Intermittent Hypoxia and Health: From Evolutionary Aspects to Mitochondria Rejuvenation

  • Arkadi F. ProkopovEmail author


Mitochondrial aging manifests as gradual depletion of energy reserves at cellular and ­systemic levels, as well as lowered stress resistance. Vital functional state of mitochondria is essential to reduce burden of age-dependent degenerative diseases and prolong health span. Two mitochondria-rejuvenating interventions: intermittent hypoxic training (IHT) and extended morning fasting (EMF), as engineered derivates of naturally occurred intermittent oxygen restriction (IOR) and intermittent calorie restriction (ICR), have been already in clinical practice. IHT and EMF utilize the familiar developmental and adaptational genetic programs, evolutionarily “preinstalled” in all aerobic organisms. Both ICR and IOR employ a common mitochondria-rejuvenating pathway, the mitoptosis – a selective elimination of the mitochondria that excessively produce reactive oxygen species in the cells. Mitoptosis is a natural process that maintains quality of mitochondria in the female germinal cells during early embryogenesis and can be stimulated and maintained by IOR and ICR also in postmitotic cells of adult organisms. ICR and IOR synergistically diminish the basal level of mitochondria-dependent oxidative stress that is supposed to be the key factor modulating life span and health span in aerobes. Furthermore, ICR and IOR influence longevity and tempo of development of age-related diseases via several mitochondria-­independent pathways, such as suppressed protein glycation, enhanced DNA repair, accelerated protein turnover, stimulation of erythropoetin, growth hormone, heat shock protein 70, and other functional proteins. In addition, the IOR specifically intensifies stem cells-dependent tissue repair. The synergistic application of IOR- and ICR-based protocols, accompanied by nutrigenomical adjustment and individualized nutraceutical supplementation, brings multiple health benefits and alleviation or cure in numerous chronic degenerative and age-related diseases. Further development of engineered ICR and IOR protocols should help their advanced clinical implementation and user-friendly, self-help applications.


Obstructive Sleep Apnea Reactive Nitrogen Species Intermittent Hypoxia Chronic Hypoxia Hypoxic Precondition 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Alternate day calorie restriction


Alternate day fasting


Adenosine triphosphate


Body mass index


Bowhead whale (Balaena mysticetus)


Central nervous system


Calorie restriction


Extended morning fasting




Growth hormone


Hypoxia-inducible factor-1


Heat shock protein 70


Intermittent caloric restriction


Intermittent hypoxic therapy/training


Intermittent oxygen restriction


Mesenchymal stem cells


Mitochondrial DNA


Nitric oxide


Nuclear DNA


Obstructive sleep apnea


Oxidative phosphorylation


Reactive nitrogen species


Reactive oxygen species


Stem cells


Superoxide dismutase


  1. 1.
    Ahmad S, Ahmad A, Gerasimovskaya E, et al. Hypoxia protects human lung microvascular endothelial and epithelial-like cells against oxygen toxicity. Role of phosphatidylinositol 3-kinase. Am J Respir Cell Mol Biol. 2003;28:179–87.PubMedCrossRefGoogle Scholar
  2. 2.
    Allen JF, et al. Separate sexes and the mitochondrial theory of ageing. J Theor Biol. 1996;180:135–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Anson RM, Guo Z, de Cabo R, et al. Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake. Proc Natl Acad Sci USA. 2003;100:6216–20.PubMedCrossRefGoogle Scholar
  4. 4.
    Balobolkin MI, Nedosugova LV, Gavriluk LI, et al. The influence of fasting on the interaction between insulin and insulin receptors in diabetic patients. Ther Arch. 1983;9:136–40 [In Russian].Google Scholar
  5. 5.
    Bassovitch O, Serebrovskaya TV. Equipment and regimes for intermittent hypoxia therapy. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms to clinical applications. New York: Nova Science Publ Inc; 2009. p. 589–601.Google Scholar
  6. 6.
    Bianchi G, Di Giulio C, Rapino C, et al. p53 and p66 proteins compete for hypoxia-inducible factor 1 alpha stabilization in young and old rat hearts exposed to intermittent hypoxia. Gerontology. 2006;52:17–23.PubMedCrossRefGoogle Scholar
  7. 7.
    Bickler PE, Donohoe PH. Adaptive responses of vertebrate neurons to hypoxia. J Exp Biol. 2002;205:3579–86.PubMedGoogle Scholar
  8. 8.
    Breitenbach M, Lehrach H, Krobitsch S. Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress. J Biol. 2007;6:10. doi: 10.1186/jbiol6.PubMedCrossRefGoogle Scholar
  9. 9.
    Broome CS, Kayani AC, Palomero J, et al. Effect of lifelong overexpression of HSP70 in skeletal muscle on age-related oxidative stress and adaptation after non-damaging contractile activity. FASEB J. 2006;20:1549–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Brucklachera RM, Vannuccia RC, Vannucci SJ. Hypoxic preconditioning increases brain glycogen and delays energy depletion from hypoxia-ischemia in the immature rat. Dev Neurosci. 2002;24:411–7.CrossRefGoogle Scholar
  11. 11.
    Butler PJ, Jones DR. Physiology of diving of birds and mammals. Physiol Rev. 1997;77:837–99.PubMedGoogle Scholar
  12. 12.
    Cahill Jr GF. Starvation in man. N Engl J Med. 1970;282:668–75.PubMedCrossRefGoogle Scholar
  13. 13.
    Chen J, Patschan S, Goligorsky MS. Stress-induced premature senescence of endothelial cells. J Nephrol. 2008;21:337–44.PubMedGoogle Scholar
  14. 14.
    Chinnery PF, Pagon RA, Bird TD, Dolan CR, et al. Mitochondrial disorders overview. In: Gene reviews. Seattle: University of Washington; 2000–2010.Google Scholar
  15. 15.
    Chizhov AI. Physiologic bases of the method to increase nonspecific resistance of the organism by adaptation to intermittent normobaric hypoxia. Fiziol Zh. 1992;38:13–7 [In Russian].PubMedGoogle Scholar
  16. 16.
    Chizov AI, Filimonov VG, Karash YM, et al. Biorhythm of oxygen tension in uterine and fetal tissues. Biull Eksp Biol Med. 1981;10:392–4 [In Russian].Google Scholar
  17. 17.
    Chu Y-D. High altitude and aging. High Alt Med Biol. 2004;5:350.Google Scholar
  18. 18.
    Civitarese AE, Carling S, Heilbronn LK, et al. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. PLoS Med. 2007;4:e76. doi: 10.1371/journal.pmed.0040076.PubMedCrossRefGoogle Scholar
  19. 19.
    Cleary MP, Jacobson MK, Phillips FC, et al. Weight-cycling decreases incidence and increases latency of mammary tumors to a greater extent than does chronic caloric restriction in mouse mammary tumor virus-transforming growth factor-alpha female mice. Cancer Epidemiol Biomarkers Prev. 2002;11:836–43.PubMedGoogle Scholar
  20. 20.
    Cowan DF. Pathology of the pilot whale. Globicephala melaena a comparative survey. Arch Pathol. 1966;82:178–89.PubMedGoogle Scholar
  21. 21.
    da Silva-Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci. 2006;119:2204–13.PubMedCrossRefGoogle Scholar
  22. 22.
    Danet GH, Pan Y, Luongo JL. Expansion of human SCID-repopulating cells under hypoxic conditions. J Clin Invest. 2003;112:126–35.PubMedGoogle Scholar
  23. 23.
    Dawkins R. The extended phenotype. Oxford: Oxford University Press; 1982.Google Scholar
  24. 24.
    Dawkins R. The selfish gene. Oxford: Oxford University Press; 1976.Google Scholar
  25. 25.
    de Bruin JP, Dorlandb M, Spekc ER, et al. Ultrastructure of the resting ovarian follicle pool in healthy young women. Biol Reprod. 2002;66:1151–60.PubMedCrossRefGoogle Scholar
  26. 26.
    de Grey AD. Inter-species therapeutic cloning: the looming problem of mitochondrial DNA and two possible solutions. Rejuvenation Res. 2004;7:95–8.PubMedCrossRefGoogle Scholar
  27. 27.
    de Guise S, Lagacé A, Béland P. Tumors in St. Lawrence beluga whales (Delphinapterus leucas). Vet Pathol. 1994;31:444–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Dhahbi J, Kim HJ, Mote PL, et al. Temporal linkage between the phenotypic and genomic responses to caloric restriction. Proc Natl Acad Sci USA. 2004;101:5524–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Erbayraktar S, Yilmaz O, Gökmen N, et al. Erythropoetin is a multifunctional-tissue-protective cytokine. Curr Hematol Rep. 2003;2:465–70.PubMedGoogle Scholar
  30. 30.
    Evans JL, Goldfine ID, Maddux BA, et al. Ketones metabolism increases the reduced form of glutathione thus facilitating destruction of hydrogen peroxide. Endocr Rev. 2002;23:599–622.PubMedCrossRefGoogle Scholar
  31. 31.
    Fischer B, Bavister BD. Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits. J Reprod Fertil. 1993;99:673–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Foster GE, Poulin MJ, Hanly PJ. Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea. Exp Physiol. 2007;92:51–65.PubMedCrossRefGoogle Scholar
  33. 33.
    Gami MS, Wolkow CA. Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan. Aging Cell. 2006;5:31–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Garrido E, Castello A, Ventura JL, et al. Cortical atrophy and other brain magnetic resonance imaging (MRI) changes after extremely high-altitude climbs without oxygen. Int J Sports Med. 1993;14:232–4.PubMedCrossRefGoogle Scholar
  35. 35.
    Gassmann M, Fandrey J, Bichet S, et al. Oxygen supply and oxygen-dependent gene expression in differentiating embryonic stem cells. Proc Natl Acad Sci USA. 1996;93:2867–72.PubMedCrossRefGoogle Scholar
  36. 36.
    Géminard C, de Gassart A, Vidal M. Reticulocyte maturation: mitoptosis and exosome release. Biocell. 2002;26:205–15.PubMedGoogle Scholar
  37. 37.
    George JC, Bada JL, Zeh J, et al. Age and growth estimates of bowhead whales (Balaena mysticetus) via aspartic acid racemization. Can J Zool. 1999;77:571–80.Google Scholar
  38. 38.
    Geppe NA, Kurchatova TV, Dairova RA, et al. Interval hypoxic training in bronchial asthma in children. Hypoxia Med J. 1995;3:11–4.Google Scholar
  39. 39.
    Geraci JR, Palmer NC, St Aubin DJ. Tumors in cetaceans: analysis and new findings. Can J Fish Aquat Sci. 1987;44:1289–300.CrossRefGoogle Scholar
  40. 40.
    Gidday JM. Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci. 2006;7:437–48.PubMedCrossRefGoogle Scholar
  41. 41.
    Gnaiger E, Méndez G, Hand SC. High phosphorylation efficiency and depression of uncoupled respiration in mitochondria under hypoxia. Proc Natl Acad Sci USA. 2000;97:11080–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Golikov MA. Health, endurance, longevity: the role of hypoxic stimulation. In: Strelkov RB, editor. Intermittent normobaric hypoxytherapy. Annals of international academy of problems of hypoxia. Vol 5. 2005. p. 164–200. [In Russian].Google Scholar
  43. 43.
    Gomez-Cabrera MC, Domenech E, Romagnoli M, et al. Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance. Am J Clin Nutr. 2008;87:142–9.PubMedGoogle Scholar
  44. 44.
    Grechin VB, Krauz EI. Spontaneous fluctuations of oxygen tension in human brain structures. Biull Eksp Biol Med. 1973;75:20–2 [In Russian].CrossRefGoogle Scholar
  45. 45.
    Gredilla R, Barja G. Minireview: the role of oxidative stress in relation to caloric restriction and longevity. Endocrinology. 2005;146:3713–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Halaschek-Wiener J, Brooks-Wilson A. Progeria of stem cells: stem cell exhaustion in Hutchinson-Gilford progeria syndrome. J Gerontol A Biol Sci Med Sci. 2007;62:3–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458–60.PubMedCrossRefGoogle Scholar
  48. 48.
    Heidel JR, Philo LM, Albert TF, et al. Serum chemistry of bowhead whales (Balaena mysticetus). J Wildl Dis. 1996;32:75–9.PubMedGoogle Scholar
  49. 49.
    Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006;295:1539–48.PubMedCrossRefGoogle Scholar
  50. 50.
    Heinicke K, Cajigal J, Viola T, et al. Long-term exposure to intermittent hypoxia results in increased hemoglobin mass, reduced plasma volume, and elevated erythropoietin plasma levels in man. Eur J Appl Physiol. 2003;88:535–43.PubMedCrossRefGoogle Scholar
  51. 51.
    Honda Y, Honda S. Oxidative stress and life span determination in the nematode Caenorhabditis elegans. Ann N Y Acad Sci. 2002;959:466–74.PubMedCrossRefGoogle Scholar
  52. 52.
    Hoppeler H, Kleinert E, Schlegel C, et al. Morphological adaptations of human skeletal muscle to chronic hypoxia. Int J Sports Med. 1990;11:S3–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Hsu AL, Murphy CT, Kenyon C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science. 2003;300:1142–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Huckabee W, Metcalfe J, Prystowsky H, et al. Blood flow and oxygen consumption of the pregnant uterus. Am J Physiol. 1961;200:274–8.PubMedGoogle Scholar
  55. 55.
    Jauniaux E, Watson A, Ozturk O. In-vivo measurement of intrauterine gases and acid-base values early in human pregnancy. Hum Reprod. 1999;14:2901–4.PubMedCrossRefGoogle Scholar
  56. 56.
    Jefferson J, Ashley J, Simoni J, et al. Increased oxidative stress following acute and chronic high altitude exposure. High Alt Med Biol. 2004;5:61–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Jelluma N, Yang X, Stokoe D, et al. Glucose withdrawal induces oxidative stress followed by apoptosis in glioblastoma cells but not in normal human astrocytes. Mol Cancer Res. 2006;4:319–30.PubMedCrossRefGoogle Scholar
  58. 58.
    Johnson JB, Summer W, Cutler RG, et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med. 2007;42:665–74.PubMedCrossRefGoogle Scholar
  59. 59.
    Khrapko K, Nekhaeva E, Kraytsberg Y, et al. Clonal expansions of mitochondrial genomes: implications for in vivo mutational spectra. Mutat Res. 2003;522:9–13.Google Scholar
  60. 60.
    Kirkwood JK, Bennett PM, Jepson PD, et al. Entanglement in fishing gear and other causes of death in cetaceans stranded on the coasts of England and Wales. Vet Rec. 1997;141:94–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Kogan AKh, Grachev SV, Eliseeva SV, et al. Carbon dioxide – a universal inhibitor of the generation of active oxygen forms by cells. Izv Akad Nauk Ser Biol. 1997;2:204–17 [In Russian].PubMedGoogle Scholar
  62. 62.
    Kolchinskaya AZ, Tsyganova TN, Ostapenko LA. Normobaric interval hypoxic training in medicine and sports. Moscow: Meditsina; 2003 [In Russian].Google Scholar
  63. 63.
    Kolesnikova EE, Serebrovskaya TV. Parkinson’s disease and intermittent hypoxia training. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms to clinical applications. New York: Nova Science Pub Inc; 2009. p. 577–88.Google Scholar
  64. 64.
    Kotlyarova LA, Stepanova EN, Tkatchouk EN, et al. The immune state of the patients with rheumatoid arthritis in the interval hypoxic training. Hypoxia Med J. 1994;2:11–2.Google Scholar
  65. 65.
    Krakauer DC, Mira A. Mitochondria and germ cell death. Nature. 1999;400:125–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001;105:369–77.PubMedCrossRefGoogle Scholar
  67. 67.
    Krysko D, Mussche S, Leybaert LD, et al. Gap junctional communication and connexin 43 expression in relation to apoptotic cell death and survival of granulosa cells. J Histochem Cytochem. 2004;52:1199–207.PubMedCrossRefGoogle Scholar
  68. 68.
    Kunze K. Spontaneous oscillations of pO2 in muscle tissue. Adv Exp Med Biol. 1976;75:631–7.PubMedGoogle Scholar
  69. 69.
    Lacza Z, Kozlov AV, Pankotai E, et al. Mitochondria produce reactive nitrogen species via an arginine-independent pathway. Free Radic Res. 2006;40:369–78.PubMedCrossRefGoogle Scholar
  70. 70.
    Laffey J, Motoschi T, Engelberts D. Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion. Am J Respir Crit Care Med. 2000;162:2287–94.PubMedGoogle Scholar
  71. 71.
    Lee W-C, Chen J-J, Ho H-Y, et al. Short-term altitude mountain living improves glycemic control. High Alt Med Biol. 2003;4:81–91.PubMedCrossRefGoogle Scholar
  72. 72.
    Lemaster JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction and aging. Rejuvenation Res. 2005;8:3–5.CrossRefGoogle Scholar
  73. 73.
    Li A-M, Quan Y, Guo Y-P, et al. Effects of therapeutic hypercapnia on inflammation and apoptosis after hepatic ischemia-reperfusion injury in rats. Chin Med J. 2010;123:2254–8.PubMedGoogle Scholar
  74. 74.
    Liu J, Ames B. Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer’s disease, and Parkinson’s disease. Nutr Neurosci. 2005;8:67–89.PubMedCrossRefGoogle Scholar
  75. 75.
    Lukyanova LD, Dudchenko AV, Germanova EL, et al. Mitochondrial signaling in formation of body resistance to hypoxia. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms to clinical applications. New York: Nova Science Pub Inc; 2009. p. 423–50.Google Scholar
  76. 76.
    Manukhina EB, Downey FH, Mallet RT. Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Exp Biol Med. 2006;231:343–65.Google Scholar
  77. 77.
    Maynard-Smith J, Szathmary E. The major transitions in evolution. Oxford: Freeman; 1995.Google Scholar
  78. 78.
    Meerson FZ, Gomzakov OA, Shimkovich MV. Adaptation to high altitude hypoxia as a factor preventing development of myocardial ischemic necrosis. Am J Cardiol. 1973;31:30–4.PubMedCrossRefGoogle Scholar
  79. 79.
    Meerson FZ. Adaptation to intermittent hypoxia: mechanisms of protective effects. Hypoxia Med J. 1993;3:2–8.Google Scholar
  80. 80.
    Meerson FZ. Mechanism of phenotypic adaptation and the principles of its use for prevention of cardiovascular disorders. Kardiologiia. 1978;18:18–29 [In Russian].PubMedGoogle Scholar
  81. 81.
    Meyer K, Foster C, Georgakopoulos N, et al. Comparison of left ventricular function during interval versus steady-state exercise training in patients with chronic congestive heart failure. Am J Cardiol. 1998;82:1382–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Milano G, Corno A, Lippa S, et al. Chronic and intermittent hypoxia induce different degrees of myocardial tolerance to hypoxia-induced dysfunction. Exp Biol Med. 2002;227:389–97.Google Scholar
  83. 83.
    Moraes CT, Kenyon L, Hao H. Mechanisms of human mitochondrial DNA maintenance: the determining role of primary sequence and length over function. Mol Biol Cell. 1999;10:3345–56.PubMedGoogle Scholar
  84. 84.
    Morris AA. Cerebral ketone body metabolism. J Inherit Metab Dis. 2005;28:109–21.PubMedCrossRefGoogle Scholar
  85. 85.
    Neubauer JA. Physiological and pathophysiological responses to intermittent hypoxia. J Appl Physiol. 2001;90:1593–9.PubMedGoogle Scholar
  86. 86.
    Nicholasa A, Kraytsberga GX, et al. On the timing and the extent of clonal expansion of mtDNA deletions: evidence from single-molecule PCR. Exp Neurol. 2009;218:316–9.CrossRefGoogle Scholar
  87. 87.
    Nikolsky I, Serebrovskaya TV. Hypoxia and stem cells. In: Xi L, Serebrovskaya TV, editors. Intermittent hypoxia: from molecular mechanisms to clinical applications. New York: Nova Science Pub Inc; 2009. p. 469–87.Google Scholar
  88. 88.
    Ning Z, Yi Z, Hai-Feng Z, Zhao-Nian Z. Intermittent hypoxia exposure prevents mtDNA deletion and mitochondrial structure damage produced by ischemia/reperfusion injury. Acta Physiologica Sinica Oct. 2000; 52 (5): 375-380.Google Scholar
  89. 89.
    Nunney L. Lineage selection and the evolution of multistage carcinogenesis. Proc Biol Sci. 1999;266:493–8.PubMedCrossRefGoogle Scholar
  90. 90.
    Ogier-Denis E, Codogno P. Autophagy: a barrier or an adaptive response to cancer. Biochim Biophys Acta. 2003;1603:113–28.PubMedGoogle Scholar
  91. 91.
    Owen OE, Morgan AP, Kemp HG, et al. Brain metabolism during fasting. J Clin Invest. 1967;46:1589–95.PubMedCrossRefGoogle Scholar
  92. 92.
    Peto R. Epidemiology, multistage models, and short-term mutagenicity tests. In: Hiatt HH, Watson JD, Winsten JA, editors. The origins of human cancer. Cold spring harbor conferences on cell proliferation. New York: Cold Spring Harbor Laboratory Press; 1977. p. 1403–28.Google Scholar
  93. 93.
    Philo LM, Shotts EB, George JC. Morbidity and mortality. In: Burns JJ, Montague JJ, Cowles CJ editors. The bowhead whale. Vol 2. Soc Mar Mamm Spec Publ; 1993. p. 275–312.Google Scholar
  94. 94.
    Prabhakar NR. Oxygen sensing during intermittent hypoxia: cellular and molecular mechanisms. J Appl Physiol. 2001;90:1986–1994. [PubMed] Scholar
  95. 95.
    Prokopov A, Voronina T. Intermittent hypoxic therapy/training (IHT): the aetiologic and pathogenetic anti-aging treatment. Rejuvenation Res. 2007;10(S1):45.Google Scholar
  96. 96.
    Prokopov A. Exploring overlooked natural mitochondria – rejuvenative intervention. The puzzle of bowhead whales and naked mole rats. Rejuvenation Res. 2007;10:543–59.PubMedCrossRefGoogle Scholar
  97. 97.
    Prokopov A, Kotliar I. The perspectives of hypoxic treatment in the anti-aging medicine. Hypoxia Med J. 2001;3:37.Google Scholar
  98. 98.
    Prokopov A. A case of recovery from dementia following rejuvenative treatment. Rejuvenation Res. 2010;13:217–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Prokopov A, Voronina T. Engineered natural longevity – enhancing interventions. In: Bentely JV, Keller MA, editors. Handbook on longevity: genetics, diet, and disease. New York: Nova Science Publ Inc; 2009.Google Scholar
  100. 100.
    Rattan S. Hormetic interventions in aging. Am J Pharmacol Toxicol. 2008;3:27–40.CrossRefGoogle Scholar
  101. 101.
    Rochefort GY, Delorme B, Lopez A, et al. Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia. Stem Cells. 2006;24:2202–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Ruscher K, Isaev N, Trendelenburg G, et al. Induction of hypoxia inducible factor-1 by oxygen glucose deprivation is attenuated by hypoxic preconditioning in rat cultured neurons. Neurosci Lett. 1998;254:117–20.PubMedCrossRefGoogle Scholar
  103. 103.
    Russell JW, Golovoy D, Vincent AM, et al. High glucose-induced oxidative stress and mitochondrial dysfunction in neurons. FASEB J. 2002;16:1738–48.PubMedCrossRefGoogle Scholar
  104. 104.
    Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9:651–8.PubMedGoogle Scholar
  105. 105.
    Sazontova TG, Arkhipenko YuV, Lukyanova LD. Comparative study of the effect of adaptation to intermittent hypoxia on active oxygen related systems in brain and liver of rats with different resistance to oxygen deficiency. In: Sharma BK, Takeda N, Ganguly NK, et al., editors. Adaptation biology and medicine. New Delhi: Narosa Publishing House; 1997. p. 260–6.Google Scholar
  106. 106.
    Serebrovskaya TV. Intermittent hypoxia research in the former Soviet Union and the Commonwealth of Independent States: history and review of the concept and selected applications. High Alt Med Biol. 2002;3:205–21.PubMedCrossRefGoogle Scholar
  107. 107.
    Serebrovskaya T, Manukhina EB, Smith ML, et al. Intermittent hypoxia: cause of, or therapy for systemic hypertension? Exp Biol Med. 2008;233:627–50.CrossRefGoogle Scholar
  108. 108.
    Singer D. Neonatal tolerance to hypoxia: a comparative-physiological approach. Comp Biochem Physiol A Mol Integr Physiol. 1999;123:221–34.PubMedCrossRefGoogle Scholar
  109. 109.
    Skrha J, Kunesova M, Hilgertova J. Short-term very low calorie diet reduces oxidative stress in obese type-2 diabetic patients. Physiol Res. 2005;54:33–9.PubMedGoogle Scholar
  110. 110.
    Skulachev V, Longo V. Aging as a mitochondria-mediated atavistic program: can aging be switched off? Ann N Y Acad Sci. 2005;1057:145–64.PubMedCrossRefGoogle Scholar
  111. 111.
    Skulachev V. Mitochondrial physiology and pathology: concepts of programmed death of organelles, cells and organisms. Mol Aspects Med. 1999;20:139–84.PubMedCrossRefGoogle Scholar
  112. 112.
    Skulachev VP. A biochemical approach to the problem of aging: “mega project” on membrane-penetrating ions. Biochemistry (Moscow). 2007;72:1385–96.CrossRefGoogle Scholar
  113. 113.
    Smigrodzki RM, Khan SM. Mitochondrial microheteroplasmy and a theory of aging and age-related disease. Rejuvenation Res. 2005;8:172–98.PubMedCrossRefGoogle Scholar
  114. 114.
    Spees JL, Olson SD, Whitney MJ, et al. Mitochondrial transfer among cells can rescue aerobic respiration. Proc Natl Acad Sci USA. 2006;103:1283–8.PubMedCrossRefGoogle Scholar
  115. 115.
    Spindler S. Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction. Mech Ageing Dev. 2005;126:960–6.PubMedCrossRefGoogle Scholar
  116. 116.
    Sun Y, Jin K, Mao XO. Neuroglobin is up-regulated by and protects neurons from hypoxic-ischaemic injury. Proc Natl Acad Sci USA. 2001;98:15306–11.PubMedCrossRefGoogle Scholar
  117. 117.
    Taylor D, Zeyl C, Cooke E. Conflicting levels of selection in the accumulation of mitochondrial defects in Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 2002;99:3690–4.PubMedCrossRefGoogle Scholar
  118. 118.
    Terman A, Dalen H, Eaton JW, et al. Mitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis. Exp Gerontol. 2003;38:863–76.PubMedCrossRefGoogle Scholar
  119. 119.
    Tkatchouk EN, Gorbatchenkov AA, Kolchinskaya AZ, et al. Adaptation to interval hypoxia for the purpose of prophylaxis and treatment. In: Meerson FZ, editor. Essentials of adaptive medicine: protective effects of adaptation. Moscow: Hypoxia Medical Ltd; 1994. p. 200–21.Google Scholar
  120. 120.
    Trevathan WR. Evolutionary medicine. Ann Rev Anthropol. 2007;36:139–54.CrossRefGoogle Scholar
  121. 121.
    Uys CJ, Best PB. Pathology of lesions observed in whales flensed at Saldanha Bay, South Africa. J Comp Pathol. 1966;76:407–12.PubMedCrossRefGoogle Scholar
  122. 122.
    Vanden Hoek T, Becker L, Shao Z, et al. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem. 1998;273:18092–8.PubMedCrossRefGoogle Scholar
  123. 123.
    Vanucci RC, Towfigi J, Heitjan DF, et al. Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Pediatrics. 1995;95:868–74.Google Scholar
  124. 124.
    Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions, ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostagl Leukot Essent Fatty Acids. 2004;70:309–19.CrossRefGoogle Scholar
  125. 125.
    Vesela A, Wilhelm J. The role of carbon dioxide in free radical reactions of the organism. Physiol Res. 2002;51:335–9.PubMedGoogle Scholar
  126. 126.
    von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27:339–44.CrossRefGoogle Scholar
  127. 127.
    Wallace DC. Mitochondrial DNA in aging and disease. Scientific Am. 1997;8:40–7.CrossRefGoogle Scholar
  128. 128.
    Wang X, Deng J, Boyle D, et al. Potential role of IGF-I in hypoxia tolerance using a rat hypoxic-ischemic model: activation of hypoxia-inducible factor 1α. Pediatr Res. 2004;55:385–94.PubMedCrossRefGoogle Scholar
  129. 129.
    West JB. Do climbs to extreme altitudes cause brain damage? Lancet. 1986;2:387.PubMedCrossRefGoogle Scholar
  130. 130.
    Wisløff U, Støylen A, Loennechen JP, et al. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study. Circulation. 2007;115:3086–94.PubMedCrossRefGoogle Scholar
  131. 131.
    Yellon DM, Downey JM. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev. 2003;83:1113–51.PubMedGoogle Scholar
  132. 132.
    Yoneda M, Chomyn A, Martinuzzi A. Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy. Proc Natl Acad Sci USA. 1992;89:11164–8.PubMedCrossRefGoogle Scholar
  133. 133.
    Zhong N, Yi Z, Fang Q, et al. Intermittent hypoxia exposure-induced heat-shock protein 70 expression increases resistance of rat heart to ischemic injury. Acta Pharmacol Sin. 2000;21:467–72.PubMedGoogle Scholar
  134. 134.
    Zhong N, Zhang Y, Zhu HF, et al. Intermittent hypoxia exposure prevents mtDNA deletion and mitochondrial structure damage produced by ischemia/reperfusion injury. Sheng Li Xue Bao. 2000;52:375–80.PubMedGoogle Scholar
  135. 135.
    Zhuang J, Zhou Z. Protective effects of intermittent hypoxic adaptation on myocardium and its mechanisms. Biol Signals Recept. 1999;8:316–22.PubMedCrossRefGoogle Scholar
  136. 136.
    Zorov DB, Krasnikov BF, Kuzminova AE, et al. Mitochondria revisited. Alternative functions of mitochondria. Biosci Rep. 1997;17:507–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2012

Authors and Affiliations

  1. 1.La Balance ClinicPalma de MallorcaSpain

Personalised recommendations