michael P.Bennett, Nigel CharlesAksentijevic, Dunja2025-02-262025-02-262024-03-27Faulkes, C.G., Eykyn, T.R., Miljkovic, J.Lj. et al. 2024, 'Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles', Nature Communications, vol. 15, art. 2204, pp.1-13. https://DOI.org/10.1038/s41467-024-46470-x.2041-1723 (online)10.1038/s41467-024-46470-xhttp://hdl.handle.net/2263/101217DATA AVAILABILITY : The RNAseq data generated in this study have been deposited in the ArrayExpress database under accession code E-MTAB-13808. All data generated in this study have been deposited (open access) in the Dryad database, and can be accessed here: https://doi.org/10.5061/dryad. w9ghx3fts and https://doi.org/10.5061/dryad.66t1g1k66. Source data are provided in this paper.The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.en© The Author(s) 2024. Open access. This article is licensed under a Creative Commons Attribution 4.0 International License.Heterocephalus glaberCardiovascular diseaseHealth spanCardiac ischemiaNaked mole-rat (Heterocephalus glaber)Naked mole-rat (NMR)SDG-03: Good health and well-beingArticle