Hyperbaric Oxygen Therapy(HBOT) for Reverse Aging

Time : March 15,2024

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Abstract:

Introduction: Aging is characterized by the progressive loss of physiological capacity. At the cellular level, two key hallmarks of the aging process include telomere length (TL) shortening and cellular senescence. Repeated intermittent hyperoxic exposures, using certain hyperbaric oxygen therapy (HBOT) protocols, can induce regenerative effects which normally occur during hypoxia. The aim of the current study was to evaluate whether HBOT affects TL and senescent cell concentrations in a normal, non-pathological, aging adult population.

Methods: Thirty-five healthy independently living adults, aged 64 and older, were enrolled 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.

Results: 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%±40.42 (p=0.007), 29.39%±23.39 (p=0.0001) and 37.63%±52.73 (p=0.007), respectively.

There was a significant decrease in the number of senescent T helpers by -37.30%±33.04 post-HBOT (P<0.0001). T-cytotoxic senescent cell percentages decreased significantly by -10.96%±12.59 (p=0.0004) 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.

Anti Aging HBOT

Introduction:

Aging can be characterized by the progressive loss of physiological integrity, resulting in impaired functions and susceptibility for 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.

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. 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. When TL reaches a critical length, cells cannot replicate and progress to senescence or programmed cell death. Goglin et al. demonstrated that adults with shorter TLs have increased mortality rates. Shortened TLs can be a direct 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.

Cellular senescence is an arrest of the cell cycle which can be caused by telomere shortening, as well as other aging associated stimuli independent of TL such as non-telomeric DNA damage. The primary purpose of senescence is to prevent 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.

A growing body of research has found several pharmacological agents that can reduce the telomere shortening rate. Several lifestyle interventions including endurance training, diets and supplements targeting cell metabolism and oxidative stress have reported relatively small effects (2-5%) on TL3.

Hyperbaric oxygen therapy (HBOT) utilizes 100% oxygen in an environmental pressure higher than one absolute atmospheres (ATA) to enhance the amount of oxygen dissolved in 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. 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. 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. 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.

Discussion:

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.

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. In another study which 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. A recent study found that aerobic endurance training or high intensity interval training for six month increased telomere length up to 5%. Additional weight loss, yoga and stress management techniques failed to show significant telomere length changes. However, most of these studies have shown significant correlations between antioxidant activity and telomerase activity.

While many genetic and environmental factors are associated with telomere shortening, the most common suggest 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. 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. 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. However, healthy individuals did not show similar results.

Exposing cell cultures to a hyperbaric environment has been previously suggested to induce significant oxidative stress and premature cells senescence. However, this was based on isolated cells grown in a hyperbaric incubator and not on the complex biological system of humans as in this study. 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. As used in the current study, the HBOT protocol utilizes the effects induced by repeated intermittent hyperoxic exposures, the so called hyperoxic hypoxic paradox. These intermittent hyperoxic exposures induce an adaptive response which includes increased upregulation of antioxidants genes and production of antioxidants/scavengers that adjust to the increased ROS generation causing the ROS/scavenger ratio to gradually becomes similar to the ratio under a normal oxygen environment. However, because the scavenger elimination half-life (T1/2) is significantly longer than the T1/2 of ROS, upon return to normoxia, following repeated hyperoxic exposures, there are significantly higher levels of scavengers and increased antioxidant activity. 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.

Additionally, intermittent hyperoxic exposures induce many of the physiological responses that occur during hypoxia. HBOT induces the release of transcription factors called hypoxic induced factors (HIF) and increase their stability and activity. In turn, HIF induces a cellular cascade including vascular endothelial growth factor and angiogenesis induction, mitochondria biogenesis, stem cells mobilization and SIRT1 increased activity. Our study confirms increased HIF expression is induced by repetitive HBOT exposures, which gradually decreases towards normalization of HIF levels at nonmonic environment.

Currently, many interventions that genetically or pharmacologically (senolytic drugs) remove senescent cells have been developed in animal models and are waiting for safety and efficacy evaluations in humans. The current study suggests a non-pharmacological method, clinically available with well-established safety profile, for senescent cells populations decrease. Our protocol 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 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.

Hyperbaric oxygen therapy is a well-established treatment modality for non-healing wounds, radiation injuries as well as different hypoxic or ischemic events (such as carbon monoxide toxicity, infections, etc). In recent years, a growing evidence from pre-clinical as well as clinical trials demonstrate the efficacy of HBOT for neurological indications including idiopathic sudden sensorineural hearing loss, post stroke and post traumatic brain injury, central sensitization syndrome such as fibromyalgia syndrome and age related cognitive decline and animal models of Alzheimer’s disease. For the first time, the current study aimed to evaluate the physiological effect on the cellular level in aging humans without any functional limiting disease.

Study Limitations:

The current study has several limitations and strengths to consider. First, the limited sample size has to be taken into account. Second, the lack of control group. However, the study suggests impressive results on TL and senescent cell clearance, which weren’t observed in other interventions. Moreover, the baseline telomere length values of our cohort match the expected values for the aging population. Third, the duration of the effect has yet to be determined in long-term follow-ups. Fourth, telomerase activity was not evaluated due to the method chosen for blood preservation and evaluation. Nevertheless, several strengths should be stressed. In this study, CD28 was used as a biomarker for senescent cells whereas CD57 was not available as a confirmatory marker for T cell senescence. Biomarkers were assessed on specific leukocytes populations rather than using the entire PBMCs as one group. The isolated HBOT effect was measured and participants were monitored for not making any lifestyle changes (such as nutrition and exercise), medications or any other intervention that may have acted as possible confounders.

In summary, the study indicates that HBOT can induce significant senolytic effects, including significant increased telomere length and clearance of senescent cells in aging populations.

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