The Hyperoxic-Hypoxic Paradox

Abstract

Effective metabolism is highly dependent on a narrow therapeutic range of oxygen. Accordingly, low levels of oxygen, or hypoxia, are one of the most powerful inducers of gene expression, metabolic changes, and regenerative processes, including angiogenesis and stimulation of stem cell proliferation, migration, and differentiation. The sensing of decreased oxygen levels (hypoxia) or increased oxygen levels (hyperoxia), occurs through specialized chemoreceptor cells and metabolic changes at the cellular level, which regulate the response. Interestingly, fluctuations in the free oxygen concentration rather than the absolute level of oxygen can be interpreted at the cellular level as a lack of oxygen. Thus, repeated intermittent hyperoxia can induce many of the mediators and cellular mechanisms that are usually induced during hypoxia. This is called the hyperoxic-hypoxic paradox (HHP). This article reviews oxygen physiology, the main cellular processes triggered by hypoxia, and the cascade of events triggered by the HHP.

Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells : a prospective trial

“…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 [ 31 ]. As used in the current study, the HBOT protocol utilizes the effects induced by repeated intermittent hyperoxic exposures, the so called hyperoxic hypoxic paradox [ 13 , 18 ]. These intermittent hyperoxic exposures induce an adaptive response which includes increased upregulation of antioxidants genes [ 32 ] 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.…”

“…These intermittent hyperoxic exposures induce an adaptive response which includes increased upregulation of antioxidants genes [ 32 ] 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 (T 1/2 ) is significantly longer than the T 1/2 of ROS, upon return to normoxia, following repeated hyperoxic exposures, there are significantly higher levels of scavengers and increased antioxidant activity [ 13 , 18 ]. Thus, similar to physical exercise and caloric restriction, a daily repeated HBOT protocol can induce the hormesis phenomenon.…”

“…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 [ 13 , 18 ].…”

“…HBOT induces the release of transcription factors called hypoxic induced factors (HIF) and increase their stability and activity [ 14 ]. In turn, HIF induces a cellular cascade including vascular endothelial growth factor and angiogenesis induction, mitochondria biogenesis, stem cells mobilization and SIRT1 increased activity [ 18 ]. Our study confirms increased HIF expression is induced by repetitive HBOT exposures, which gradually decreases towards normalization of HIF levels at nonmonic environment.…”

“…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 [ 17 ]. 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 [ 18 ]. However, no study to date has examined HBOT’s effects on TL and senescent cell accumulation.…”