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Biogerontology

, Volume 20, Issue 5, pp 677–686 | Cite as

Hypercapnic hypoxia as a potential means to extend life expectancy and improve physiological activity in mice

  • Vladimir P. Kulikov
  • Pavel P. TregubEmail author
  • Ilya S. Osipov
  • Arseniy I. Trukhanov
Research Article
  • 39 Downloads

Abstract

The application of combined hypoxia and hypercapnia (hypercapnic hypoxia) during respiratory exercises results in a maximum increase in resistance to acute hypoxia and ischemic tolerance of the brain. The results of those researches allow the assumption that hypercapnic hypoxia is a promising method for prophylaxis, treatment, and rehabilitation, as well as a means to increase life expectancy. The study was conducted to verify the hypothesis that it is possible to extend the life span through regular courses of respiratory exercises with hypercapnic hypoxia. In the present experimental research carried out on mice, the geroprotective effect of regular hypercapnic-hypoxic exercises (PO2—90 mm Hg and PCO2—50 mm Hg) was assessed in the context of the average life expectancy and the main criteria of its quality (reproductive function, muscle strength, and behavior). Results suggest that with regular training, life span is extended significantly by 16%. This result was accompanied by improved reproductive and cognitive functions, increased motor and search activities, and physical stamina in old age mices. This important phenomenon is accompanied by improved reproductive and cognitive functions, high motor function and search activity, as well as better physical stamina in old-aged mices. Recurring respiratory training under combined hypoxia and hypercapnia (hypercapnic hypoxia) during the lifetime significantly extended the life span of mice in the experiments.

Keywords

Hypoxia Hypercapnia Hypercapnic hypoxia Rejuvenation Lifespan Healthy longevity 

Notes

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Human and animal rights

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed (EU Directive 2010/63/EU for animal experiments).

References

  1. Agadzhanian NA, Radysh IV, Severin AE, Ermakova NV (1995) Ecology, adaptation and biorhythms. Aviakosm Ekolog Med 29(3):16–19Google Scholar
  2. Anisimov VN, Popovich IG, Zabezhinski MA (2007) Methods of evaluating the effect of of pharmacological drugs on aging and life span in mice biological aging: methods and protocols. In: Tollefsbol TO (ed) Methods in molecular biology, vol 371. Humana Press, Totowa, pp 227–236Google Scholar
  3. Bespalov AG, Tregub PP, Kulikov VP, Pijanzin AI, Belousov AA (2014) The role of VEGF, HSP-70 and protein S-100B in the potentiation effect of the neuroprotective effect of hypercapnic hypoxia. Patol Fiziol Eksp Ter 2:24–27Google Scholar
  4. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279:349–352CrossRefGoogle Scholar
  5. Boretto JM, Cabezas-Cartes F, Ibargüengoytía NR (2018) Slow life histories in lizards living in the highlands of the Andes Mountains. J Comp = Physiol B 188:491–503Google Scholar
  6. Bourin M, Hascoët M (2003) The mouse light/dark box test. Eur J Pharmacol 463(1–3):55–65CrossRefGoogle Scholar
  7. Calabrese V, Scapagnini G, Davinelli S, Koverech G, Koverech A, De Pasquale C, Salinaro AT, Scuto M, Calabrese EJ, Genazzani AR (2014) Sex hormonal regulation and hormesis in aging and longevity: role of vitagenes. J Cell Commun Signal 8(4):369–384CrossRefGoogle Scholar
  8. Chen WJ, Chen HW, Yu SL (2005) Gene expression profiles in hypoxic preconditioning using cDNA microarray analysis: altered expression of an angiogenic factor, carcinoembryonic antigen-related cell adhesion molecule 1. Shock 24:124–131CrossRefGoogle Scholar
  9. de Jesus BB, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, Blasco MA (2012) Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 4(8):691–704CrossRefGoogle Scholar
  10. Fierstra J, Sobczyk O, Battisti-Charbonney J, Mandell DM, Poublanc J, Crawley AP, Mikulis DJ, Duffin J, Fisher JA (2013) Measuring cerebrovascular reactivity: what stimulus to use? J Physiol 591(23):5809–5821CrossRefGoogle Scholar
  11. Finch CE (2009) Update on slow aging and negligible senescence—a mini-review. Gerontology 55:307–313CrossRefGoogle Scholar
  12. Flurkey K, Currer JM, Harrison DE (2007) The mouse in aging research. In: Fox JG et al (eds) The mouse in biomedical research second III. Academic Press, Cambridge, pp 637–672CrossRefGoogle Scholar
  13. Gould TD, Dao DT, Kovacsics CE (2010) The open field test in mood and anxiety related phenotypes in mice. Neuromethods 42:1–20Google Scholar
  14. Gustin SE, Western PS, McClive PJ, Harley VR, Koopman PA, Sinclair AH (2008) Testis development, fertility, and survival in ethanolamine kinase 2-deficient mice. Endocrinology 149(12):6176–6186CrossRefGoogle Scholar
  15. Hall CS (1936) Emotional behavior in the rat. The relationship between emotionality and ambulatory activity. J Comp Physiol Psychol 22:345–352CrossRefGoogle Scholar
  16. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253):392–395CrossRefGoogle Scholar
  17. Helenius IT, Krupinski T, Turnbull DW, Gruenbaum Y, Silverman N, Johnson EA, Sporn PH, Sznajder JI, Beitel GJ (2009) Elevated CO2 suppresses specific Drosophila innate immune responses and resistance to bacterial infection. Proc Natl Acad Sci USA 106(44):18710–18715CrossRefGoogle Scholar
  18. Jackson HF, Broadhurst PL (1982) The effects of parachlorophenylalanine and stimulus intensity on open-field test measures in rats. Neuropharmacology 21(12):1279–1282CrossRefGoogle Scholar
  19. Jafari M (2015) Healthspan pharmacology. Rejuvenation Res 18(6):573–580CrossRefGoogle Scholar
  20. Jaitovich A, Angulo M, Lecuona E, Dada LA, Welch LC, Cheng Y, Gusarova G, Ceco E, Liu C, Shigemura M, Barreiro E, Patterson C, Nader GA, Sznajder JI (2015) High CO2 levels cause skeletal muscle atrophy via AMP-activated kinase (AMPK), FoxO3a protein, and muscle-specific Ring finger protein 1 (MuRF1). J Biol Chem 290(14):9183–9194CrossRefGoogle Scholar
  21. Krivoruchko A, Storey KB (2010) Forever young: mechanisms of natural anoxia tolerance and potential links to longevity. Oxid Med Cell Longev 3(3):186–198CrossRefGoogle Scholar
  22. Kulikov VP, Bespalov AG, Yakushev NN (2009) The state of cerebral hemodynamics in conditions of prolonged adaptation to hypercapnic hypoxia. Neurosci Behav Physiol 39(3):269–273CrossRefGoogle Scholar
  23. Kulikov VP, Osipov IS, Tregub PP (2015) Optimal hypercapnic hypoxia conditions for increasing resistance to acute hypoxia. Aviakosm Ekolog Med 49(5):25–28Google Scholar
  24. Laffey JG, Tanaka M, Engelberts D, Luo X, Yiang S, Tanswell TK, Post M, Lindsay T, Kavanagh BP (2000) Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir Crit Care Med 162:2287–2294CrossRefGoogle Scholar
  25. Leak RK, Calabrese EJ, Kozumbo WJ, Gidday JM, Johnson TE, Mitchell JR, Ozaki CK, Wetzker R, Bast A, Belz RG, Bøtker HE, Koch S, Mattson MP, Simon RP, Jirtle RL, Andersen ME (2018) Enhancing and extending biological performance and resilience. Dose Response 16(3):1559325818784501CrossRefGoogle Scholar
  26. Lin HJ, Wang CT, Niu KC, Gao C, Li Z, Lin MT, Chang CP (2011) Hypobaric hypoxia preconditioning attenuates acute lung injury during high-altitude exposure in rats via up-regulating heat-shock protein 70. Clin Sci (Lond) 121(5):223–231CrossRefGoogle Scholar
  27. Lukyanova LD, Germanova EL, Kopaladze RA (2009) Development of resistance of an organism under various conditions of hypoxic preconditioning: role of the hypoxic period and reoxygenation. Bull Exp Biol Med 147:400–404CrossRefGoogle Scholar
  28. Matsubayashi K, Okumiya K (2012) Field medicine: a new paradigm of geriatric medicine. Geriatr Gerontol Int 12(1):5–15CrossRefGoogle Scholar
  29. Muradian K (2013) “Pull and push back” concepts of longevity and life span extension. Biogerontology 14(6):687–691CrossRefGoogle Scholar
  30. Neckár J, Papousek F, Nováková O, Ost’ádal B, Kolár F (2002) Cardioprotective effects of chronic hypoxia and ischaemic preconditioning are not additive. Basic Res Cardiol 97(2):161–167CrossRefGoogle Scholar
  31. Obrenovitch TP (2008) Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev 88(1):211–247CrossRefGoogle Scholar
  32. Pruimboom L, Muskiet FAJ (2018) Intermittent living; the use of ancient challenges as a vaccine against the deleterious effects of modern life—a hypothesis. Med Hypotheses 120:28–42CrossRefGoogle Scholar
  33. Serebrovskaya TV, Xi L (2016) Intermittent hypoxia training as non-pharmacologic therapy for cardiovascular diseases: practical analysis on methods and equipment. Exp Biol Med (Maywood) 241(15):1708–1723CrossRefGoogle Scholar
  34. Sharabi K, Hurwitz A, Simon AJ, Beitel GJ, Morimoto RI, Rechavi G, Sznajder JI, Gruenbaum Y (2009) Elevated CO2 levels affect development, motility, and fertility and extend life span in Caenorhabditis elegans. Proc Natl Acad Sci USA 106(10):4024–4029CrossRefGoogle Scholar
  35. Sharp FR, Ran R, Lu A, Tang Y, Strauss KI, Glass T, Ardizzone T, Bernaudin M (2004) Hypoxic preconditioning protects against ischemic brain injury. NeuroRx 1(1):26–35CrossRefGoogle Scholar
  36. Shatilo VB, Korkushko OV, Ischuk VA, Downey HF, Serebrovskaya TV (2008) Effects of intermittent hypoxia training on exercise performance, hemodynamics, and ventilation in healthy senior men. High Alt Med Biol 9(1):43–52CrossRefGoogle Scholar
  37. Siafakas NM, Jordan M, Wagner H, Breen EC, Benoit H, Wagner PD (2001) Diaphragmatic angiogenic growth factor mRNA responses to increased ventilation caused by hypoxia and hypercapnia. Eur Respir J 17:681–687CrossRefGoogle Scholar
  38. Tao T, Liu Y, Zhang J, Xu Y, Li W, Zhao M (2013) Therapeutic hypercapnia improves functional recovery and attenuates injury via antiapoptotic mechanisms in a rat focal cerebral ischemia/reperfusion model. Brain Res 1533:52–62CrossRefGoogle Scholar
  39. Tregub P, Kulikov V, Bespalov A (2013) Tolerance to acute hypoxia maximally increases in case of joint effect of normobaric hypoxia and permissive hypercapnia in rats. Pathophysiology 20(3):165–170CrossRefGoogle Scholar
  40. Tregub P, Kulikov V, Motin Y, Bespalov A, Osipov I (2015) Combined exposure to hypercapnia and hypoxia provides its maximum neuroprotective effect during focal ischemic injury in the brain. J Stroke Cerebrovasc Dis 24(2):381–387CrossRefGoogle Scholar
  41. Van Zutphen LF, Baumans V, Beynen AC (2001) Principles of laboratory animal science. Elsevier, New YorkGoogle Scholar
  42. Yang CC, Lin LC, Wu MS (2009) Repetitive hypoxic preconditioning attenuates renal ischemia/reperfusion induced oxidative injury via upregulating HIF-1 alpha-dependent bcl-2 signaling. Transplantation 88:1251–1260CrossRefGoogle Scholar
  43. Zakynthinos S, Katsaounou P, Karatza MH, Roussos C, Vassilakopoulos T (2007) Antioxidants increase the ventilatory response to hyperoxic hypercapnia. Am J Respir Crit Care Med 175(1):62–68CrossRefGoogle Scholar
  44. Zhou Q, Cao B, Niu L, Cui X, Yu H, Liu J, Li H, Li W (2010) Effects of permissive hypercapnia on transient global cerebral ischemia–reperfusion injury in rats. Anesthesiology 112:288–297CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.LLC “Altai Medical Institute of Postgraduate Education”BarnaulRussia
  2. 2.“Professor VF Voyno-Yasenetsky Krasnoyarsk State Medical University” of the Ministry of Health of RussiaKrasnoyarskRussia
  3. 3.Federal Scientific Clinical Center for Reanimatology and RehabilitationMoscowRussia

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