Metabolic remodelling of mice by hypoxic-hypercapnic environment: imitating the naked mole-rat

  • Denis A. Tolstun
  • Anna Knyazer
  • Tetiana V. Tushynska
  • Tatyana A. Dubiley
  • Vladislav V. Bezrukov
  • Vadim E. FraifeldEmail author
  • Khachik K. MuradianEmail author
Research Article


We hypothesised that hypoxic-hypercapnic environment (HHE) could induce metabolic suppression and associated benefits for health and longevity, as observed in the naked-mole rat (NMR). We developed a model of self-produced HHE (similar to a natural habitat of NMRs), which is simple, reliable and natural, and does not require external sources of gases or complex technical equipment. Here, we showed for the first time that a chronic exposure of mice to HHE could be a unique tool for NMR-like metabolic remodeling, resulting in a long-term and substantial decrease in metabolic rate, body temperature, and food consumption, without significant changes in expression of stress-related genes. Unexpectedly, the HHE accelerated skin wound healing, despite the lower energy expenditure. The self-produced HHE could be considered a model of voluntary calorie restriction. All in all, a chronic exposure to HHE offers a potential of being a lifespan-extending intervention as well as an efficient tool for treating the overweight and associated metabolic disorders.


Hypometabolism Hypothermia Hypoxia Hypercapnia Voluntary calorie restriction Mice Age 



Calorie restriction


Free triiodothyronine


Free thyroxine


Glyceraldehyde 3-phosphate dehydrogenase


Hypoxic-hypercapnic environment


Heat Shock Protein 90 Alpha Family Class A Member




Mesenchymal stem cells


Naked mole-rat(s)


Quantitative real time polymerase chain reaction


Oxygen consumption


Carbon dioxide production


Mitochondrial uncoupling protein 2



We thank Dr. Irina Pishel for her assistance in conducting the experiments. This work was supported in part by the Fund in Memory of Dr. Amir Abramovich (to V.E.F.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10522_2019_9848_MOESM1_ESM.pptx (66 kb)
Online Resource 1 Relationships between Vco2 and atmospheric CO2 in (a) young and (b) old male CBA mice (PPTX 65 kb)
10522_2019_9848_MOESM2_ESM.pptx (195 kb)
Online Resource 2 (a) The head skin excision model, and (b) time-course of skin wound closure in young male C57Bl/6 mice upon chronic exposure to self-produced HHE. Each mouse was subjected to a single head punch wound. Wound area was expressed as percentage of the original wound size (PPTX 194 kb)


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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.State Institute of Gerontology of National Academy of Medical Sciences of UkraineKievUkraine
  2. 2.The Shraga Segal Department of Microbiology, Immunology and Genetics, Center for Multidisciplinary Research on AgingBen-Gurion University of the NegevBeer ShevaIsrael

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