Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 3 • June/July 2012


The more corrupt the State the more numerous the laws.
— Cornelius Tacitus

To have a license number of one’s automobile as low as possible is a social advantage in America.
— Andre Mauros

(D&S: This is true. Local police tend to respond to lower numbers as indicative of higher-status local residents.)

So much of left-wing thought is a kind of playing with fire by people who don’t even know that fire is hot.
— George Orwell

Wealth is not without its advantages and the case to the contrary, although it has often been made, has never proved widely persuasive.
— John Kenneth Galbraith, The Affluent Society

A common mistake that people make when trying to design something completely fool-proof is to underestimate the ingenuity of complete fools.
— Douglas Adams
The Hitchhiker’s Guide to the Galaxy

More on the Developing Field of Hydrogen Therapy

We wrote a long paper [see “Hydrogen Therapy” in the June issue] on the exciting new research being published on hydrogen therapy, in which hydrogen acts as a highly selective antioxidant that particularly targets hydroxyl radicals and less efficiently the potent oxidant peroxynitrite (that forms from the chemical reaction between superoxide and nitric oxide). Moreover, and of particular importance, hydrogen is able to move rapidly throughout the body and is able to penetrate mitochondria, which are the source of much of the ROS (reactive oxygen species) that plays a key role in many diseases resulting from increased oxidative stress, such as diabetes, cardiovascular disease, cancer, and aging. Interestingly, most antioxidants are not able to penetrate mitochondria or do so poorly, so that mitochondria (which do not have a very effective antioxidant defense system and are, therefore, vulnerable to oxidative damage) cannot be easily protected by supplemental antioxidants. Indeed, lifespan studies using antioxidants have not generally been very successful in increasing maximum lifespan and it is suspected that this is due to most antioxidants not being able to get into mitochondria very well.1

As we explained in our paper, some researchers are trying to develop mitochondria-targeted antioxidants to overcome the problem of limited ability of most antioxidants to get into mitochondria.

As noted in some of the papers we reviewed for “Hydrogen Therapy,” hydrogen has been administered in animal studies and/or human clinical trials by inhaling it, by consuming it as hydrogen enriched saline or hydrogen dissolved in water or (and this was of particular interest to us) by consuming certain prebiotics (carbohydrates that are not fully absorbed in the upper digestive tract and, therefore, reach the lower digestive tract) to increase hydrogen gas production by resident intestinal bacteria. The hydrogen gas produced by the resident intestinal bacteria (you need a little help from your friends) reaches virtually all body tissues, including mitochondria, ultimately being exhaled from the lungs.

Here we report on four very recent papers that describe new developments in hydrogen therapy. We just downloaded the paper on molecular hydrogen and radiation protection2 today (May 13, 2012) from the Informa Healthcare website.

Molecular Hydrogen and Radiation Protection

This new paper2 describes work on radioprotective potential of hydrogen. The authors showed that in HIEC cells pretreated with hydrogen and then irradiated, cell survival fractions were increased by hydrogen treatment but that treating cells with hydrogen AFTER they were irradiated resulted in no significant protection. In another experiment, the authors examined the radioprotective effects of hydrogen in an animal study on testis; hydrogen was administered by intraperitoneal injection in C57BL/6 mice. “H2-rich saline significantly reduced the testicular fluorescence intensity in irradiated C57BL/6 mice. However, when we treated these mice with the hydroxyphenyl fluorescein peroxidized by hydroxyl radicals the intensity did not decrease, supporting that H2 directly reduced hydroxyl radicals.”2 Moreover, additional studies by the authors on the late radiation damage in cardiac myocytes (heart muscle cells) and pulmonary alveoli showed that pretreatment with H2 significantly suppressed the radiation-induced fibrosis.

The authors also describe a randomized, placebo-controlled human study done by others that found consumption of hydrogen to improve the quality of life of patients treated with radiotherapy for liver tumors, while no differences in tumor response to radiotherapy as a result of hydrogen therapy were observed.

The paper2 also described the process by which colonic bacteria in the human body under physiological conditions produce hydrogen (H2) gas (approximately 12 liters of hydrogen per day),* with the amounts possibly reaching the concentration required to exert selective antioxidant effects. For that reason, the authors suggest that some of the side effects of systemic antibiotics “are related to suppression of intestinal bacteria which generate the endogenous H2.” The authors also mention that “[s]ome reports showed that up-regulation of the ‘endogenous H2’ [the H2 produced by the resident colonic bacteria] could be a strategy for [treating] diseases.”


* This is 1 gram or 1/2 mole of hydrogen per day. (Not everybody produces this much.) This amount is enough hydrogen to saturate over 500 kg of water. See www.engineeringtoolbox.com


The authors explain that they found only 3 researches that tested molecular H2 not as an antioxidant but for other possible mechanisms. Itoh et al was reported to suggest for the first time that H2 may become a gaseous signaling molecule like nitric oxide, carbon monoxide, and hydrogen sulfide. The Itoh group showed that H2 suppressed FcepsilonR1-associated signal transduction and prevented degranulation of mast cells, but not through the reduction of hydroxyl radicals;2b they also demonstrated that H2 inhibited lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in the macrophage.2c Of particular interest, a paper was cited by the authors3 that reported an assay of DNA microarrays in the livers of rats after 4 weeks of drinking hydrogen-enriched water that found 548 upregulated genes and 695 downregulated genes; of those, genes for oxidoreduction-related proteins were enriched in the up-regulated groups. Consequently, we see that some progress is being made in an attempt to track down mechanisms other than the scavenging of hydroxyl radicals and peroxynitrite to explain the effects of hydrogen therapy. This study2 of radioprotection and hydrogen was supported by a grant from the National Natural Science Foundation of China, presumably a government entity. In fact, considering the affiliation of the corresponding author, Dr. Jianming Cai, who is at the Dept. of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University in Shanghai, China, the study appears to have been supported by the Chinese military.

References

1. See, for example, Miquel. Can antioxidant diet supplementation protect against age-related mitochondrial damage? Ann N Y Acad Sci 959:508-516 (2002).
2. Chuai, Sun, and Cai. Molecular hydrogen and radiation protection. 10.3109/10715762.2012.689429.
2b. Itoh et al. Molecular hydrogen suppresses FcepsilonRI-mediated signal transduction and prevents degranulation of mast cells. Biochem Biophys Res Commun 389(4):651-6 (2009).
2c. Itoh et al. Molecular hydrogen inhibits lipopolysaccharide/interferon γ-induced nitric oxide production through modulation of signal transduction in macrophages. Biochem Biophys Res Commun 411(1):143-9 (2011).
3. Nakai et al. Hepatic oxidoreduction-related genes are upregulated by administration of hydrogen-saturated drinking water. Biosci Biotechnol Biochem 75:774-776 (2011).

Human Study Finds that Drinking Hydrogen-Rich Water Can Protect Against Exercise-Induced Muscle Fatigue in Elite Athletes

Researchers investigated the potential protective effects of hydrogen-rich water against oxidative stress and muscle fatigue in response to acute exercise.

The subjects of the study4 were ten young (20.9 ± 1.3 years old) male soccer players. They were studied in a cross-over design (where they received either HW (hydrogen-rich water) or PW (placebo water) for one week intervals. The subjects were “requested” (presumably there was no test for compliance) to use a cycle ergometer at a 75% maximal oxygen uptake for 30 minutes, followed by measurement of peak torque and muscle activity throughout 100 repetitions of maximal isokinetic knee extension, during which oxidative stress and creatine kinase in the peripheral blood were sequentially measured.

The results showed that: “Although acute exercise resulted in an increase in blood lactate levels in the subjects given PW, oral intake of HW prevented an elevation of blood lactate [as occurs during muscle fatigue] during heavy exercise. Peak torque of PW significantly decreased during maximal isokinetic knee extension, suggesting muscle fatigue, but peak torque of HW didn’t decrease at early phase. There was no significant change in blood oxidative injury markers … or creatine kinase after exercise.”4

The authors therefore conclude: “Adequate hydration with hydrogen-rich water pre-exercise reduced blood lactate levels and improved exercise-induced decline of muscle function.” We note that increased availability of hydrogen via fermentation by intestinal microbiota wouldn’t, unlike hydrogen in water, provide water for hydration (e.g., protection against dehydration, which can be important in athletes doing vigorous exercise), but water for hydration can be easily obtained and consumed — it is the hydrogen that requires a special source.

4. Aoki et al, “Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes,” Med Gas Res 2:12 (2012) doi:10.1186/2045-9912-2-12URL: http://www.medicalgasresearch.com/content/2/1/12.

Review Paper: Data on Protective Effects of Hydrogen in Brain Trauma, Stroke and Neonatal Hypoxia-Ischemia

A 2012 paper5 provides a summary of findings of recent preclinical studies on hydrogen administration, either via gas inhalation or ingestion in water, in treatment for neurological disorders including traumatic brain injury, surgically induced brain injury, stroke, and neonatal hypoxic-ischemic insult. The authors note that “[m]ost reviewed studies demonstrated neuroprotective effects of hydrogen administration. Even though antioxidative potentials have been reported in several studies, further neuroprotective mechanisms of hydrogen therapy remain to be elucidated. Hydrogen may serve as an adjunct treatment for neurological disorders.”

Rather naively, we think, the authors note: “Currently, to our knowledge, there are no FDA approved therapeutic regimens involving hydrogen gas or dissolved hydrogen.” Considering the immense expense for getting FDA approval (currently estimated at about $3 billion or more for a prescription drug) it is unlikely that anybody will seek such approval. Even if FDA approval as a medical device, generally much less expensive than for prescription drugs, were to be sought, however, the federal government has imposed a special new medical devices tax that is going to impose extra costs on manufacturers of medical devices in America; worse yet, however, because there is a chemical component of hydrogen therapy, another new regulation (decreed by FDA despite Congressional statutory wording that precludes it* will require that hydrogen therapy via gas or dissolved hydrogen be deemed a drug.


* The reason for this is that agencies have been able to get extremely broad deference from the courts for nearly any interpretation the agency wants to attach to a Congressional statute. Lots of dysfunctional agency rules are thus largely the result of two failures: the failure of Congress to oversee the rules devised by regulatory agencies pursuant to Congressional statute and the failure of courts to strike down rules created by regulatory agencies in the absence of Congressional authority and when they deviate significantly from the clear wording of a statute.


The good news, though, is that the FDA has no authority beyond regulating health and safety to limit marketing of prebiotics, food carbohydrates such as long chain fructooligosaccharides that reach the lower digestive tract and provide food for certain gut microbiota to ferment, producing hydrogen gas and short chain fatty acids. Tough luck, FDA! (Of course, the agency will still attempt to prohibit the communication of truthful information on labels or ads on the health effects of hydrogen produced by gut microbes, since FDA deems information on the prevention or treatment of disease to turn a food into a drug. Still, the information will get around. It just takes longer.)

Some of the nine animal studies that examined neuroprotection by hydrogen that were reviewed here4 were reviewed in our “Hydrogen Therapy” [see “Hydrogen Therapy” in the June issue]. In all, the new review provided 37 references. We got and read one of the papers6 cited in the review on the effects of hydrogen on mitochondrial dysfunction that we had not seen before and review it below briefly.

Hydrogen May Protect Against Diseases Resulting from Mitochondrial Dysfunction

We are particularly interested in new work revealing effects of hydrogen on mitochondrial dysfunction. A recent paper6 on hydrogen therapy in a small sample of patients with mitochondrial and inflammatory myopathies (muscle disorders) provided some data. The researchers performed an open-label (no blinding) trial of drinking 1.0 liter per day of hydrogen-enriched water for 12 weeks in five patients with progressive muscular dystrophy (PMD), four patients with polymyositis/der­ma­to­my­o­si­tis (PM/DM), and five patients with mitochondrial myopathies (MM, muscle disorders due to mitochondrial dysfunction). The researchers also conducted a randomized, double-blind, placebo controlled, crossover trial of 0.5 liter per day of hydrogen enriched water or placebo water for 8 weeks in 10 patients with DM and 12 patients with MM.

These were very small, short-term trials. In the open-label trial, hydrogen-enriched water was found to improve mitochondrial function in MM and inflammatory processes in PM/DM as measured by significant effects on lactate-to-pyruvate ratios in PMD and MM, fasting blood glucose in PMD, serum matrix metalloproteinase-3 (MMP-3) in PM/DM and serum triglycerides in PM/DM. No objective improvement or worsening of symptoms of the disorders was observed.

In the double-blind trial, the researchers observed significant improvements in lactate levels in MM. They also reported favorable responses in lactate-to-pyruvate ratios in MM and MMP3 in DM but these changes were not significant. As in the open-label trial, there were no objective improvement or worsening of symptoms of the disorders observed. In one insulin-treated MELAS (a type of MM) patient, there was a hypoglycemic episode, which subsided by reducing the insulin dose.

A few comments: These are very preliminary works. As the authors note: “[s]mall numbers of participants in both the open-label and double-blind studies might have failed to disclose statistical significant effects of HEW [hydrogen enriched water].”6 In MM, mitochondrial DNA mutations cause defective mETS (mitochondrial electron transfer system). “Thus, lactate and L/P ratio are useful surrogate markers to estimate functions of mETS, and are usually abnormally elevated in MM.”6 Also, a limitation in the open-label study was that drinking of 1.0 liter of hydrogen enriched water (HEW) was difficult for most myopathic patients, which was the reason for decreasing the amount of HEW to 0.5 liters in the double-blind studies. The authors note that hydrogen doesn’t show simple dose-response relationships in rodents, and ad lib administration of even 5%-saturated HEW significantly attenuated development of Parkinson’s disease in a mouse study. Having to drink a lot of HEW wouldn’t be a problem with hydrogen derived from the activities of gut microbiota.

Here we see what it takes to begin to develop a new area of medical science especially during a period of economic decline when scientific funding is difficult to find. Fortunately, the selective antioxidant effects of hydrogen and its ability to penetrate into tissues including mitochondria, combined with the inexpensiveness of ingesting a prebiotic for the gut microbiota to use in generating additional hydrogen makes this a low risk and low cost method for people who want to try hydrogen for mitochondrial and/or inflammatory disorders. No prescription required!

5. Eckermann et al. Potential application of hydrogen in traumatic and surgical brain injury, stroke, and neonatal hypoxia-ischemia. Med Gas Res 2:11 (2012). doi:10.1186/2045-9912-2-11URL: http://www.medicalgasresearch.com/content/2/1/11 http://www.medicalgasresearch.com/content/2/1/11.
Ito et al. Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Med Gas Res 1:24 (2011) http://www.medicalgasresearch.com/content/1/1/24.

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