Dose–response relationship of intermittent normobaric hypoxia to stimulate erythropoietin in the context of health promotion in young and old people
Erythropoietin (EPO) has multifactorial positive effects on health and can be increased by intermittent normobaric hypoxia (IH). Recommendations about the intensity and duration of IH to increase EPO exist, but only for young people. Therefore, the aim of the study was to investigate the dose–response relationship regarding the duration of hypoxia until an EPO expression and the amount of EPO expression in old vs. young cohorts.
56 young and 67 old people were assigned to two separate investigations with identical study designs (3-h hypoxic exposure) but with different approaches to adjust the intensity of hypoxia: (i) the fraction of inspired oxygen (FiO2) was 13.5%; (ii) the FiO2 was individually adjusted to an oxygen saturation of the blood of 80%. Age groups were randomly assigned to a hypoxia or control group (normoxic exposure). EPO was assessed before, during (90 and 180 min), and 30 min after the hypoxia.
EPO increased significantly after 180 min in both cohorts and in both investigations [old: (i) + 16%, p = 0.007 and (ii) + 14%, p < 0.001; young: (i) + 27%, p < 0.001 and (ii) + 45%, p = 0.007]. In investigation (i), EPO expression was significantly higher in young than in old people after 180 min of hypoxic exposure (p = 0.024) and 30 min afterwards (p = 0.001).
The results indicate that after a normobaric hypoxia of 180 min, EPO increases significantly in both age cohorts. The amount of EPO expression is significantly higher in young people during the same internal intensity of hypoxia than in old people.
KeywordsEPO Aging Hypoxic intensity Hypoxic duration Altitude training
Arterial oxygen content
Fraction of inspired oxygen
Investigation where the intensity of hypoxia was applied to external parameters
Investigation where the intensity of hypoxia was applied to internal parameters
Red blood cells
Oxygen saturation of the blood
Receptor tyrosine kinase B
Compliance with ethical standards
Conflict of interest
None of the authors have any conflicts of interests.
- Burtscher M, Pachinger O, Ehrenbourg I, Mitterbauer G, Faulhaber M, Pühringer R, Tkatchouk E (2004) Intermittent hypoxia increases exercise tolerance in elderly men with and without coronary artery disease. Int J Cardiol 96(2):247–254. https://doi.org/10.1016/j.ijcard.2003.07.021 CrossRefGoogle Scholar
- Costa E, Fernandes J, Ribeiro S, Sereno J, Garrido P, Rocha-Pereira P, Coimbra S, Catarino C, Belo L, Bronze-da-Rocha E, Vala H, Alves R, Reis F, Santos-Silva A (2013) Aging is associated with impaired renal function, INF-gamma induced inflammation and with alterations in iron regulatory proteins gene expression. Aging Dis 5(6):356–365. https://doi.org/10.14366/AD.2014.0500356 Google Scholar
- Eckardt KU, Dittmer J, Neumann R, Bauer C, Kurtz A (1990) Decline of erythropoietin formation at continuous hypoxia is not due to feedback inhibition. Am J Physiol 258(5 Pt 2):F1432–F1437Google Scholar
- Fliser D, Haller H (2007) Erythropoietin and treatment of non-anemic conditions–cardiovascular protection. Semin Hematol 44(3):212–217. https://doi.org/10.1053/j.seminhematol.2007.04.008 CrossRefGoogle Scholar
- Ge R-L, Witkowski S, Zhang Y, Alfrey C, Sivieri M, Karlsen T, Resaland GK, Harber M, Stray-Gundersen J, Levine BD (2002) Determinants of erythropoietin release in response to short-term hypobaric hypoxia. J Appl Physiol 92(6):2361–2367. https://doi.org/10.1152/japplphysiol.00684.2001 CrossRefGoogle Scholar
- Genc S, Koroglu TF, Genc K (2004) Erythropoietin as a novel neuroprotectant. Restor Neurol Neurosci 22(2):105–119Google Scholar
- Jedlickova K, Stockton DW, Chen H, Stray-Gundersen J, Witkowski S, Ri-Li G, Jelinek J, Levine BD, Prchal JT (2003) Search for genetic determinants of individual variability of the erythropoietin response to high altitude. Blood Cells Mol Dis 31(2):175–182. https://doi.org/10.1016/S1079-9796(03)00153-0 CrossRefGoogle Scholar
- Millet GP, Brocherie F, Girard O, Wehrlin JP, Troesch S, Hauser A, Steiner T, Peltonen JE, Rusko HK, Constantini K, Fulton TJ, Hursh DG, Noble TJ, Paris HLR, Wiggins CC, Chapman RF, Levine BD, Kumar VHS, Schmidt WFJ (2016) Commentaries on Viewpoint. Time for a new metric for hypoxic dose? J Appl Physiol 121(1):356–358. https://doi.org/10.1152/japplphysiol.00460.2016 CrossRefGoogle Scholar
- Pokorski M, Walski M, Dymecka A, Marczak M (2004) The aging carotid body. J Physiol Pharmacol 55(Suppl 3):107–113Google Scholar
- Rivard A, Berthou-Soulie L, Principe N, Kearney M, Curry C, Branellec D, Semenza GL, Isner JM (2000) Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity. J Biol Chem 275(38):29643–29647. https://doi.org/10.1074/jbc.M001029200 CrossRefGoogle Scholar
- Santhanam AVR, d’Uscio LV, Katusic ZS (2010) Cardiovascular effects of erythropoietin an update. Adv Pharmacol (San Diego. Calif) 60:257–285. https://doi.org/10.1016/B978-0-12-385061-4.00009-X CrossRefGoogle Scholar
- Serebrovskaya TV, Karaban IN, Kolesnikova EE, Mishunina TM, Swanson RJ, Beloshitsky PV, Ilyin VN, Krasuk AN, Safronova OS, Kuzminskaya LA (2000) Geriatric men at altitude: hypoxic ventilatory sensitivity and blood dopamine changes. Respiration 67(3):253–260. https://doi.org/10.1159/000029507 CrossRefGoogle Scholar
- Viviani B, Bartesaghi S, Corsini E, Villa P, Ghezzi P, Garau A, Galli CL, Marinovich M (2005) Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor. J Neurochem 93(2):412–421. https://doi.org/10.1111/j.1471-4159.2005.03033.x CrossRefGoogle Scholar