Current perspectives on the physiological and therapeutic effects of intermittent hypoxia-hyperoxia therapy in older adults
- Authors: Reutova A.A.1, Prilipko N.S.1, Badalov N.G.1,2
-
Affiliations:
- Federal Scientific and Clinical Center for Medical Rehabilitation and Balneology
- The First Sechenov Moscow State Medical University
- Issue: Vol 24, No 2 (2025)
- Pages: 64-73
- Section: Review
- Published: 19.05.2025
- URL: https://rjpbr.com/1681-3456/article/view/646419
- DOI: https://doi.org/10.17816/rjpbr646419
- EDN: https://elibrary.ru/nbafru
- ID: 646419
Cite item
Abstract
Intermittent hypoxia-hyperoxia therapy has been proposed as a potential method for influencing aging processes, enhancing quality of life in older adults, and reducing morbidity in this population. Even short-term intermittent hypoxic exposure is a sufficient stimulus for the accumulation of reactive oxygen species, the upregulation of hypoxia-inducible factor 1-alpha (HIF-1α), and the subsequent activation of adaptive mechanisms that enhance resistance to hypoxia and oxidative stress. Another well-studied physiological phenomenon induced by intermittent hypoxia is long-term facilitation, which is characterized by reduced motor neuron activity and modulated lung ventilation, primarily manifesting as an increase in tidal volume. Increased serotonergic activity induced by intermittent hypoxia-hyperoxia therapy promotes the synthesis of brain-derived neurotrophic factor, which plays a crucial role in higher neural functions. Brain-derived neurotrophic factor deficiency is associated with the development of various psychiatric and neurodegenerative disorders, as well as brain aging. intermittent hypoxia-hyperoxia therapy has demonstrated beneficial effects on clinical markers of heart failure, lipid and glucose metabolism disorders, inflammatory processes and liver enzymatic activity. Thus, the primary theoretical justification for intermittent hypoxia-hyperoxia therapy is to enhance the body’s adaptive capacity and increase resistance to hypoxia, which plays a key role in the course of various pathological conditions.
Full Text

About the authors
Alina A. Reutova
Federal Scientific and Clinical Center for Medical Rehabilitation and Balneology
Email: reutovaaa@mrik-fmba.ru
ORCID iD: 0000-0001-5558-6545
SPIN-code: 3939-8893
Russian Federation, Moscow
Nina S. Prilipko
Federal Scientific and Clinical Center for Medical Rehabilitation and Balneology
Author for correspondence.
Email: n_prilipko@mail.ru
ORCID iD: 0000-0002-1034-2640
SPIN-code: 4540-9590
MD, Dr. Sci. (Medicine)
Russian Federation, MoscowNazim G. Badalov
Federal Scientific and Clinical Center for Medical Rehabilitation and Balneology; The First Sechenov Moscow State Medical University
Email: prof.badalov@gmail.com
ORCID iD: 0000-0002-1407-3038
SPIN-code: 2264-4351
MD, Dr. Sci. (Medicine), Рrofessor
Russian Federation, Moscow; MoscowReferences
- Dziechciaż M, Filip R. Biological psychological and social determinants of old age: Bio-psycho-social aspects of human aging. Ann Agric Environ Med. 2014;21(4):835–838. doi: 10.5604/12321966.1129943
- Oeppen J, Vaupel JW. Demography. Broken limits to life expectancy. Science. 2002;296(5570):1029–31. doi: 10.1126/science.1069675
- Kyriazis M. Ageing Throughout History: The Evolution of Human Lifespan. J Mol Evol. 2020;88(1):57–65. doi: 10.1007/s00239-019-09896-2
- Rudnicka E, Napierała P, Podfigurna A, et al. The World Health Organization (WHO) approach to healthy ageing. Maturitas. 2020;139:6–11. doi: 10.1016/j.maturitas.2020.05.018
- Beard JR, Officer A, de Carvalho IA, et al. The World report on ageing and health: a policy framework for healthy ageing. Lancet. 2016;387(10033):2145–2154. doi: 10.1016/S0140-6736(15)00516-4
- Goldman DP, Cutler D, Rowe JW, et al. Substantial health and economic returns from delayed aging may warrant a new focus for medical research. Health Aff. 2013;32(10):1698–705. doi: 10.1377/hlthaff.2013.0052
- Bayer U, Glazachev OS, Likar R, et al. Adaptation to intermittent hypoxia-hyperoxia improves cognitive performance and exercise tolerance in elderly. Adv Gerontol. 2017;30(2):255–261. EDN: YQGBYD
- Behrendt T, Bielitzki R, Behrens M, et al. Effects of intermittent hypoxia-hyperoxia on performance- and health-related outcomes in humans: a systematic review. Sports Med Open. 2022;8(1):70. doi: 10.1186/s40798-022-00450-x
- Glazachev OS. Optimization of the use of interval hypoxic training in clinical practice. Medical Technology. 2013;3(279):21–24. DN: QBMKPF
- Uzun AB, Iliescu MG, Stanciu LE, et al. Effectiveness of intermittent hypoxia-hyperoxia therapy in different pathologies with possible metabolic implications. Metabolites. 2023;13(2):181. doi: 10.3390/metabo13020181
- Chen PW, Hsu CC, Lai LF, et al. Effects of hypoxia-hyperoxia preconditioning on indicators of muscle damage after acute resistance exercise in male athletes. Front Physiol. 2022;13:824210. doi: 10.3389/fphys.2022.824210
- Rybnikova E, Lukyanova L. Molecular mechanisms of adaptation to hypoxia. Int J Mol Sci. 2023;24(5):4563. doi: 10.3390/ijms24054563
- Michiels C. Physiological and pathological responses to hypoxia. Am J Pathol. 2004;164(6):1875–82. doi: 10.1016/S0002-9440(10)63747-9
- Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006;70(5):1469–80. doi: 10.1124/mol.106.027029
- Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med. 2004;36(1):1–12. doi: 10.1038/emm.2004.1
- Corrado C, Fontana S. Hypoxia and HIF signaling: one axis with divergent effects. Int J Mol Sci. 2020;21(16):5611. doi: 10.3390/ijms21165611
- Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002;64(5–6):993–8. doi: 10.1016/s0006-2952(02)01168-1
- Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271(4 Pt 1):1172–80. doi: 10.1152/ajpcell.1996.271.4.C1172
- Burtscher J, Mallet RT, Pialoux V, et al. Adaptive responses to hypoxia and/or hyperoxia in humans. Antioxid Redox Signal. 2022;37(13–15):887–912. doi: 10.1089/ars.2021.0280
- Sazontova TG, Glazachev OS, Bolotova AV, et al. Adaptation to hypoxia and hyperoxia improves physical endurance: the role of reactive oxygen species and redox-signaling. Russian Journal Of Physiology. 2012;98(6):793–807. EDN: NNAOGA
- Sazontova TG, Arkhipenko YV. Intermittent hypoxia in resistance of cardiac membrane structures: role of reactive oxygen species and redox signaling. In: Xi L, Serebrovskaya TV, editors. Intermittent Hypoxia: From Molecular Mechanisms to Clinical Applications. NY: Nova Science Publishers; 2009. P. 113–150.
- Dempsey JA, Morgan BJ. Humans in hypoxia: a conspiracy of maladaptation?! Physiology. 2015;30(4):304–16. doi: 10.1152/physiol.00007.2015
- Cai Z, Manalo DJ, Wei G, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation. 2003;108(1):79–85. doi: 10.1161/01.CIR.0000078635.89229.8A
- Hassan A, Arnold BM, Caine S, et al. Acute intermittent hypoxia and rehabilitative training following cervical spinal injury alters neuronal hypoxia- and plasticity-associated protein expression. PLoS One. 2018;13(5):e0197486. doi: 10.1371/journal.pone.0197486
- Arkhipenko YuV, Sazontova TG, Zhukova AG. Adaptation to periodic hypoxia and hyperoxia improves resistance of membrane structures in heart, liver, and brain. Bulletin of Experimental Biology and Medicine. 2005;140(9):257–260. EDN: HSYAGT
- Pamenter ME, Powell FL. Signalling mechanisms of long term facilitation of breathing with intermittent hypoxia. F1000Prime Rep. 2013;5:23. doi: 10.12703/P5-23.
- Pamenter ME, Powell FL. Time domains of the hypoxic ventilatory response and their molecular basis. Compr Physiol. 2016;6(3):1345–85. doi: 10.1002/cphy.c150026
- Brodin E, Linderoth B, Goiny M, et al. In vivo release of serotonin in cat dorsal vagal complex and cervical ventral horn induced by electrical stimulation of the medullary raphe nuclei. Brain Res. 1990;535(2):227–36. doi: 10.1016/0006-8993(90)91605-g
- Morris KF, Gozal D. Persistent respiratory changes following intermittent hypoxic stimulation in cats and human beings. Respir Physiol Neurobiol. 2004;140(1):1–8. doi: 10.1016/j.resp.2003.12.002
- Popova NK, Ilchibaeva TV, Naumenko VS. Neurotrophic factors (BDNF and GDNF) and the serotonergic system of the brain. Biochemistry. 2017;82(3):308–317. doi: 10.1134/S0006297917030099
- Baker-Herman TL, Fuller DD, Bavis RW, et al. BDNF is necessary and sufficient for spinal respiratory plasticity following intermittent hypoxia. Nat Neurosci. 2004;7(1):48–55. doi: 10.1038/nn1166
- Brigadski T, Leßmann V. BDNF: a regulator of learning and memory processes with clinical potential. e-Neuroforum. 2014;5:1–11. doi: 10.1007/s13295-014-0053-9
- Ryou MG, Chen X, Cai M, et al. Intermittent hypoxia training prevents deficient learning-memory behavior in mice modeling alzheimer's disease: a pilot study. Front Aging Neurosci. 2021;13:674688. doi: 10.3389/fnagi.2021.674688
- Meng SX, Wang B, Li WT. Intermittent hypoxia improves cognition and reduces anxiety-related behavior in APP/PS1 mice. Brain Behav. 2020;10(2):e01513. doi: 10.1002/brb3.1513
- Bonnitcha P, Grieve S, Figtree G. Clinical imaging of hypoxia: Current status and future directions. Free Radic Biol Med. 2018;126:296–312. doi: 10.1016/j.freeradbiomed.2018.08.019
- Glazachev OS, Dudnik EN, Zapara MA, et al. Adaptation to dosed hypoxia-hyperoxia as a factor in the improvement of quality of life for elderly patients with cardiac pathology. Advances in gerontology. 2019;32(1–2):145–151. EDN: ZHEJPV
- Bestavashvili A, Glazachev O, Bestavashvili A, et al. Intermittent hypoxic-hyperoxic exposures effects in patients with metabolic syndrome: correction of cardiovascular and metabolic profile . Biomedicines. 2022;10(3):566. doi: 10.3390/biomedicines10030566
- Syrkin AL, Glazachev OS, Kopylov FYu, et al. Adaptation to interval hypoxia-hyperoxia in the rehabilitation of patients with coronary heart disease: exercise tolerance and quality of life. Cardiology. 2017;57(5):10–16. doi: 10.18565/cardio.2017.5.10-16 EDN: YPQJWX
- Afina AB, Oleg SG, Alexander AB, et al. The effects of intermittent hypoxic-hyperoxic exposures on lipid profile and inflammation in patients with metabolic syndrome. Front Cardiovasc Med. 2021;8:700826. doi: 10.3389/fcvm.2021.700826
- Wojan F, Stray-Gundersen S, Massoudian SD, Lalande S. Brief exposure to intermittent hypoxia increases erythropoietin levels in older adults. J Appl Physiol. 2023;135(1):88–93. doi: 10.1152/japplphysiol.00172.2023
- Van Meijel RLJ, Venema K, Canfora EE, et al. Mild intermittent hypoxia exposure alters gut microbiota composition in men with overweight and obesity. Benef Microbes. 2022;13(4):355–364. doi: 10.3920/BM2021.0159
- Serebrovska ZO, Xi L, Tumanovska LV, et al. Response of circulating inflammatory markers to intermittent hypoxia-hyperoxia training in healthy elderly people and patients with mild cognitive impairment. Life. 2022;12(3):432. doi: 10.3390/life12030432
- Gao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential. Transl Neurodegener. 2022;11(1):4. doi: 10.1186/s40035-022-00279-0
- Bayer U, Likar R, Pinter G, et al. Intermittent hypoxic-hyperoxic training on cognitive performance in geriatric patients. Alzheimers Dement. 2017;3(1):114–122. doi: 10.1016/j.trci.2017.01.002
- Behrendt T, Bielitzki R, Behrens M, et al. Effects of intermittent hypoxia-hyperoxia exposure prior to aerobic cycling exercise on physical and cognitive performance in geriatric patients — a randomized controlled trial. Front Physiol. 2022;13:899096. doi: 10.3389/fphys.2022.899096
- Behrendt T, Quisilima JI, Bielitzki R, et al. Brain-Derived neurotrophic factor and inflammatory biomarkers are unaffected by acute and chronic intermittent hypoxic-hyperoxic exposure in geriatric patients: a randomized controlled trial. Ann Med. 2024; 56(1):2304650. doi: 10.1080/07853890.2024.2304650
- Behrendt T, Altorjay AC, Bielitzki R, et al. Influence of acute and chronic intermittent hypoxic-hyperoxic exposure prior to aerobic exercise on cardiovascular risk factors in geriatric patients-a randomized controlled trial. Front Physiol. 2022;13:1043536. doi: 10.3389/fphys.2022.1043536
- Glazachev O, Kopylov P, Susta D, et al. Adaptations following an intermittent hypoxia-hyperoxia training in coronary artery disease patients: a controlled study. Clin Cardiol. 2017;40(6):370–376. doi: 10.1002/clc.2267084
- Myers J, McAuley P, Lavie CJ, et al. Physical activity and cardiorespiratory fitness as major markers of cardiovascular risk: their independent and interwoven importance to health status. Prog Cardiovasc Dis. 2015;57(4):306–14. doi: 10.1016/j.pcad.2014.09.011
- Dudnik E, Zagaynaya E, Glazachev OS, Susta D. Intermittent hypoxia-hyperoxia conditioning improves cardiorespiratory fitness in older comorbid cardiac outpatients without hematological changes: a randomized controlled trial. High Alt Med Biol. 2018;19(4):339–343. doi: 10.1089/ham.2018.0014
- Glazachev OS, Dudnik EN, Pozdnyakov YuM. Adaptation to interval hypoxia-hyperoxia in the rehabilitation of patients with coronary heart disease. Man and his health. 2014;1:58–64. EDN: SNMMHR
- Serebrovska TV, Grib ON, Portnichenko VI, et al. Intermittent hypoxia/hyperoxia versus intermittent hypoxia/normoxia: comparative study in prediabetes. High Alt Med Biol. 2019;20(4):383–391. doi: 10.1089/ham.2019.0053
- Imerb N, Thonusin C, Chattipakorn N, Chattipakorn SC. Aging, obese-insulin resistance, and bone remodeling. Mech Ageing Dev. 2020;191:111335. doi: 10.1016/j.mad.2020.111335
- Glazachev OS, Zvenigorodskaya LA, Dudnik EN, et al. Interval hypo-hyperoxic training in the treatment of metabolic syndrome. Experimental and Clinical Gastroenterology. 2010;7:51–56. (In Russ.) EDN: MVAJUH
- Hamrick MW, Stranahan AM. Metabolic regulation of aging and age-related disease. Ageing Res Rev. 2020;64:101175. doi: 10.1016/j.arr.2020.101175
- López-Otín C, Blasco MA, Partridge L, et al. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243–278. doi: 10.1016/j.cell.2022.11.001
- Zhang Q, Zhao W, Li S, et al. Intermittent hypoxia conditioning: a potential multi-organ protective therapeutic strategy. Int J Med Sci. 2023;20(12):1551–1561. doi: 10.7150/ijms.86622
Supplementary files
