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Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles

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  • Chris G. Faulkes

    (Queen Mary University of London)

  • Thomas R. Eykyn

    (School of Biomedical Engineering and Imaging Sciences, King’s College London, St Thomas’ Hospital)

  • Jan Lj. Miljkovic

    (University of Cambridge, Keith Peters Building)

  • James D. Gilbert

    (Queen Mary University of London)

  • Rebecca L. Charles

    (Queen Mary University of London)

  • Hiran A. Prag

    (University of Cambridge, Keith Peters Building
    University of Cambridge, Cambridge Biomedical Campus)

  • Nikayla Patel

    (Queen Mary University of London)

  • Daniel W. Hart

    (University of Pretoria)

  • Michael P. Murphy

    (University of Cambridge, Keith Peters Building)

  • Nigel C. Bennett

    (University of Pretoria)

  • Dunja Aksentijevic

    (Queen Mary University of London)

Abstract

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.

Suggested Citation

  • Chris G. Faulkes & Thomas R. Eykyn & Jan Lj. Miljkovic & James D. Gilbert & Rebecca L. Charles & Hiran A. Prag & Nikayla Patel & Daniel W. Hart & Michael P. Murphy & Nigel C. Bennett & Dunja Aksentije, 2024. "Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46470-x
    DOI: 10.1038/s41467-024-46470-x
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    References listed on IDEAS

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    1. Eun Bae Kim & Xiaodong Fang & Alexey A. Fushan & Zhiyong Huang & Alexei V. Lobanov & Lijuan Han & Stefano M. Marino & Xiaoqing Sun & Anton A. Turanov & Pengcheng Yang & Sun Hee Yim & Xiang Zhao & Mari, 2011. "Genome sequencing reveals insights into physiology and longevity of the naked mole rat," Nature, Nature, vol. 479(7372), pages 223-227, November.
    2. Dunja Aksentijević & Anja Karlstaedt & Marina V. Basalay & Brett A. O’Brien & David Sanchez-Tatay & Seda Eminaga & Alpesh Thakker & Daniel A. Tennant & William Fuller & Thomas R. Eykyn & Heinrich Taeg, 2020. "Intracellular sodium elevation reprograms cardiac metabolism," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Edward T. Chouchani & Victoria R. Pell & Edoardo Gaude & Dunja Aksentijević & Stephanie Y. Sundier & Ellen L. Robb & Angela Logan & Sergiy M. Nadtochiy & Emily N. J. Ord & Anthony C. Smith & Filmon Ey, 2014. "Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS," Nature, Nature, vol. 515(7527), pages 431-435, November.
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