Hyperbaric oxygen therapy for healthy aging: From mechanisms to therapeutics

Abstract

Hyperbaric oxygen therapy (HBOT), a technique through which 100% oxygen is provided at a pressure higher than 1 atm absolute (ATA), has become a well-established treatment modality for multiple conditions. The noninvasive nature, favorable safety profile, and common clinical application of HBOT make it a competitive candidate for several new indications, one of them being aging and age-related diseases. In fact, despite the conventional wisdom that excessive oxygen accelerates aging, appropriate HBOT protocols without exceeding the toxicity threshold have shown great promise in therapies against aging. For one thing, an extensive body of basic research has expanded our mechanistic understanding of HBOT. Interestingly, the therapeutic targets of HBOT overlap considerably with those of aging and age-related diseases. For another, pre-clinical and small-scale clinical investigations have provided validated information on the efficacy of HBOT against aging from various aspects. However, a generally applicable protocol for HBOT to be utilized in therapies against aging needs to be defined as a subsequent step. It is high time to look back and summarize the recent advances concerning biological mechanisms and therapeutic implications of HBOT in promoting healthy aging and shed light on prospective directions. Here we provide the first comprehensive overview of HBOT in the field of aging and geriatric research, which allows the scientific community to be aware of the emerging tendency and move beyond conventional wisdom to scientific findings of translational value.

Keywords: Age-related disease; Aging intervention; Cellular senescence; Hyperbaric oxygen therapy; Oxidative stress.

Fig. 1

Potential strategies against aging and their deficiencies. Strategies under development to intervene aging include stem cell therapy, young plasma transfusion, physical exercise, intermittent fasting and senotherapeutics. Despite the great promise of these mainstream strategies, there are three deficiencies among them. (1) Stem cell transplantation and young plasma transfusion involve a certain degree of invasiveness. (2) Physical exercise and intermittent fasting alone may not be sufficient enough to ensure definitive efficacy. (3) The efficacy of senotherapeutics is not yet fully understood in humans and the development pipelines are complex, time-consuming and expensive.

Fig. 2

The biological consequences of aging with respect to oxygen levels. In terms of aging, the truth is not a duality when it comes to the trade-off between hypoxia and hyperoxia, especially when issues such as oxidative stress and scavengers are involved. First, large deviations from normoxia (either increases or decreases in oxygen levels) generally lead to increased oxidative stress and reduced longevity. To the contrary, modest modulation of oxygen levels (either increases or decreases in oxygen levels) can enhance the antioxidant defenses and slow the aging process. These facts suggest both an alert threshold in hypoxia and a toxicity threshold in hyperoxia in the biological consequences of aging with respect to oxygen levels.

Fig. 3

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 summarized 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.

Fig. 4

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 stabilize HIF-1 in its active form (Another way HBOT stabilizes 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.

Fig. 5

The effects of HBOT on aging in different organs or tissues. In pre-clinical and clinical investigations, HBOT has shown great potential in improving cognition, inhibiting intrinsic skin aging and photoaging, improving glucose metabolism (by increasing thermogenesis and volume of brown adipose tissue and promoting oxidative ability of skeletal muscle), preventing bone and muscle loss, and enhancing myocardial and pulmonary function. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)