• Hypoxia has selective properties — As explained by Prokopov, when you reduce the partial pressure of oxygen in tissues that are being irradiated, there's a significant protective effect on healthy tissues. Tumors are not protected, however, because they're already hypoxic, so they're not affected by the small, physiological decrease of oxygen partial pressure.

• Hypoxia begins at the embryonic stage — Early pioneers also discovered that intermittent hypoxia takes place during embryonic development. So, in utero, there are significant variations of partial pressure of oxygen.

It was not clear what the physiological purpose of these oscillations was, but now, decades later, "we understand that this is a powerful mechanism to control the quality of mitochondria," Prokopov says.

• Other settings where intermittent hypoxia occurs — Intermittent hypoxia is also very common in other instances. "For instance, when we have some physical activity, when we stress our muscles, when they are contracted, the circulation is blocked and the muscle experiences [mild] hypoxia. Then, during relaxation, blood delivery [resumes] and muscles become again [saturated with] oxygen and nutrients,” Prokopov says.

He continues, stating that, “This is the universal mechanism which is providing continuous repair and recovery of the mitochondria and other cellular structures. So why not to use this natural mechanism for other purposes, like enhancement of endurance in athletes? Now, this is very well known as altitude training. Thousands of athletes use altitude training."

• How to create immediate hypoxia — As explained by Prokopov, one of the simplest ways to stimulate your mitochondrial function through hypoxia is simply to intermittently hold your breath.

Intermittent flow of oxygen-depleted air can also be administered via a face mask. These machines are known as hypoxic generators. The latest models also include computerized biofeedback, and allow for all sorts of protocols to be administered. I've been participating in the development of such devices for the last two decades.

Basically, it cycles through the amount of oxygen you breathe, from the therapeutic low of 10% to 14%, to a high up to 21% to 34%.

• Control your breathing — If you routinely overbreathe (breathe too deeply or too rapidly, or both), you end up with lower CO₂ levels than are ideal. This kind of subclinical hyperventilation is frequently a learned response to stress, and needs to be unlearned — something we discuss in my interview with Peter Litchfield, which will be posted next week.

• Healthier mitochondria help you stop overbreathing — Interestingly, Prokopov claims that once people improve the quality of their mitochondria, they typically stop overbreathing automatically. He explains, “Because where do we get carbon dioxide from? From the mitochondria. It's an element metabolite, the byproduct of oxidative phosphorylation. And if the mitochondria are not active enough, they just don't produce enough carbon dioxide."

• Most people don’t generate enough carbon dioxide — Normally, the urge to breathe is stimulated and regulated by a slight increase in CO₂, which happens in any physical activity.

But today, in stressful situations, we rarely switch on the "fight-or-flight" response that revs up metabolism and raises CO₂ production. Instead, we have only a fast increase of CO₂ removal by accelerated breathing, but without an increase of physical activity that would produce more CO₂ and would compensate for its drop.

Add stress, when you hyperventilate even more, which further reduces your CO₂ level. Before you know it, you're in a vicious doom loop that can send you to the emergency room.

• An easy way to induce hypoxia — One way to increase the amount of CO₂, thereby breaking this loop, is to breathe into a paper bag. That can reduce many symptoms of overbreathing and hyperventilating in just a couple of minutes. A hypoxia generator can also be used. The drawback of these kinds of tools is that they only offer temporary relief.

"It's just a symptomatic treatment if used only sporadically," Prokopov says. "As soon as you stop it, you overbreathe again and you have the same problems. But if regenerate your mitochondria, if you make them work more efficiently, more economically, it produces a much better level of endogenous carbon dioxide.

Normal partial pressure of carbon dioxide in blood plasma is from 35 to 45 torr, but most people are below 35. If mitochondria are functioning optimally, it automatically [resets the partial pressure of CO₂] and we see reduction or complete elimination of all problems connected to overbreathing."

• Glucose metabolism is preferred to fat metabolism — As mentioned, virtually all the CO₂ is produced in the electron transport chain of your mitochondria. Fat metabolism reduces mitochondrial efficiency by 25% to 50%.

• More structured water is produced — Glucose metabolism also increases structured water (mitochondria-produced water), also known as deuterium-depleted water, and reduces reactive oxygen species (ROS) production in the mitochondria.

• Switch your schedule once mitochondrial health improves — Once your mitochondria are sufficiently healthy to handle intermittent fasting, Prokopov suggests an 8/16 schedule, where you eat all your meals within an eight-hour window, and fast for the remaining 16 hours.

• Shorten the eating window further — As your metabolic flexibility improves, which is also wholly dependent on the functionality of your mitochondria, your eating window can be narrowed to six hours or even less. Prokopov personally eats all his meals within a four- to five-hour window. Intermittent fasting also works synergistically with hypoxic training.

• Your body produces stress hormones to synthesize glucose — When you don't have enough glucose to fuel the mitochondria, when you deplete your glycogen level, then stress hormones — adrenaline and cortisol — are released to trigger endogenous production of glycogen.

• Increased production of stress hormones harms your health — The stress hormones are pathologic, and if they're continuously released at high levels to compensate for insufficient glucose, it will accelerate disease and premature death. There's no question in my mind that these stress hormones are bad news.

Cortisol, for example, drains the amino acids, the protein, from your tissues, thereby decreasing bone density and muscle mass, which is bad news.

• Take care not to fast for too long — If you go for a lot longer, certainly after two or three days, then your glycogen stores will be completely depleted and your stress hormones will be activated, because that's the only route left to remain alive. The stress hormones will prevent your glucose level from dropping too low, as that could cause you to go into a coma and eventually die.

• Fasting is a balancing act — The problem is that 30% of adults in the U.S. have nonalcoholic fatty liver disease (NAFLD), which impairs your body's ability to produce glucose through gluconeogenesis. You also can't store as much. If your liver function is impaired, you will not be able to store as much glycogen in your liver.

Then you have to be more careful about not letting your glucose level drop for too long, because then the stress response will kick in as there is less reserve glucose in your liver.

• Other roles of CO₂ in your body — CO₂ modulates the functional expression of the proteins. This is important as nearly all hormones are proteins, and their function can be modulated by CO₂ levels. So, you can activate and radically increase the efficiency of proteins and hormones in your body. Histones are proteins that surround nuclear DNA, and they modulate the expression of that DNA.

• Akkermansia is an important gut bacteria — Akkermansia muciniphila, a specific type of anaerobic bacteria, increases glucagon like peptide (GLP), which can be useful in the treatment of diabetes and obesity. Ideal levels of Akkermansia are about 10% of your microbiome. But most populations now have less than 1%, likely due to inadequate mitochondrial function and resultant oxygen leakage in the gut.

Akkermansia is a gram-negative bacterium, but it does not produce lipopolysaccharide (LPS) or endotoxin. In fact, if their population is increased, they will crowd out the endotoxin-producing gram-negative bacteria by competitive inhibition. Akkermansia also produces mucin, a thick, protective gel-like substance that lines the gastrointestinal tract.

• The role of mucin — It forms a protective barrier on the gut lining, shielding the epithelial cells of the intestinal wall from mechanical damage, chemical irritation from stomach acids and digestive enzymes, and pathogenic organisms like bacteria and viruses.

• Eating more fiber — The short-chain fatty acids that form from fiber as it ferments in your intestines feed beneficial bacteria, including Akkermansia.

• Increasing FODMAPs in your diet — FODMAP refers to "fermentable oligo-, di- and mono-saccharides and polyols," which include fructose (found in fresh fruit) and lactose (found in milk and other dairy products).

• Boosting intake of dietary polyphenols — Black tea, red wine grape extract, and Concord grape, specifically, have all been shown to significantly promote growth of Akkermansia.

• Avoiding alcohol and high-fat diets — Several studies have shown a correlation between high-fat diets (60% fat or higher) and significantly reduced Akkermansia colonization. Ditto for alcohol consumption.

• Supplementing with probiotics and prebiotics that promote Akkermansia growth in the gut — Specific examples include Lactobacillus rhamnosus, Bifidobacterium animalis, Lactococcus lactis (probiotics), and oral fructo-oligosaccharides (oligofructose or FOS, a common prebiotic).