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

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 Aksentijevic

doi:10.1038/s41467-024-46470-x

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

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 Aksentijevic

Pharmacy

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2204
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-46470-x
Publication status	Published - 27 Mar 2024

Keywords

Animals
Mice
Oxygen
Longevity/genetics
Hypoxia/genetics
Mole Rats/genetics
Ischemia

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-024-46470-x

Cite this

Faulkes, C. G., Eykyn, T. R., Miljkovic, J. L., Gilbert, J. D., Charles, R. L., Prag, H. A., Patel, N., Hart, D. W., Murphy, M. P., Bennett, N. C., & Aksentijevic, D. (2024). Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles. Nature Communications, 15(1), 2204. https://doi.org/10.1038/s41467-024-46470-x

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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.",

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AU - Eykyn, Thomas R

AU - Miljkovic, Jan Lj

AU - Gilbert, James D

AU - Charles, Rebecca L

AU - Prag, Hiran A

AU - Patel, Nikayla

AU - Hart, Daniel W

AU - Murphy, Michael P

AU - Bennett, Nigel C

AU - Aksentijevic, Dunja

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N2 - 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.

AB - 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.

KW - Animals

KW - Mice

KW - Oxygen

KW - Longevity/genetics

KW - Hypoxia/genetics

KW - Mole Rats/genetics

KW - Ischemia

U2 - 10.1038/s41467-024-46470-x

DO - 10.1038/s41467-024-46470-x

M3 - Article

C2 - 38538579

SN - 2041-1723

VL - 15

SP - 2204

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

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