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The hyperbaric oxygen therapy among Anti-aging strategies

at 10.01.2022
Impact on telomere length and immunosenescence

An Israeli prospective trial, entitled “Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells”, was designed to evaluate whether hyperbaric oxygen therapy (HBOT) affects telomere length (TL) and senescent cell concentrations in a normal, non-pathological, aging adult population. They found that repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. In this study, for the first time in humans, it was found that repeated daily HBOT sessions can increase PBMC telomere length by more than 20% in an aging population, with B cells having the most striking change. In addition, HBOT decreased the number of senescent cells by 10-37%, with T helper senescent cells being the most effected.
Aging's physiological manifestations
Aging can be characterized by the progressive loss of physiological integrity, resulting in impaired functions and susceptibility to diseases and death. This biological deterioration is considered a major risk factor for cancer, cardiovascular diseases, diabetes, and Alzheimer’s disease among others. At the cellular level, there are two key hallmarks of the aging process: shortening of telomere length and cellular senescence [1].
Telomeres are tandem nucleotide repeats located at the end of the chromosomes which maintain genomic stability. Telomeres shorten during replication (mitosis) due to the inherent inability to fully replicate the end part of the lagging DNA strand [2]. Telomere length (TL), measuring between 4 to 15 kilobases, gradually shorten by ~20-40 bases per year and is associated with different diseases, low physical performance, and cortical thinning of the brain [3]. When TL reaches a critical length, cells cannot replicate and progress to senescence or programmed cell death [4]. Goglin et al. demonstrated that adults with shorter TLs have increased mortality rates [5]. Shortened TLs can be a directly inherited trait, but several environmental factors have also been associated with shortening TL including stress, lack of physical endurance activity, excess body mass index, smoking, chronic inflammation, vitamins deficiency, and oxidative stress [6].
Cellular senescence is an arrest of the cell cycle that can be caused by telomere shortening [7], as well as other aging-associated stimuli independent of TL such as non-telomeric DNA damage [1]. The primary purpose of senescence is to prevent the propagation of damaged cells by triggering their elimination via the immune system. The accumulation of senescent cells with aging reflects either an increase in the generation of these cells and/or a decrease in their clearance, which in turn aggravates the damage and contributes to aging [1].

Telomere length and lifestyle 
A growing body of research has found several pharmacological agents that can reduce the telomere shortening rate [8]. Several lifestyle interventions including endurance training, diets, and supplements targeting cell metabolism and oxidative stress have reported relatively small effects (2-5%) on TL3, [6].
A substantial number of associations between telomere length and lifestyle modifications have been observed. This has led to several interventional studies which included diet, supplements (such as omega-3, and walnuts among others), physical activity, stress management, and social support. A two-year trial conducted on cognitively healthy elderly adults, using a diet rich in walnuts, showed a non-significant trend to preserve telomere length when compared to a control diet [9]. In another study that evaluated the effect of a twelve-week low-frequency explosive-type resistance training in elderly people, telomere length was better preserved in the intervention group without a significant increase [10]. A recent study found that aerobic endurance training or high-intensity interval training for six months increased telomere length up to 5% [11]. Additional weight loss, yoga, and stress management techniques failed to show significant telomere length changes [12]. However, most of these studies have shown significant correlations between antioxidant activity and telomerase activity [12].
While many genetic and environmental factors are associated with telomere shortening, the most common suggested mechanism is oxidative stress. Oxidative stress can occur from imbalances between the production of reactive oxygen species (ROS) and cellular scavengers. Telomeres are highly sensitive to oxidative DNA damage, which can induce telomere shortening and dysfunction [13]. The association between oxygen and/or oxidative stress and telomere length has been debated for the past several decades. Human cell culture studies consistently show that mild oxidative stress accelerates telomere shortening, whereas antioxidants and free radical scavengers decrease shortening rates and increase the cellular proliferative lifespan [14]. Several clinical studies on pathological conditions (such as diabetes, inflammatory diseases, Parkinson’s disease) have shown correlations between oxidative stress markers, reactive oxygen species scavengers levels, and telomere length [15]. 

HBOT’s effects on aging phenomenon
Thirty-five healthy independently living adults, aged 64 and older, were enrolled in the trial [16] to receive 60 daily HBOT exposures. Whole blood samples were collected at baseline, at the 30th and 60th session, and 1-2 weeks following the last HBOT session. Peripheral blood mononuclear cells (PBMCs) telomeres length and senescence were assessed.
Telomeres length of T helper, T cytotoxic, natural killer, and B cells increased significantly by over 20% following HBOT. The most significant change was noticed in B cells which increased at the 30th session, 60th session and post HBOT by 25.68%, 29.39%, and 37.63%, respectively. There was a significant decrease in the number of senescent T helpers by -37.30% post-HBOT. T-cytotoxic senescent cell percentages decreased significantly by -10.96% post-HBOT. In conclusion, the study indicates that HBOT may induce significant senolytic effects including significantly increasing telomere length and clearance of senescent cells in the aging populations.
Hyperbaric oxygen therapy (HBOT) utilizes 100% oxygen in an environmental pressure higher than one absolute atmosphere (ATA) to enhance the amount of oxygen dissolved in the body’s tissues. Repeated intermittent hyperoxic exposures, using certain HBOT protocols, can induce physiological effects which normally occur during hypoxia in a hyperoxic environment, the so-called hyperoxic-hypoxic paradox [17]. In addition, it was recently demonstrated that HBOT can induce cognitive enhancements in healthy aging adults via mechanisms involving regional changes in cerebral blood flow [18]. On the cellular level, it was demonstrated that HBOT can induce the expression of hypoxia-induced factor (HIF), vascular endothelial growth factor (VEGF) and sirtuin (SIRT), stem cell proliferation, mitochondrial biogenesis, angiogenesis, and neurogenesis [19]. However, no study to date has examined HBOT’s effects on TL and senescent cell accumulation. The aim of the current study was to evaluate whether HBOT affects TL and senescence-like T-cells population in aging adults.
In this study, for the first time in humans, it was found that repeated daily HBOT sessions can increase PBMC telomere length by more than 20% in an aging population, with B cells having the most striking change. In addition, HBOT decreased the number of senescent cells by 10-37%, with T helper senescent cells being the most affected.
Similar to the current study, a previous prospective one-year observational study in divers exposed to intense hyperbaric oxygen, showed significant telomere elongation in leukocytes [20]. These intermittent hyperoxic exposures induce an adaptive response which includes increased upregulation of antioxidants genes [21]. Thus, similar to physical exercise and caloric restriction, a daily repeated HBOT protocol can induce the hormesis phenomenon. Single exposures increase ROS generation acutely, triggering the antioxidant response, and with repeated exposures, the response becomes protective [22]. 
The protocol used by the Israeli team included 60 sessions of 100% oxygen at 2 ATA including three air breaks during each session to utilize the hyperoxic hypoxic paradox and minimize the risk of oxygen toxicity. Interestingly, both TL and senescent cell reduction peaked at the 30th session. However, the dose-response curve related to the applied pressure, time, and the number of HBOT exposures and its relation to HIF expression and its related regenerative effects are still not fully understood and further studies are needed to find the optimal HBOT protocols. 

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Thus, a healthy lifestyle that includes exercise and a nutritious diet, combined with a daily HBOT protocol, can induce the phenomenon of telomere lengthening and decreased immunosenescence, slowing the aging and deterioration of the body.

References
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