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Why Molecular Hydrogen Is a Superior Antioxidant

STORY AT-A-GLANCE In this interview, repeat guest Tyler LeBaron, MSc., Ph.D., reviews some of the many benefits of molecular hydrogen (H ).

Why Molecular Hydrogen Is a Superior Antioxidant

Perhaps most importantly, molecular hydrogen acts as a selective antioxidant, meaning it doesn't indiscriminately suppress free radicals. It uses your body's own biological systems and feedback loops to identify where and when you're under oxidative stress, and when found, antioxidant genes are stimulated

and key antioxidants are transcribed from your DNA. So, molecular hydrogen is not in and of itself a direct radical-scavenging antioxidant. Rather, it helps your body make its own endogenous antioxidants. This is what makes molecular hydrogen so unique. This is crucial because excessive antioxidants use can be deleterious and molecular hydrogen serves as a redox regulator, so, just like Goldilocks, you get just the right amount, not too much and not too little, which makes your cells very happy.

H Activates Nrf2 Pathway

One of the pathways activated by H when free radicals are present is the Nrf2 pathway. LeBaron explains:

"In your cell you have this protein, Nrf2, and it's attached to Keap1. They'realways attached together. But when you get oxidative stress … it can cleave off.[Oxidative stress] causes the cleaving off of the Nrf2 and the Keap1, and theNrf2 can then diffuse into the nucleus [where] it binds to the ARE, theantioxidant response element of the DNA. [This triggers] the production of allthese endogenous antioxidants — Phase 2 enzymes of detoxification andantioxidation — and there are over 200 of them."

This is one of the primary benefits of molecular hydrogen . It's also what makes molecular hydrogen so useful for such a wide variety of conditions. According to LeBaron, it's been shown to have therapeutic benefits in more than 170 different animal disease models.

"What this means is, for example, there are lots of ways to induce diabetes in ananimal model. Using these different models, we can show molecular hydrogenhas therapeutic effects. And, yes, the Nrf2 in some cases seems to beextremely important. In fact, by using gene knockout or or interfering RNA, youcan blunt the benefits of molecular hydrogen. So, the Nrf2 is very important,"

LeBaron says. 2

Molecular Hydrogen Is an Important Nrf2 Regulator

Sulforaphane, found in broccoli, is another well-studied Nrf2 activator. But in contrast to sulforaphane (as well as other Nrf2 activators), molecular hydrogen does not disturb redox homeostasis within the cell by adding too many antioxidants. Redox homeostasis is when there's a specific balance between reducing and oxidizing reactions within the cell. Homeostasis is what you need for optimal cellular health, and either too many free radicals or too many antioxidants can have detrimental effects. When you add molecular hydrogen to a cell that is already at redox homeostasis, however, there's no increase in Nrf2 or other proteins, so it doesn't accidentally push it out of homeostasis. As explained by LeBaron:

"That's important because we don't want to have reductive stress. If you were toinduce the Nrf2 pathway indiscriminately and just keep it going, that would bereductive stress and that would be problematic.In fact, there are genetic mutations where the Nrf2 is hyperactivated, and thatleads to all sorts of problems. Cancer sometimes can activate the Nrf2 reallystrongly … So what we really are talking about is the regulation of Nrf2.When we administer molecular hydrogen to healthy cells, we don't see changesin the Nrf2 level at the protein level. However, if we were to administer a toxin orsome other stress, that's when we would see that molecular hydrogen was ableto induce the Nrf2 — and many other proteins, not just the Nrf2 — and provide aprotective effect.That is different than anything else out there. And it has this pretreatment effectas well. So, for example, in one study, they administered molecular hydrogeninto a cell culture, and after that, they administered a common environmentaltoxin.The exposure caused a decrease in the antioxidant status. So, you could seemarkers of increased oxidative stress, you could see decrease in superoxidedismutase levels, all these important antioxidants, as well as a decrease inNAD+ to NADH ratio. Having a high ratio is very important, and this stresscaused a reduction in this ratio.However, in the cells that were pretreated with molecular hydrogen, it preventedthose reductions from happening, and it provided a protective effect for 24hours even after the hydrogen gas was out of the cell culture and there was nomolecular hydrogen left. That's because molecular hydrogen works at the genelevel, epigenetically even, modulating proteins, the signaling pathways and thephosphorylation cascades …So, we're not just activating Nrf2. We're regulating its production so it's not toohigh, not too low … [Molecular hydrogen is an] adaptogenic redox regulator,basically …And, we are able to provide a protective effect for, say, 24 hours in this case, asopposed to only when it's present. It's amazing to think that molecular hydrogenis able to change how the genes express themselves so that it's going to havefavorable effects even after it's out of the body."

Considerations When Administering Molecular Hydrogen

While there's no risk of overdosing on molecular hydrogen, intermittent exposure produces the best results. It's also important to get the optimal concentration of H molecules to your cells, at least a concentration of about 10 micromolar or higher at the cellular level. Dose-dependent benefits are seen between 10 micromolar all the way up to 800 micromolar, which is considered the saturation level of molecular hydrogen in water at sea level. The therapeutic dose of regular hydrogen water is 0.5 milligrams per liter (mg/L). Saturation is reached at 1.57 mg/L, but some technologies such as tablets can give much higher levels.

So, when we talk about the "right" and "wrong" ways to take molecular hydrogen, it has to do with the concentration of H that you're getting. For example, the "wrong" way to drink H water might be to take a few sips every few minutes, finishing it in an hour. With each passing minute, the H concentration reduces, leaving you with next to nothing by the time you're finished. You also won't get that approximate 10 micromolar level concentration required to transcribe the DNA to produce your endogenous antioxidants. When using molecular hydrogen tablets, which is my preferred method, the nanobubbles contain hydrogen gas, so once the bubbles are gone, you've lost most of the hydrogen. So, to ensure maximum concentration, you have to drink it as soon as the tablet has dissolved and the water is still cloudy-looking. Hydrogen is the smallest-known molecule in the universe and it has no electrical charge, so it can easily penetrate any cell membrane once in your body. However, it will follow a concentration gradient, so when you drink hydrogen water, it'll go to the stomach first, followed by the intestines and liver before entering your systemic circulation.

"Through Brownian motion and this diffusion gradient, it'll be a passivediffusion, simple diffusion into the cells, where it's going to induce effects,"

LeBaron says.

"So going back to the tablets, the concentration of the hydrogen in the tablets isnot just in dissolved form, but it's in this quasi-suspended, micro-macro nanobubble form that has a lot of hydrogen density, so to speak, in the water.So, it's not going to be as stable. So, absolutely, in that case, you've got to drinkit very, very quickly while it's still cloudy. Otherwise, you're going to lose a highpercentage of the hydrogen …Unfortunately, some hydrogen products do not reach that threshold of 0.5 mg/L.But with the tablets, because so much [hydrogen] is dissolved and a lot of thatis in the suspended or quasi form, you have a very high volume of molecular
hydrogen, which requires you to drink it faster, but you can get these higherdoses of molecular hydrogen."

What to Look for When Buying Molecular Hydrogen

When it comes to buying a high-quality H product, make sure it's certified according to the International Hydrogen Standards Association (IHSA). This is your assurance that the product is truly capable of at least delivering the proper amount of molecular hydrogen. LeBaron explains:

"We published a paper showing how ORP [oxidation-reduction potential] is veryinaccurate, especially if the pH is anything but neutral. So, with the tablets, youmight measure something like 0.5 mg/L when really it's 5 mg/L because of thepH. So, we really can't use ORP-type meters or other methods.It has to be gas chromatography. And IHSA uses the gold standard, gaschromatography, and then does a series of testing for safety and purity and anumber of other things in order to be classified as a product that could berecommended and used in clinical studies."

In the interview, LeBaron also does a quick review on the ideal dosing when using inhaled hydrogen. I've limited my summary to hydrogen water here, as this is the easiest way to get it, and in many cases, drinking hydrogen water is more effective than inhalation. Molecular tablets are also ideal when traveling, as you can simply drop one in a glass of water.

"In certain cases, it's 100 times more effective, just looking at different proteinexpressions, for example,"

LeBaron says.

"But in other scenarios, the inhalationmight be able to work on different pathways, different areas that the drinkingcannot, and so they don't really compete with each other and there could be anadditive or synergistic benefit from them.In the past, I would say most of the research has been done on drinkinghydrogen water in clinical studies, and that's still probably the case, but there
are more and more clinical studies being done now with the inhalation ofmolecular hydrogen that are showing favorable effects."

Molecular Hydrogen Protects Against Radiation Damage

One of the benefits of molecular hydrogen is that it helps protect against radiation damage, including X-rays from medical diagnostics and the gamma rays you're exposed to during fiights. Every time I fiy, I take it just before takeoff, as it takes about an hour before the ARE enzymes are activated and you start producing endogenous antioxidants. Then I take it once every hour for as long as I'm in the air. If you're using tablets, put one tablet in 16 ounces of room temperature water and drink it as soon as it's dissolved. Cold water will make the tablet dissolve slower, so you'll lose some H while waiting for it to fully dissolve. Don't use carbonated water as the carbon dioxide gas will lower the concentration of hydrogen gas that you can have in the water. Alternatively, you could pretreat yourself by taking molecular hydrogen for two or three days beforehand. That way, by the time you're exposed to the radiation, you'll already have a level of built-in protection. If you need a CT scan, consider pretreating yourself for a couple of days and then take another dose about 30 minutes or so directly before the test.

Molecular Hydrogen Helps Ward Off EMF Damage

Molecular hydrogen may also help ward off some of the damage incurred by nonionizing electromagnetic fields (EMF). One theory advanced by Martin Pall, Ph.D., is that the primary danger of EMFs is the mitochondrial damage triggered by peroxynitrites, one of the most damaging types of reactive nitrogen species. Low-frequency microwave radiation activates the voltage-gated calcium channels (VGCCs) in the outer membrane of your cells, causing them to open, thus allowing an

abnormal infiux of calcium ions. This activates nitric oxide, which is a precursor for peroxynitrite.

What we need to do is decrease the excessiveproduction of superoxide or nitric oxide. Then wecould essentially prevent peroxynitrite formation. Andthat's exactly what molecular hydrogen does. ~ TylerLeBaron, MSc, Ph.D.

These potent reactive nitrogen species are associated with an increased level of systemic infiammation and mitochondrial dysfunction and are thought to be a root cause for many of today's chronic diseases. Clearly, limiting your EMF exposure should be your primary strategy, but if for whatever reason you cannot, then you may want to consider taking molecular hydrogen regularly to increase your endogenous antioxidants and limit the damage from peroxynitrite and other oxidative stressors. How does this work? LeBaron explains:

"One of the first studies, published in Nature Medicine in 2007 … found that inaddition to [molecular hydrogen's] ability to reduce hydroxyl radicals, [it could]reduce peroxynitrite. We see a reduction of the peroxynitrite levels, and we alsosee reductions — like in animals and tissue samples — of nitrotyrosine levels,which is a marker of the peroxynitrite as well.Now, calcium signals can induce nitric oxide and activate various NOX enzymesto increase superoxide production, and then you have superoxide and nitricoxide, and they react instantaneously. If they come in contact with each other,they will form peroxynitrite. The only thing that limits how fast they react is therate of diffusion.So, what we need to do is … decrease the excessive production of superoxide ornitric oxide. Then we could essentially prevent peroxynitrite formation. And
that's exactly what molecular hydrogen does.This is really fascinating because if you took other antioxidants and you putthem in the presence of nitric oxide or superoxide, you could scavenge them.They would donate their electrons and neutralize them. That can be good, but itcan also be bad, because your body makes and specifically uses things likesuperoxide to increase mitochondrial biogenesis, or nitric oxide forvasodilation.So, we don't want to just neutralize all of these. Hydrogen [is] selective, and ifyou put molecular hydrogen in the presence of superoxide or nitric oxide, thereis no reaction. They don't have a strong enough oxidizing power for hydrogen toreact, so we don't have to worry about that happening.The question then is, how does hydrogen help with the superoxide and the nitricoxide when their levels are in excess production? That goes to this signalmodulating effect. With superoxide, typically that's from NADPH oxidase or NOXenzymes that can become hyperactivated.Molecular hydrogen has this ability to down-regulate this NOX enzyme, so youend up producing less superoxide in the first place. And, if you have lesssuperoxide, then you're going to make less peroxynitrite.And then, on the other side, when you have nitric oxide production, you havethree main isozymes or enzymes. You have the neuronal nitric oxide synthase(nNOS), endothelial nitric oxide synthase (eNOS) and the inducible nitric oxidesynthase (iNOS). eNOS, that's in the endothelial cells, so typically, that's good.You want more of that, you kind of lose that as you get older.Incidentally enough, on a side note, molecular hydrogen can actually improveeNOS. So, we can have better blood perfusion and things in this way.But the iNOS, specifically from macrophages, can be problematic. And hydrogenhas this ability to down-regulate the activity of iNOS, of making this excessivenitric oxide production. So now you're decreasing superoxide and nitric oxidelevels, and consequently you get less peroxynitrite."

How Molecular Hydrogen Can Optimize Exercise Performance

Molecular hydrogen can also be used to boost exercise endurance. LeBaron published a paper on this in the Canadian Journal of Physiology and Pharmacology a few years ago . There are also several others, including a systematic review and meta-analysis, that detail its favorable effects. As explained by LeBaron, it can help you push yourself harder, improve blood fiow and reduce fatigue.

"One of the earliest studies found [molecular hydrogen could] prevent fatigueduring a maximal isokinetic knee extension exercise. Isokinetic just meanssame speed, so you're on a machine and you're just doing these leg extensions.I think they did 50 in a row, and you just do them as hard as you can.The group that took molecular hydrogen was able to maintain a higher forceoutput during those 50 maximal isokinetic knee extensions. Also, they looked atexercising at around 70% your VO2 max, which is about close 70% of your maxheart rate, and those who were doing this were able to exercise longer [and] hadlower levels of lactate …One interpretation is that molecular hydrogen may have improved the functionof the mitochondria … Now, if we're getting our ATP production from themitochondria using aerobic respiration, then we don't have to go through theanaerobic pathway of making lactate.So that's … why we're seeing lactate decrease; we're able to use themitochondria to make ATP, so now we can exercise better, longer and have lessfatigue, especially the perceived exertion.There are also explanations in terms of lactate clearance and accelerating theCori cycle and different things. But mitochondrial bioenergetics are probably amajor target of molecular hydrogen …[It's also] protective, because when you exercise, you breathe a lot more andthat's going to make more free radicals. A lot of those free radicals are going tobe very good for your body because it's going to force you to make moreantioxidants, it's going to increase mitochondrial bioenergetics and all this stuff,but you're still causing damage.You're still damaging DNA. With molecular hydrogen, you can negate or reducethe damaging effects of exercise while not inhibiting the benefits of exercise,and in fact, maybe even potentiating the benefits of exercises. This is the ideathat hydrogen in some ways can act as an exercise mimetic. Not in the truesense, but maybe it's a pseudo mimetic because it can activate some of thesame metabolic pathways that exercise does.And, in this case, it can maybe potentiate those benefits of exercise. Thenagain, to compare that to conventional antioxidants … taking high doseantioxidants can negate the benefits of exercise training.Normally, with exercise you have improved insulin sensitivity, your glucoselevels go down, you have better antioxidant status. Taking high levels ofsynthetic antioxidants can completely negate those benefits. So, again,hydrogen is superior because it doesn't do that."

How Molecular Hydrogen Rejuvenates Your Mitochondria

Interestingly, molecular hydrogen also induces heat shock protein responses , thereby mimicking some of the benefits of sauna therapy. One of the most important benefits of heat shock proteins is that they help refold misfolded proteins that no longer work properly and facilitates their removal if they can't be properly refolded. Some of LeBaron's colleagues in Japan investigated this, showing molecular hydrogen is able to induce mtUPR, the mitochondrial unfolded protein response, which is thought to promote rejuvenation of the mitochondria. Molecular hydrogen has also been shown to upregulate collagen biosynthesis, which is important both for youthfulness and post- injury healing.

More Information

So, to recap, the reason molecular hydrogen can have such diverse benefits in so many different disease models is because, essentially, all of them have excessive oxidative stress, redox dysregulation and infiammation as their root cause. By regulating the oxidative pathways, molecular hydrogen can address these root causes. It's also selective and doesn't create reductive stress by avoiding making excessive antioxidants if your body doesn't need them. For these reasons, it's my absolute favorite antioxidant and, I believe, the best option for most. One potential contraindication would be if you have small intestinal bowel overgrowth (SIBO), as, theoretically, those bacteria may feed on the hydrogen. This has not been confirmed, but it's a theoretical possibility. So, if you have SIBO, carefully evaluate how you feel after taking it. If you want to take a deep dive into the science and application of molecular hydrogen, check out LeBaron's courses, available at . The institute offers four levels of certification, plus an apprentice course, but you don't have to be a health professional to take them.

"These courses are specifically designed to eradicate a lot of themisinformation, get the correct information out and allow you to think abouthow to use molecular hydrogen the best, how to optimize it and so on. So I thinkpeople are going to really like them,"

he says.

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