Treatments and therapies that aim to improve vascular and cerebrovascular health have been associated with increased health-span (period of healthy living) in aging (Brown et al., 2007; Drummond et al., 2011; Seals et al., 2016). Administration of 100 percent oxygen to a patient in a pressurized environment results in hemoglobin saturation. Unbound extra oxygen can dissolve in the plasma producing hyperoxygenated blood (Goyal et al., 2019), so that the dissolved fraction becomes the main source of O₂ available to cells (Demchenko et al., 2005). Hyperoxygenation together with higher atmospheric pressure have been observed to exert multiple effects on the brain and its cerebrovasculature (Figure 1), ranging from restoration of blood brain barrier (BBB) permeability (Li et al., 2018a), improved angiogenesis (Johnson and Wilgus, 2014), edema reduction (Sukoff and Ragatz, 1982; Yagishita et al., 2017), to the modulation of perceived painful stimuli (Sutherland et al., 2016). Cerebromicrovascular mechanisms are also extensively studied in the context of age-related vascular dementias. It is well recognized that age-related microvascular rarefaction (Tucsek et al., 2014), increased BBB permeability (Li et al., 2018a), endothelial dysfunction (Herrera et al., 2010; Ungvari et al., 2018a), inflammation (Csiszar et al., 2014; Ungvari et al., 2018b; Fulop et al., 2018), and impairment of neurovascular coupling responses (Tarantini et al., 2017c) are among critical factors in the development of cerebromicrovascular pathologies associated with neurodegeneration and loss of cognitive function which are responsible for loss of quality of life and diminished healthspan in aging.

Over the past decades a growing number of studies have implicated HBOT for the treatment of vascular dementias through the following possible mechanisms: increased oxygen supply and tissue oxygen partial pressure (pO₂), relieving cerebral edema (Sukoff and Ragatz, 1982), decreasing intracranial pressure, promoting tissue healing and angiogenesis (Johnson and Wilgus, 2014), improved metabolism, reduced apoptosis, alleviating oxidative stress, increased mitochondrial function and promoting cell differentiation and regeneration (Robertson and Hart, 1999; Feldmeier, 2003; Wang et al., 2016) (Figure 1). During inhalation of normobaric air, arterial pO₂ is approximately 100 and 55 mmHg in the tissues. However when breathing 100 percent oxygen at 3 ATA arterial pO₂ can increase to about 2,000 mmHg and to 500 mmHg in the tissues (Tibbles and Edelsberg, 1996). By exceeding the oxygen carrying capacity of hemoglobin, the oxygen in solution saturates the blood plasma and can better oxygenate areas where red blood cells cannot reach or where hemoglobin oxygen carriage is impaired (Figure 1C), such as in microvascular injury or carbon monoxide poisoning (Leach et al., 1998; Phillips, 2000).

HBOT not only provides increased access of oxygen to damaged tissue via plasma saturation, but also encourages new blood vessel formation by activation transcription factors such as VEGF (Goyal et al., 2019). Although the mechanisms are not fully understood, HBOT is a well-established treatment for decompression sickness. This condition affects individuals that experience trauma, surgery, or deep-sea diving, resulting in the formation of air embolisms. Additional therapeutic targets that deserve more investigation include cognition. As such, recent studies have aimed to investigate the cellular and molecular mechanisms underlying HBOT to better understand its potential clinical role in age-related cognitive impairment. HBOT is particularly effective in wound healing, it works by amplifying the oxygen diffusion gradients along ischemic wounds, promoting extracellular matrix synthesis required for angiogenesis (Knighton et al., 1981; Hunt, 1988).

In the cerebral microvasculature, age-related pathological changes include loss of vascular density (Tucsek et al., 2014) and decreased angiogenesis (Lin et al., 2018), increased incidence of ischemic and hemorrhagic microvascular injury (Ungvari et al., 2017b), and neuroinflammation which is associated with loss of cognitive function. The physiological basis and documented effects of HBOT as it was studied on peripheral vasculature and tissues could be applied to the cerebral microvasculature to study the potential therapeutic effects of hyperoxia against age-related vascular cognitive impairment. In healthy vasculature hyperoxia has been found to rapidly elicit robust vasoconstriction S V, 1990, however Zamboni demonstrated that the increased oxygen carriage of hyperoxygenated plasma compensated well for the reduced flow of red blood cells. Additionally, microvascular blood flow in ischemic tissue is in fact improved with HBOT (Zamboni et al., 1993). Further studies showed hyperoxia had beneficial microcirculatory and metabolic effects by limiting the loss of ATP production and decreased accumulation of lactate in ischemic tissue (Cianci et al., 2013). Other researchers have been interested in the consequences of HBOT on CBF, studies using laser doppler flowmetry (Chavko et al., 1998) suggested no systematic changes (Zhang et al., 1995) or small improvements in CBF (Thom et al., 2002) in response to HBOT-induced nNOS activation. However, Sato measured the production of cortical NO during HBOT in rats and found that NO production was improved proportionally to the CBF increase (Sato et al., 2001).

The coenzyme NAD⁺ plays a critical role in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging (Imai and Guarente, 2014; Kane and Sinclair, 2018) causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies (Verdin, 2015) including vascular dementia (Fricker et al., 2018), Alzheimer’s disease (Gong et al., 2013; Hou et al., 2018), and vascular cognitive impairment (Tarantini et al., 2019a; Tarantini et al., 2019b; Kiss et al., 2019). In a recent study mitochondrial NADH redox state were assessed in the brain of awake rats undergoing HBOT treatment. NADH was found to be oxidized to NAD⁺ in parallel to the tissue oxygenation increase, showing maximal tissue oxygenation and greatest accumulation of cellular mitochondrial NAD⁺ after HBOT (Meirovithz et al., 2007). Another study found HBOT significantly increased the level of NAD⁺ 6 h after MCAO, suggesting that the hyperoxygenation exerts a long-lasting effect (Hu et al., 2017). This evidence suggests that treatments aimed at boosting NAD⁺ levels may contribute as a promising avenue to counter age-associated cognitive decline by restoring CBF, improving tissue pO₂, and ameliorating cellular bioenergetics in the brain (Dave et al., 2003; Mouchiroud et al., 2013; Rajman et al., 2018).

A growing body of evidence implicates bioenergetic deficits, mitochondrial dysfunction, and impaired reduction‐oxidation (redox) homeostasis in the age-related development of neurodegenerative diseases (Mandal et al., 2012; Venkateshappa et al., 2012; Grimm and Eckert, 2017) and cognitive impairment (Mandal et al., 2012). Studies investigating the effects of HBOT on mitochondrial function (Dave et al., 2003) and cellular energetics in endothelial progenitor cells (Hauer-Jensen, 2017; Hsu et al., 2019) and neurons (Yang et al., 2016) have shown that HBOT significantly modulates the basal respiration, improved respiratory capacity, and increased mitochondrial mass following a single HBOT session. Bullock et al. (Zhou et al., 2007) found that hypoxia alone increased cerebral ATP levels in rats, while HBOT improved cognitive recovery and reduced the loss of hippocampal neurons following lateral fluid-percussion injury.

Other prominent features of aging are pro-inflammatory phenotypic alterations of cerebral vessels mediated by the decreased activity of Nrf2 (NF-E2-related factor 2), a key redox sensitive transcription factor, which is a key modulator for the expression of antioxidant and detoxicant enzymes, as well as factors involved in repair of oxidative macromolecular damages and other cell survival pathways. Several recent studies have shown that Nrf2 activity exerts multifaceted anti-aging vasoprotective effects against the pathogenesis of age-related vascular cognitive impairment (Ungvari et al., 2010; Ungvari et al., 2011a; Valcarcel-Ares et al., 2012; Tarantini et al., 2018a). Recent studies administering HBOT in isolated human microvascular endothelial cells (Godman et al., 2010) and diabetic mice (Verma et al., 2015) have identified HBOT as a Nrf2 activator and -mediated oxidative stress response as one of the primary responders to HBOT. HBOT has also been widely used as a treatment adjunct for vascular disease, and in addition to increasing oxygen delivery to the marginally perfused ischemic/hypoxic tissues, HBOT has also been shown to promote angiogenesis and improve cellular metabolism that has been impaired by hypoxia while significantly reducing post-ischemic edema, an effect that persists after treatment (Goyal et al., 2019). Dietary habits leading to metabolic stress and aging have been linked to a decline in microvascular density both in the brain of mouse models of aging (Balasubramanian et al., 2020).

In a recent study the measured hippocampal microvascular rarefaction and the loss of hippocampal-dependent cognitive function positively correlated (Tucsek et al., 2014). Endothelial cells lining the brain microvasculature have been found to be particularly sensitive to these stressors (Ungvari et al., 2011b) and could be implicated in the age-dependent loss of neurovascular coupling responses (Tarantini et al., 2017c; Tarantini et al., 2018b; Tarantini et al., 2019a; Levit et al., 2020), and brain microvascular rarefaction (Tucsek et al., 2014). Additionally, HBOT-induced angiogenesis and fibroplasia has been shown to promote healing to radiated tissue. This is especially useful because radiated tissue does not spontaneously revascularize due to their unique wounding pattern (Goyal et al., 2019). Aged mice exhibit vascular endothelial growth factor (VEGF) signaling insufficiency (Grunewald et al., 2021). At the molecular level, increase in VEGF production mediates the effects of HBOT on angiogenesis. Several mechanisms have been put forth to explain how HBOT induces VEGF signaling to promote angiogenesis. The first mechanism involves increase in VEGF at the transcriptional level which is mediated by HBOT-induced binding of the transcription factor AP-1 to VEGF promoter. In vitro studies in human umbilical endothelial cells show that stress-activated protein kinase/c-June N-terminal kinase (SAPK/JNK) pathway and the extracellular signal-regulated kinase (ERK) pathway are involved in HBOT mediated increase in VEGF transcription through AP-1 (Lee et al., 2006). The second mechanism involves HIF-1α mediated VEGF induction. The intermittent normoxic periods between the HBOT session is sensed as hypoxia and results in increase in HIF1α which subsequently induces VEGF expression and angiogenesis (Cimino et al., 1985).

In summary HBOT has been showed to have complex effects on oxygen transport and microvascular hemodynamics. The potential beneficial effects of HBOT, such as reduction in hypoxia, decreased edema, pro-angiogenic effects on the microcirculation, and preservation of tissue energetics and metabolism through NAD⁺ repletion should be further investigated to understand their potential therapeutic effects against microvascular mechanisms of vascular aging and the associated loss of cognitive function.

In humans, age-related vascular cognitive impairment accounts for about 30 percent of all cases of dementia, second only to Alzheimer’s disease which accounts for 60 percent (Kalaria et al., 2008). The symptoms of vascular dementia and VCI are consequences of accumulation of age-related vascular phenotypical alterations pathologically affecting the structure and function of the cerebral microvasculature (Jellinger, 2004; Iadecola, 2013; Ungvari et al., 2018a; Ungvari et al., 2018b). Finding preventative and therapeutic prospects remains one of the greatest challenges in the field of geroscience, as many laboratories and investigators have dedicated their efforts to develop therapeutic strategies against VCI (Smith et al., 2017). Growing evidence in animal models has warranted the necessity for human clinical trials to investigate the role of HBOT against VCI in humans (Table 1).

The combination of pure oxygen and higher pressure leads to increases in tissue oxygenation while also targeting oxygen and pressure-sensitive genes. The result is restored and enhanced tissue metabolism. Extant studies in rodents demonstrated that, among other effects, HBOT can improve the blood supply and promote neurogenesis in the piriform cortex (Zhang et al., 2010), and in the hippocampus J Y, 2007, to enhance learning and memory, however, the exact mechanisms remain unclear. In humans, the early works performed by Jacobs et al. in 1969 on a group of 13 elderly male patients with a mean age of 68 indicate that intermittent hyperoxygenation can improve cognitive function in the elderly, with the beneficial effects outlasting the duration of the increased pO₂ ¹¹². In another study performed a few years later on a cohort of 20 elderly individuals, treated with 100 percent oxygen at 2 ATA for a total duration of 15 sessions, some of the treated participants reported increased visual acuity in addition to improvements across a range of cognitive domains (Edwards and Hart, 1974). In these studies, the beneficial effect of hyperbaric oxygen was presumed to be due to improved blood flow, providing compelling evidence of the relationship between restoration of tissue oxygenation and improvement in function.

The clinical evidence for the role of HBOT against cognitive decline in the elderly is not without controversy, in a report, Raskin et al. focused on the psychological and psychomotor test variables administered prior to and following hyperbaric oxygen treatment and failed to detect any cognitive differences as a function of sex, CO2 loading test, or presumed evidence of cerebrovascular disease (Raskin et al., 1978). In 2012 Xiao et al. published a Cochrane review analyzing the effectiveness and safety of HBOT for vascular dementia (Xiao et al., 2012). However, the evidence they presented was insufficient to support HBOT as an effective treatment for patients with vascular dementia since only one study involving 64 patients was included. This work compared HBOT as an adjuvant to donepezil against donepezil alone. Patients receiving HBOT plus donepezil had significantly better cognitive function than the donepezil only group after 12 weeks of treatment, measured by MMSE scoring or by Hasegawa’s Dementia Rating Scale (HDS). A very recent clinical meta-analysis on the efficacy and safety of hyperbaric oxygen as that HBOT can be recommended as an effective and safe complementary therapy for the treatment of vascular dementia (You et al., 2019). This meta-analysis included twenty-five randomized clinical trials and included almost 2,000 patients that underwent HBOT between 2008 and 2017. The results indicated that HBOT markedly improved the Mini-Mental State Examination (MMSE) scores, activities of daily living by Barthel index, and total efficacy rate, while adverse effects were not statistically different between HBOT and control groups (You et al., 2019). Subgroup analysis revealed that 7–8 weeks of 60 min HBOT administration produce the maximum therapeutic effect to VCI patients, and the positive outcomes are more precise and reliable within this administration regimen. To provide some mechanistic insight, a recent study published this year from Xu et al. included a total of 158 patients with vascular dementia which were randomly divided into control and hyperbaric oxygen groups (Xu et al., 2019). HBOT was administered 5 days per week for 12 weeks, with each session lasting 60 min each at 2 ATA 100% O₂. The findings from Xu et al. concluded that after the treatment period, patients receiving HBOT not only showed significantly higher MMSE scores but also exhibited higher serum Humanin levels, compared to control, which highly correlated with MMSE scores. Humanin is a mitochondrial-derived peptide with strong neuroprotective effects (Zárate et al., 2019), which has been found to prevent cognitive decline in clinical and experimental studies (Yen et al., 2018).

HBOT cognitive protection and pro-vascular effects beneficially extend to the vascular endothelium. In a study, 98 patients admitted with chest discomfort were divided in a control group to receive conventional treatment and a hyperbaric oxygen administration group, which received HBOT in addition to conventional treatment. Patients who were administered additional HBOT therapy for 4 weeks exhibited improved flow-mediated vasodilation (FMD) response of the brachial artery, increased plasma nitric oxide (NO), increased calcitonin-gene related peptide (CGRP), and decreased levels of endothelin-1 (ET-1) and high sensitivity C-reactive protein (hsCRP) (Li et al., 2018b). The HBOT-induced improvement in cognitive performance is not limited to individuals suffering from age-related VCI. A prospective, double-blind randomized control, crossover trial including 22 healthy volunteers showed that, compared to the performance at normobaric conditions, both cognitive and motor single tasks scores were significantly enhanced by the hyperbaric oxygen environment (Vadas et al., 2017).

Currently, the U.S. Food and Drug Administration (FDA) and the undersea and hyperbaric medical society (UHMS) are the key agencies providing guidelines and indications for marketing and use of HBOT (Weaver, 2014; Fife et al., 2016). At this time HBOT is approved for the medical treatment of 13 conditions: 1) decompression illness, 2) carbon monoxide poisoning, 3) air or gas embolism, 4) crush injury syndrome, 5) clostridial myositis and myonecrosis, 6) adjunctive treatment of selected problem wounds, 7) chronic refractory osteomyelitis, 8) exceptional blood loss anemia, 9) necrotizing soft-tissue infections, 10) late radiation tissue injury, 11) thermal burns, 12) ischemic skin graft and flaps, and 13) intracranial abscess (Fife et al., 2016). Since, among its proven beneficial effects, HBOT has the unique ability to ameliorate tissue hypoxia, reduce pathologic inflammation, mitigate ischemia reperfusion injury, as well as reduce brain edema, the Department of Defense (DoD) has funded trials to evaluate the use of HBOT in chronic traumatic brain injury (TBI), which thus far is not supported by the evidence (Wolf et al., 2012; Cifu et al., 2014a; Cifu et al., 2014b; Walker et al., 2014; Miller et al., 2015). Patients with TBI may present cognitive deficits within the first 24 h after trauma, in the so-called “acute phase,” which in turn may lead to long-term cognitive impairment and decrease in quality of life. The outcome of this research initiative proved that, in two randomized clinical trials comprised of 143 active-duty or veteran military personnel, composite total scores improved from baseline with administration of HBOT (Weaver et al., 2019).

WBI is a mainstream therapy for patients with both identifiable brain metastases and is associated with significant neurotoxicity. However, it also promotes accelerated senescence in healthy tissues and leads to progressive cognitive dysfunction in up to 50% of tumor patients (Ungvari et al., 2017a). The long-term risk for radiation-induced brain inflammation and necrosis inducing secondary cognitive impairments are increasing concerns. Currently there is no effective treatment for preventing long term radiation-induced brain damage. HBOT is currently indicated as an experimental therapy for patients with suspected radiation-induced neurotoxicity and was proven to reduce further development of radiation damage. In a case report, a 45-year-old man who developed brain radionecrosis in the right frontal and left temporoparietal lobes and, after receiving WBI, was referred to HBOT administration. After HBOT, both clinical and cognitive findings improved, suggesting that akin to experimental results (Warrington et al., 2013), treatments that restore cerebromicrovascular function after WBI-related injuries are associated with improved health outcomes (Cihan et al., 2009).

Duration and HBOT exposure are not standardized, however administration of HBOT for 2 h/day, 5 days/week, for 3 months (Hadanny et al., 2020) was able to produce cognitive improvements. The authors of this recent study measured in 63 healthy, active adults, changes in cognitive function via a standardized battery of comprehensive computerized cognitive assessments, and CBF by functional magnetic resonance imaging. The results showed improved attention, cognitive processing speeds and executive function, adding to the growing body of evidence that HBOT has regenerative effects on the brain (Hadanny et al., 2020). Remarkably, this is the first study to demonstrate the beneficial pro-cognitive effects of HBOT on healthy older subjects (Hadanny et al., 2020), providing evidence for the potential effects of HBOT on the healthspan of aged individuals. Similarly, a double-blind placebo-controlled clinical trial provided additional supporting evidence for the beneficial effects of HBOT by testing the effect of HBOT on brain function and cognitive outcomes in mildly cognitively impaired elderly individuals with diabetes (BenAri et al., 2020). Although there is clinical and experimental evidence in favor of HBOT to improve cognitive function in patients with age-related vascular pathologies, oxygen therapy is not without consequences and should be administered with caution. As such, the mechanism of HBOT warrants further investigation.

Overall, the available evidence suggested that application of HBOT as adjuvant therapy has additional benefits on VCI patients, individuals exposed to WBI, and individuals suffering from TBI, and is generally regarded as safe.

Individuals that reside in high-altitude environments are exposed to decreased oxygen tension. Currently, the effects of HBOT on high-altitude dwellers has not been examined, however individuals that are consistently exposed to lower environmental pO2 have shown higher hemoglobin concentration (Mairbäurl et al., 1985). The effects of HBOT on these populations is unclear since during HBOT oxygen can be carried by hyperoxygenated plasma in addition to saturated hemoglobin. An additional interesting clinical finding shows that HBOT could aid in perinatal resuscitation of the newborn with perinatal asphyxia (Yilmaz et al., 2020). Conflicting evidence has shown that excessive oxygen may cause retinopathy or bronchopulmonary dysplasia, providing evidence against the use of HBOT in neonates (Liu et al., 2006). However, HBOT has been used to treat newborns with neonatal hypoxic-ischemic encephalopathy in clinical studies in China. The time window of HBOT is still controversial. In clinical studies, HBOT is usually initiated within one to 7 days after birth, administered one to three times per day at 0.15–0.17 MPa for 60–120 min, and continued for one to four courses of treatment (Liu et al., 2006).