Some of the most powerful medical interventions to move the needle for mitochondrial repair go back to the basics. For example, red light therapy, both visible and infrared, are part of the electromagnetic spectrum from sunlight. (The rest of the colors of the visible spectrum are beneficial too, by the way).
Oxygen is another one of those basics—the fundamental building blocks for ATP production in the mitochondria are electrons from food, and oxygen. In the absence of oxygen, at the tissue level, mitochondria can still make ATP, but a lot less of it—by an order of magnitude. You might think, therefore, that more oxygen is better… which is true, to a point. But principles of hormesis apply here: in a living system, there can always be both too much, or too little of a good thing. So oxygen therapies can be very useful—in some cases, and in their proper place.
Exercise With Oxygen Therapy (EWOT)
Exercise with Oxygen Therapy (EWOT) is a trend in biohacking circles. The concept is to exercise with heart rate at a therapeutic range (this varies greatly by age and fitness levels), while breathing oxygen from an oxygen concentrator through a mask. Just like a workout that is easy for you at sea level will likely be much more difficult at an elevation of 10,000 feet, so adding supplemental oxygen should, in theory, improve both exercise and mitochondrial efficiency.
The principle of hormesis, though, means that the body always triggers a rebound response in the opposite direction of any intervention. When it comes to EWOT, the rebound is known as the “normobaric oxygen paradox” (NOP), or the tendency of the body to perceive normal oxygen levels as oxygen shortage after hyperoxic exposure.
To a point, this is good: the body’s initial response is to trigger hypoxia-inducible factor 1 (HIF-1α), which in turn decreases the amount of oxygen consumed, increases breakdown of glucose for energy, and triggers production of new red blood cells and blood vessels. HIF-1α also triggers autophagy (breakdown of damaged cells)–a necessary first step to rebuild newer, healthier ones.
HIF-1α also triggers Nuclear factor (erythroid-derived 2)-like 2 (NRF2), a classic antioxidant and detoxification cascade. So far so good, as NRF2 is a primary regulator of mitochondrial function. At 30% oxygen concentration delivered to healthy volunteers during an hour of exercise, the body sends signals to make new, healthy mitochondria. Great.
At higher O2 concentrations of 100% and 140% in those same healthy volunteers, however, the body exceeded the NRF2 “buffer zone” where it can effectively quench oxidative stress, triggering Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB rises when the body perceives a threat. Under those circumstances, there’s no mitochondrial rebuilding going on—rather, the soaring oxidative stress shifts the priority to damage control.
Exercise itself also triggers oxidative stress—this is part of the hormetic benefit of exercise, as long as it’s matched to a person’s tolerance and fitness level. But now we potentially have two oxidative stressors added together.
These studies were, again, also performed in healthy volunteers. In someone who’s been chronically ill, NF-κB is likely already high, which in turn suppresses NRF2, and means low antioxidant reserves. It’s possible that in someone who is chronically ill, the “safe” O2 threshold is lower than 30%, particularly when combined with exercise. (O2 in normal air is around 21%, for comparison.)
So who might benefit from EWOT? Can EWOT help boost mitochondrial biogenesis and performance for athletes? According to this study, gains were marginal at best, with no change in exercise efficiency. Presumably this is because athletes have already optimized their mitochondria. In those with “normal” mitochondria, though, there were some adaptive responses.
EWOT is perhaps most useful for those with metabolic dysfunction, and particularly Type 2 Diabetes, improving exercise function and metabolism.
IHHT (intermittent hypoxic-hyperoxic training)
One potential alternative to EWOT is intermittent hypoxic-hyperoxic training. This is basically EWOT without the continuous oxygen delivery (breaks with regular air are built in), and without the exercise. The alternation between higher O2 and regular air leans on the normobaric oxygen paradox (NOP) to try to induce HIF-1α and NRF2, without spilling over into NF-κB activation.
This study shows that IHHT improves functional capacity and quality of life for long COVID patients, while this one shows that geriatric patients improved functional mobility, physical performance, and cognition with IHHT.
Hyperbaric Oxygen Therapy (HBOT)
Hyperbaric oxygen therapy (HBOT) combines oxygen with pressure, a separate “active therapeutic ingredient” which dramatically increases the amount of oxygen dissolved in plasma, compared to just oxygen delivery alone. Typical O2% in HBOT is 100%, too, but generally with five minutes of regular air every 20-30 minutes to trigger the “intermittent” feedback mechanism.
These breaks may be the reason that, while 100% O2 delivery in EWOT was maladaptive, in HBOT it can be beneficial—even though with HBOT, that same 100% O2 dramatically increases O2 delivery to tissues. Presumably the breaks work like a course correction, to clear accumulated oxidative stress and get back into the therapeutic zone.
This study in fibromyalgia patients shows that HBOT delivery (at 40 sessions, 5 days per week, at 90 minutes each) led to dramatic symptom relief, and improved quality of life, persisting even up to a year after the last HBOT session was completed.
HBOT is also specifically beneficial for wound healing, and for inducing neuroplasticity—improving cognition, fatigue, sleep, pain, and even offering relief in severe emotional disorders such as PTSD.
One caveat: I have had a number of patients over the years with chronic infections who have experienced acute exacerbation of symptoms with HBOT (generally attributed to a Herxheimer reaction, or “die-off.”) My suspicion is that this is due to high NF-κB, with low antioxidant reserves secondary to chronic illness. I generally recommend that people suffering from chronic infections such as Lyme Disease postpone HBOT treatment until we’ve laid some groundwork, so that it will be better tolerated.
The Upshot
Oxygen therapies can be very beneficial in their place, but too much continuous oxygen delivery without breaks can be harmful. Thus far, the data seems to favor IHHT, or HBOT over EWOT for most people.
