Hyperbaric Oxygen Therapy: A Promising Approach for Promoting Regenerative Processes and Enhancing Healthy Aging
Dr Nur Ozyilmaz Fri 27th September 2024
Ageing is characterised by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases Lopez-Otin et al., 2013
Research on ageing has significantly increased in recent years, particularly with the discovery that the rate of ageing is partially controllable. The ultimate goal for scientists is to identify both pharmaceutical and non-pharmaceutical interventions that can improve human health and slow the ageing process, while minimising adverse side effects.
In this article, I will summarise the role of hyperbaric oxygen therapy in the context of regenerative medicine and its potential applications for promoting healthy ageing based on existing scientific evidence.
As individuals age, they experience a gradual deterioration in physiological capacities, which manifests as diminished physical abilities, such as reduced mobility and organ dysfunction, as well as cognitive impairments, particularly in the domains of executive function and language processing.
Numerous factors, including but not limited to oxidative stress, mitochondrial dysfunction, chronic inflammation, and epigenetic alterations, have been implicated in the ageing process. Emerging evidence suggests that hyperbaric oxygen therapy may be a promising intervention to mitigate some of these age-related changes.
The physiological mechanisms by which HBOT may promote healthy ageing can be summarised into categories below:
Hyperoxia-Hypoxia Paradox: Patients in the hyperbaric oxygen chamber breathe pure oxygen instead of the typical 21% oxygen found at sea level. When pure oxygen is breathed at elevated pressures of 2 ATA or higher, the amount of dissolved oxygen increases significantly, allowing the body’s oxygen supply to meet all its energy requirements. Hyperbaric oxygen therapy characteristically elevates the dissolved oxygen concentration in the patient’s body by approximately 15-fold, fully saturating the body with oxygen.
After patients have breathed pure oxygen for twenty minutes, they are instructed to remove the mask and inhale medical-grade air in the chamber during their break from the high-oxygen environment. This rapid transition from the elevated oxygen levels back to normal atmospheric oxygen concentration simulates a state of oxygen deprivation (relative hypoxia), despite the body still maintaining high oxygen saturation. This phenomenon was first described by Professor Balestra in 2006 (Balestra C et al., 2006), whereby exposing the body to a hyperoxic (high-oxygen) environment may produce effects similar to a hypoxic (low-oxygen) state. More recently, in 2020, Hadanny and Efrati re-examined this concept, focusing specifically on the physiological implications of hyperbaric oxygen exposure, which they termed as “The Hyperoxic-Hypoxic Paradox”. This sudden rapid change in the oxygen triggers a series of regenerative biochemical responses in cells. This includes increased expression of hypoxia-inducible factor-1 (HIF-1), enhanced activity of matrix metalloproteinases (MMP), elevated levels of vascular endothelial growth factor (VEG-F), stimulation of stem cell proliferation, and upregulation of factors that promote new blood vessel formation, among other regenerative mechanisms.
Angiogenesis, the generation of new blood vessels, known as angiogenesis, is a crucial mechanism by which hyperbaric oxygen therapy can promote healthy aging. Aging leads to a decline in capillary density throughout the body, resulting in compromised vascular homeostasis and diminished angiogenic capacity, which plays significant role in aging and developing age-related diseases.
HBOT promotes angiogenesis mainly by increasing (HIF-1) and nitric oxide (NO) production, which leads to the upregulation of growth factors such as epidermal growth factor (EGF) and the most prominent proangiogenic factor called vascular endothelial growth factor (VEGF), alongside other angiogenic factors such as nuclear factor E2-related factor 2 (Nrf2), EGF, PDGF, CXCL10, IL- 1α, FGF-2 and SDF-1 that are crucial for tissue regeneration and repair. The generation of new vasculature enables enhanced tissue oxygenation in patients even after they have completed a regimen of hyperbaric oxygen therapy. Huang X et al., 2020 , Dhamodharan U et al., 2019
Figure 1. The mechanisms by which HBOT promotes healthy aging. HBOT can cause a wide range of cellular, biochemical and physiological changes. The proven biological mechanisms by which HBOT may promote healthy aging can be summarised into five categories. (1) HBOT enhances angiogenesis mainly by increasing the expression of HIF-1α and a series of angiogenic markers. (2) HBOT reduces inflammation by regulating the number and activity of extensive inflammatory cell types such as neutrophils, lymphocytes, astrocytes and microglia. At the molecular level, HBOT can inhibit pro-inflammatory factors while promoting anti-inflammatory factors. (3) HBOT enhances antioxidant defenses by modulating the balance between free radicals and scavengers. The process is closely correlated with the regulation of mitochondrial function. (4) HBOT interferes with the detrimental effects of cellular senescence, manifested by cell cycle re-entry and attenuation of senescence markers such as p16/p21/p53, SA-β-gal, lipofuscin and the SASP. HBOT also plays a role in inhibiting telomere shortening, one of the major stimuli of cellular senescence. (5) HBOT increases the number of circulating stem cells by stimulating stem cell mobilization, and changes stem cell properties by promoting proliferation and differentiation. Reference: Qiaoyu Fu et al., 2022
Anti-inflammatory effects: The persistent, low-grade inflammatory state associated with aging, referred to as “inflammaging”, plays a crucial role in the development and progression of age-related diseasesFerrucci L et al., 2018. Numerous scientific studies have demonstrated that hyperbaric oxygen therapy is an exceptionally powerful anti-inflammatory intervention while more comprehensive research is expected to clarify the systemic effects of HBOT on age-related inflammatory state. Studies show that various pro-inflammatory cytokines and inflammatory mediators are reduced in the peripheral blood following HBOT, including IL-1β, IL-2, IL-6, TNF-α, IFN-γ, PGE2, COX-2. The same goes for the levels of inflammatory markers in different tissues. Meanwhile, HBOT can lead to increases in some anti-inflammatory cytokines, including IL-1Ra, IL-4 and IL-10 Dhamodharan U et al., 2019 , Shapira R et al., 2018 , Hao Y et al., 2020 Bai X et al., 2014, Weisz G et al.,1997, Al-Waili N.S et al., 2006 , Chen X et al.,2016 , Arıcıgil M et al., 2018
Stimulating Stem Cell Mobilisation and Functional Enhancement: The renewal ability of human tissues declines with aging of stem cells altering their capacity to differentiate in different types of cells Ahmed AS et al., 2017. Moreover, age-related loss of self-renewal in stem cells leads to a reduction in stem cell number Jones DL et al., 2011.
A study MacLaughlin KJ et al., 2014published in Front Neurology found that HBA can mobilise stem progenitor cells (SPCs). The study showed that: – After nine exposures, SPCs were mobilised nearly two-fold – After the final exposure, SPCs were mobilised three-fold 72 hours later
Other studies found: – A single exposure to 2.0 atmospheres absolute (ATA) of oxygen for two hours doubled the population of CD34 cells in the peripheral circulation (6) Thom SR et al., 2006 – 20 treatments of hyperbaric oxygen, eight-fold increase Thom SR et al., 2006
Figure 2. Mean CD34+ population in blood of humans before and after HBO2 treatments. Data are the fraction of CD34+ cells within the gated population using leukocytes obtained from 26 patients before and after their 1st, 10th, and 20th HBO2 treatment. *Repeated-measures one-way ANOVA, P < 0.05 vs. the pre-HBO2 first treatment value. Reference: Thom SR et al., 2006
Elevation of antioxidant activity and Mitochondrial Biogenesis: Similar to other beneficial hormetic stressors like exercise, a single exposure to hyperbaric oxygen therapy temporarily induce oxidative stress, which in turn triggers the activation of the body’s endogenous antioxidant defence systems and promotes Mitochondrial Biogenesis via the SIRT-1/PGC-1α Pathway. Research indicates that SIRT1 plays a crucial role in mitochondrial biogenesis – the creation of new mitochondria. HBOT has also been linked to improved mitochondrial function and potentially, biogenesis.Yuan Y., 2016 , Singh V et al., 2020
Figure 3. The effects of HBOT on oxidative stress balance and mitochondrial properties. In HBOT, the inhaled oxygen passes through the lungs, effectively elevating the content of oxygen dissolved in the plasma, which in turn causes a plethora of oxygen within tissues. In mitochondria of tissue cells, the citric acid cycle is boosted under hyperoxia. NADH, a product of the citric acid cycle, can react directly with oxygen to produce ROS in the mitochondria. The overproduced ROS activates HIF-1α, which conjugates with HIF-1β to stabilise HIF-1 in its active form (Another way HBOT stabilises HIF-1 arises from the hypoxic-like state during intermittent periods). HIF-1 inhibits mitochondrial biogenesis. On the other hand, consumption of more NADH by mitochondria results in higher NAD + levels. In the presence of elevated NAD+, SIRT1 is activated, which improves mitochondrial biogenesis via acetylation of PGC-1α and induces antioxidant responses via deacetylation of FOXO3a. Notably, as an adaptive mechanism, high ROS levels can produce more endogenous scavengers as well. The elimination half-life of scavengers is much longer than that of ROS, underlying the antioxidant effects of HBOT. The molecular mechanisms by which HBOT stimulates antioxidant defenses include activation of Nrf2 and its downstream targets such as HO-1, NQO-1, CAT, GPx, SOD and GCLC, as well as decreased expression of pro-oxidant enzymes such as iNOS and gp91-phox. Reference: Qiaoyu Fu et all., 2022
Suppression of senescence and telomere elongation: A 2020 study by Hachmo Y et al., 2020reported that following 60 daily sessions of hyperbaric oxygen therapy over a three-month period, the telomere length in T helper, T cytotoxic, natural killer, and B cells increased by more than 20%. Additionally, the number of senescent cells declined by 10-37% in the study participants. More research is needed to fully evaluate the potential of hyperbaric oxygen therapy for the telomere theory of aging.
The Therapeutic Potential of Hyperbaric Oxygen Therapy for Mitigating Age-Related Conditions
Reversing vascular aging and cognitive impairment
“Cellular and molecular mechanisms of vascular aging such as Blood Brain Barrier (BBB) permeability, increased inflammation, mitochondrial dysfunction, oxidative stress, loss of Nrf2 activity, and NAD+ depletion contribute to the pathogenesis of age-related cerebromicrovascular diseases. Growing evidence presented in this review suggests that HBOT targets these very same processes, ameliorating and reversing microvascular pathologies such as endothelial dysfunction (Godman et al., 2010), microvascular rarefaction (Dhamodharan et al., 2019; Yu et al., 2019), improved blood‐brain‐barrier features (Li et al., 2018a), mitochondrial function (Nukhet Aylin Burns et al., 2018; Lippert and Borlongan, 2019), cellular metabolism, inflammation, and oxidative stress (Efrati and Ben-Jacob, 2014), as well as ameliorating decreased NVC responses (Cardenas et al., 2015) which contribute to the development of age-related neurodegeneration and VCI. Further studies are warranted to explore the cerebromicrovascular effects of HBOT in animal models of aging. Balasubramanian et al., 2021”
Figure 4. Summary representation of the cerebrovascular effects of hyperbaric oxygen treatment. (A) Representation of a branching cerebral arteriole. In young healthy individuals, inhaled 21% O2 is sufficient to ensure adequate brain oxygenation. (B) Age-related cerebromicrovascular disease is associated with increased BBB permeability, neuroinflammation, declining endothelial function, mitochondrial dysfunction, oxidative stress, loss of Nrf2 activity, increase in senescent cell burden, and NAD+ depletion (C)Administration of 100 percent oxygen in a pressurised environment results in hemoglobin saturation and hyperoxygenated plasma Hyperoxygenation exerts multiple beneficial effects that ameliorate and reverse brain microvascular pathologies. (D) HBOT targets many of the age-related impairments in vascular mechanisms that drive regulation of blood flow and cognition. Reference: Balasubramanian et al., 2021.
Hadanny A et al., 2020 reported that hyperbaric oxygen therapy was found to elicit cognitive improvements in healthy older adults through mechanisms involving regional cerebral blood flow changes. The primary enhancements observed were in the domains of attention, information processing speed, and executive functions, which typically decline with the aging process.
Improvements in cardiac function
Leitman M et al., 2020 have shown that hyperbaric oxygen therapy can enhance systolic function of both the left and right ventricles, as well as overall cardiac performance, in elderly individuals. However, the existing evidence regarding its impact on diastolic function is limited.
Enhancing respiratory capacity and physical performance
Hadanny A et al., 2024 found that hyperbaric oxygen therapy can significantly enhance physical performance in older adults. Key improvements were observed in maximal oxygen consumption and the first ventilatory threshold, indicating enhanced physical capacity.
The enhanced myocardial perfusion observed through cardiac imaging is believed to be a crucial mechanism mediating the improvements in physical performance associated with hyperbaric oxygen therapy. The findings suggest that HBOT holds promise as an intervention to counteract age-related declines in physical performance and cardiac function among aging adults.
Hadanny A et al., 2022concluded that hyperbaric oxygen therapy can enhance physical performance metrics in elite athletes, with significant increases observed in maximal oxygen uptake (VO2Max) and oxygen uptake at the first ventilatory threshold (VO2AT). The findings suggest that combining HBOT with high-intensity training may produce synergistic effects, warranting further investigation into optimal training protocols. The study highlights the importance of mitochondrial adaptations in enhancing endurance performance, with HBOT showing promise in improving both mitochondrial respiration and mass.
Further research with larger sample sizes is required to thoroughly understand the precise mechanisms underlying how hyperbaric oxygen therapy may improve physical performance across diverse populations.
Skin aging
This prospective clinical study by Hachmo et al., 2021examined skin biopsies from 13 male participants to assess the effects of hyperbaric oxygen therapy on normal aging. The findings indicated significant improvements, including increased collagen density, elongated elastic fibers, and elevated blood vessel counts, as well as decreased fiber fragmentation and reduced senescent cells in the tissue. However, no changes were observed in elastic fiber density or thickness. Given the small sample size, further research is needed to expand upon these promising results.
Mitigating Insulin Resistance
A randomised placebo-controlled crossover trial bySarabhai T et al., 2023 found that a single hyperbaric oxygen treatment with 100% oxygen rapidly improved tissue-specific insulin sensitivity and mitochondrial capacity in humans with type 2 diabetes. The study revealed that this treatment rapidly enhanced insulin sensitivity in skeletal muscle, liver, and white adipose tissue. In skeletal muscle, the improved insulin sensitivity was linked to increased insulin-stimulated Akt phosphorylation and reduced inhibitory IRS-1 phosphorylation. Additionally, the hyperbaric oxygen therapy enhanced mitochondrial capacity and stimulated antioxidative defenses in skeletal muscle and white adipose tissue, suggesting a role for mitohormesis in its insulin-sensitising effects, in the absence of systemic inflammation.
Wilkinson D et al., 2012 found that hyperbaric oxygen therapy improved insulin sensitivity in both non-obese individuals without diabetes and obese patients with Type 2 diabetes. Insulin sensitivity increased significantly after just 3 sessions and was maintained through 30 sessions, comparable to the effects of moderate weight loss. However, the underlying mechanisms require further investigation.
Liu Y et al., 2020 concluded that hyperbaric oxygen (HBO) therapy significantly ameliorates insulin sensitivity in a type 2 diabetes mellitus (T2DM) mouse model. This improvement is primarily attributed to the increased expression of glucose transporter type 4 (GLUT4) in skeletal muscle and the stimulation of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). The study also highlighted that HBO increases the activity of AMP-activated protein kinase (AMPK) in skeletal muscle, which is an insulin-independent pathway that regulates energy metabolism. This suggests that HBO may promote both glucose utilisation and fatty acid oxidation. HBO treatment leads to an increase in UCP1 expression in BAT, which is associated with enhanced energy expenditure and potentially contributes to maintaining body weight. This effect is consistent across both T2DM and high-fat diet (HFD) mouse models. The findings suggest that HBO could be a viable therapy for improving glucose tolerance and insulin sensitivity in T2DM. However, the exact mechanisms by which increased partial pressure of oxygen (PO2) in tissues improves insulin sensitivity remain to be fully elucidated.
Research Summary
Hyperbaric oxygen therapy has been shown to significantly promote regenerative processes and enhance healthy aging by stimulating a range of cellular, molecular, and physiological mechanisms. It has been demonstrated to enhance various physiological functions, including cognitive abilities, cardiorespiratory performance, metabolic function, and skin health. These observed improvements suggest that HBOT holds promise as a potential intervention to mitigate the detrimental effects associated with the aging process. However, it is important to recognise that aging is a complex and multifaceted phenomenon, and HBOT should be utilised as part of a comprehensive lifestyle optimisation approach, which may include a healthy diet, regular exercise, managing stress, optimising emotional and mental well-being and other supportive interventions, to achieve the best possible outcomes for healthy aging.
Hyperbaric oxygen therapy is generally safe and well-tolerated when properly administered, but there is a risk of rare side effects. However, hyperbaric oxygen therapy may not be appropriate for individuals with certain pre-existing medical conditions. Therefore, it is crucial for patients to undergo a careful assessment by a physician specialised in hyperbaric oxygen medicine before considering Hyperbaric Oxygen Therapy.
The number of sessions required varies among individuals based on their medical background and should be determined by a medical doctor specialised in hyperbaric oxygen medicine. Typically, a regimen of 10 to 60 hyperbaric oxygen therapy sessions is necessary to achieve the substantial physiological improvements mentioned above.
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