Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 5 • September 2012


APPETIZERS

When faced with a problem you do not understand, do any part of it you do understand, then look at it again.
— Robert A. Heinlein, The Moon is a Harsh Mistress, 1966

Nothing uses up alcohol faster than political argument.
— Robert A. Heinlein, The Moon is a Harsh Mistress, 1966

He’s dead, Jim.
— Dr. McCoy, first time said, in Star Trek episode “The Enemy Within,” 1966

Never trust a species that grins all the time. It’s up to something.
— Terry Pratchett [on dolphins], Pyramids, 1989

The researches of many commentators have already thrown much darkness on this subject, and it is probable that, if they continue, we shall soon know nothing at all about it.
— Mark Twain, quoted in
The Sciences, Sept.-Oct. 1989


HYDROGEN THERAPY UPDATE

We continue here our series on the emerging new area of the use of hydrogen as a therapy for diseases associated with oxidative stress and inflammation. We refer you to our original article “Hydrogen Therapy” (see June issue of Life Enhancement) in which we describe mechanisms that may explain how hydrogen works, as has been reported in scientific and clinical studies, to provide beneficial effects in ischemia/reperfusion injury (as occurs in heart attacks and strokes), insulin resistance, protection against radiation-induced tissue injury, neuroprotection (as studied in animal models of Parkinson disease and cognitive impairment), atherosclerosis, and others.

Hydrogen is a selective antioxidant that protects against the highly toxic hydroxyl radicals and against the potent oxidant peroxynitrite (a natural product of the reaction between superoxide radicals and nitric oxide). Conveniently, hydrogen gas is produced naturally in the gut by certain resident bacteria and diffuses throughout the body, reaching even into mitochondria and crossing the blood-brain barrier, leaving the body largely by exhalation from the lungs (though some of the hydrogen is taken up and used as energy by hydrogen-metabolizing bacteria). Importantly, hydrogen production by those resident gut bacteria that produce hydrogen (as a byproduct of fermentation) can be enhanced by eating appropriate prebiotics (foods for your intestinal microbiota). We feed our microscopic friends two or three times a day.

Hydrogen (In the Form of Hydrogen-Rich Saline) Reported to Attenuate Vascular Dysfunction in Spontaneously Hypertensive Rats

The authors of a new paper1 studied the possible protective effects of hydrogen (administered via hydrogen-rich saline (HRS) that was injected intraperitoneally each morning for 3 months in the experimental animals) on the usual development of hypertension in spontaneously hypertensive rats (SHR).

The rats were 8 week old male SHR and age-matched normotensive Wistar-Kyoto (WKY) rats. The animals were divided into four groups (with 12 animals in each group) and treated for 3 months as follows: WKY treated with saline only (containing no dissolved hydrogen); WKY treated with HRS; SHR treated with saline; and SHR treated with HRS.

Results showed that HRS significantly improved endothelium-mediated vascular relaxation in the hydrogen-rich saline treated SHR as compared to the SHR that received only saline. SHR had increased oxidative stress in aorta (total ROS, superoxide, and peroxynitrite were all significantly higher than in WKY animals), but treatment with HRS resulted in a significant reduction in all of these markers of oxidative stress. Anti-inflammatory effects of HRS were revealed in treated SHR, which had a significant reduction in levels of pro-inflammatory cytokines IL-6 and IL-1 beta in serum and aorta as compared to untreated SHR. HRS also significantly reduced activation of NF-kappaB, a major regulator of inflammation, in aorta of SHR as compared to SHR that did not receive HRS.

Interestingly, mitochondrial dysfunction in SHR (reduced activities of Complex I and III and reduced ATP production) was ameliorated via significantly decreasing ROS production, increasing ATP production, and reducing mitochondrial swelling. These results confirm that hydrogen is able to enter mitochondria to provide protective effects.

The results of this study showed that hydrogen treatment had potent antioxidative and antiinflammatory effects in spontaneously hypertensive rats.

Reference

1. Zheng and Yu. Chronic hydrogen-rich saline treatment attenuates vascular dysfunction in spontaneous hypertensive rats. Biochem Pharmacol 83:1269-77 (2012).

Hydrogen Ameliorates Inflammatory Arthritis in Mice

Another recent study2 reports on the use of hydrogen in cell culture and mouse studies to detect the effects of inflammation induced by LPS (lipopolysaccharide, a bacterial cell wall component that potently induces release of inflammatory components of the immune system such as proinflammatory cytokines) in cells (mouse macrophages) and as a result of intravenous injection of an arthritis-inducing cocktail in five week old female BALB/c Cr Slc mice.

Hydrogen treatment in the cells significantly reduced the nitric oxide release induced by exposure to LPS and the interferon-gamma released as a result of that exposure. Stimulation with LPS/IFN-gamma upregulates expression of pro-inflammatory genes such as the gene expressing iNOS (inducible nitric oxide synthase) and COX2. The authors report “a robust increase in protein expression of iNOS and COX2 at 6 hours after treatment [with LPS], which was markedly suppressed by treatment with hydrogen.”2

The animals receiving treatment with the arthritis-inducing cocktail (a model for human rheumatoid arthritis) were given LPS by injection after introduction of the cocktail to increase the incidence and severity of the response. The animals developed redness and swelling of the hind and front paws, which was alleviated in mice fed with hydrogen-rich water compared to mice receiving ordinary (control) water. The left and right hind paw volume decrease in hydrogen-treated mice was statistically significant only for the left hind paw.

“Taken together, our studies indicate that hydrogen inhibits LPS/IFN-gamma-induced NO [nitric oxide] production through modulation of signal transduction in macrophages and ameliorates inflammatory arthritis in mice, providing the molecular basis for hydrogen effects on inflammation and a functional interaction between two gaseous signaling molecules, NO and molecular hydrogen.”

Reference

2. Itoh et al. Molecular hydrogen inhibits lipopolysaccharide/interferon gamma-induced nitric oxide production through modulation of signal transduction in macrophages. Biochem Biophys Res Commun 411:143-149 (2011).

HYPOTHESIS: Hydrogen Therapy May Be an Effective Treatment for Deadly Aplastic Anemia

A new paper3 has been published by Chinese scientists who propose hydrogen therapy as a way to treat aplastic anemia, a rare bone marrow failure disorder with a high mortality rate. The paper is a hypothesis paper as they have not yet begun trials for treating the disease: “We propose that our study on treating aplastic megaloblasts with hydrogen gas will start as soon as possible.” What they may mean here is “as soon as we get the money.” The paper which was itself funded by a grant from the National Natural Science Foundation of China (No. 30,770,503) appears to be a solicitation for additional funding aimed at the Chinese military.

A comment (not part of the paper) from Beijing Navy General Hospital of Qian Liren said (in our —Thanks, Will — translation from the Chinese): “Hydrogen can also treat the disease? If considered from the perspective of infection, inflammation, toxicity, pathogenesis, may be hydrogen have some therapeutic effect on the disease. But may not be sure, there is no any studies have shown treatment of the disease. The point of view need to study confirms.”

The hypothesis paper was published.3 In it, the authors referred to (with included citations) hydrogen’s antioxidant and antiinflammatory effects as suggesting that it might be effective in treating aplastic anemia. They noted that “[t]he key cellular events in the development of aplastic anemia (AA), are the activation and expansion of T cells, which leads to an autoimmuune response and hypersecretion of inflamatory cytokines such as IFN-g [interferon-gamma] and TNF-alpha [tumor necrosis factor-alpha]. The autoimmune response results in destruction of hematopoietic stem and progenitor cells in the BM [bone marrow] by cytotoxic lymphocyytes … Many studies have suggested … that abnormalities of TNF-alpha and IL-6 [interleukin-6] may play important roles in the pathogenesis of AA. The production of TNF-alpha and IL-6 has been found to be significantly elevated in the AA patients. Elevated TNF-alpha levels may also contribute to bone marrow failure by upregulating the Fas receptors on the progenitor of the cells, which leads to apoptosis [a type of programmed cell death] of the target of hematopoietic precursors and by enhancing production of reactive oxygen free radicals, which are detrimental to progenitors.” (References in the paper have not been shown here.)

The researchers describe currently used treatments for aplastic anemia that include immunosuppression and hematopoietic stem-cell transplantation therapy, noting that they may alleviate the disease but are associated with many adverse effects, such as anaphylaxis, fever, chills, and hives in the case of one drug (ATG) and severe allergic reactions, chest pain, diarrhea, fast or irregular heartbeat, flushing of the face, etc. in the case of cyclosporine, an immunosuppressive drug. “In addition, it is difficult to avoid complications, particularly second malignancies, even with conditioning regimens. Our hypothesis is that hydrogen gas may have a therapeutic effect on aplastic anemia.” “Our hypothesis is based on the theory that hydrogen can selectively reduce hydroxyl and peroxynitrite radicals [sic. peroxynitrite molecules are potent oxidants, but are not radicals] and down-regulate cytokines such as IL-6 and tumour necrosis factor-alpha (TNF-alpha). Free radicals have been suggested to play an important role in aplastic megaloblasts [references provided but deleted here]. The production of TNF-alpha and IL-6 have been found significantly higher in AA patients.”

An earlier paper by a different group of scientists3b found that hydrogen-rich saline treatment in a rat model of amyloid-beta-induced Alzheimer’s disease resulted in a reduction in TNF-alpha, which has been detected at elevated levels (compared to healthy controls) in bone marrow plasma and peripheral blood plasma from patients with aplastic anemia.3c However, this reduction (shown in Fig. 4 graphics in the paper,3b while it may be statistically significant, is very small and, hence, may not be physiologically meaningful. It certainly doesn’t qualify for the authors’ description that “hydrogen-rich saline PREVENTED the elevation of IL-6 and TNF- alpha.” (Emphasis added.) Unfortunately, this is the only paper we’ve seen in which the effect of hydrogen therapy on TNF-alpha was measured. Hence, we conclude that the experimental evidence supporting a potentially therapeutic effect of hydrogen on aplastic anemia is weak. (You have to watch out for scientists competing for limited grant money and for glory, especially in a newly developing area of science, and the tendency arising from these conditions to hype their experimental results.)

In fact, if you do enough very precise measurements, you are likely to find statistically significant changes that may not be physiologically meaningful.

In conclusion, the authors hypothesize that hydrogen gas may provide therapeutic treatment of aplastic anemia with few adverse effects.

Our comments: We do not see any problem in trying hydrogen as a therapy for aplastic anemia but think that the scientific basis as described by the researchers3 for expecting positive results in a trial are weak (though not nonexistent) due to very limited data. We note that the Chinese military is (quite reasonably) concerned about the 30,000 plus atomic bombs still in the hands of the Russian military and no certainty that a state of “peace” between China and Russia will continue indefinitely. Hence, the Chinese military are worried about having to deal with widespread radiation injury and radiation-associated medical conditions such as aplastic anemia, difficult to treat and with a high mortality. Hydrogen therapy is, therefore, of considerable interest as a potential low cost low toxicity treatment that has already been shown to have protective effects against radiation damage in animal studies (probably largely because of its efficacy in detoxifying hydroxyl radicals, the major cause of tissue damage by radiation).

References

3. Qian et al. Hydrogen therapy may be an effective and specific novel treatment for aplastic megaloblasts. Med Sci Monit 18(6):HY19-22 (2012) [in Chinese] [Epub ahead of print] PubMed PMID: 22,648,259.
3b. Li et al. Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res 1328:152-161 (2010).
3c. Schultz and Shahidi. Detection of tumor necrosis factor-alpha in bone marrow plasma and peripheral blood plasma from patients with aplastic anemia,” Am J Hematology 45:32-38 (1994).

U.S. Government Supports Drug Development Against Radiation Sickness

Interestingly, the U.S. government “has launched programs to support the development of medical countermeasures (MCMs) against radiological, nuclear, and other threats.”4 That includes prevention and treatment of radiation poisoning. The National Institute of Allergy & Infectious Diseases (NIAID, a part of the National Institutes of Health) guides the radiation MCM research, while the Biomedical Advanced Research & Development Authority (pronounced “authoriteh,” as per South Park’s Cartman), part of the Dept. of Health & Human Services supports later-stage product development at small firms and university centers. According to an article on the MCM programs that appeared in the 25 June 2012 Chemical & Engineering News (a publication of the American Chemical Society), “[s]uccess is far from ensured. The Food & Drug Administration, which launched its MCM initiative in 2010, has yet to approve a single drug for treating radiation syndrome (ARS).”4

Apparently, the use of hydrogen as a cheap, safe therapy for radiation sickness (a potent scavenger of hydroxyl radicals, the source of most tissue damage from radiation) that is already available4b is not even being considered. Being considered are such treatments as granulocyte-colony-stimulating factor Neupogen and a PEGylated version called Neulasta, both developed and marketed by Amgen (the two drugs have combined annual sales for about $5 billion for use (with antibiotics to attenuate the side effects, which include potent immunosuppression) in the treatment of cancer patients. But to get these drugs approved for radiation sickness will require an immense investment of more money. (The purpose of the government MCM programs is presumably to provide at least some of this money, or else why would anybody bother to become part of the program.) New drugs, such as the encouragingly named AEOL-1050 and GI-ARS, are being studied as candidates for radiation treatment. (For example, Aeolus signed a five-year, up to $118 million contract with BARDA for lung-ARS.) “The BARDA contract [with Aeolus] is designed to produce the data needed for FDA approval under the agency’s ‘animal rule’.”4 That rule allows the drug to be approved for use in people on the basis of studies in two validated animal models, when a drug cannot be tested in people. Aeolus says that its BARDA contract “anticipates a regulatory filing at the start of 2016.” “‘Most of the work done in the first 12 months of the contract was in the chemistry, manufacturing, and controls area,” says the company’s representative, also noting that the company has also met with the FDA to discuss the appropriate animal models.

There is a lot more along the same lines as the examples given above. Over the past five years, the article reports, NIH’s radiation countermeasures program has interacted with more than 130 companies and, in the coming five years, the agency plans to expand its search to more small and large drug companies. Right. Of course, nothing is approved yet, while hydrogen is available, safe, has proven effective in cell culture and animal studies of the prevention of radiation damage and its treatment, and is cheap. Unfortunately for hydrogen, however, its use as a radiation therapy would not support the jobs of (probably) thousands of government bureaucrats in MCMs wielding large sums of money to distribute to their favorite companies.

This use of hydrogen gas is also an unpatentable discovery under U.S. patent law; hence, there is no incentive for any private party to pay for the astronomical FDA approval costs.

Your tax money at work, folks. By the time the government approves treatments for radiation, we’ll all be dead … but probably not from radiation, since hydrogen therapy is already available. See our article on “Hydrogen Therapy” in the June issue of Life Enhancement.

References

4. Thayer. The drugs that may never be used. Chem Eng News 90(26):23–26 (June 25, 2012).
4b. See, for example, Qian et al. Radioprotective effect of hydrogen in cultured cells and mice. Free Radical Res 44(3):275-82 (2010); also, see Chuai et al. Hydrogen-rich saline protects spermatogenesis and hematopoiesis in irradiated BALB/c mice. Med Sci Monit 18(3):BR89–94 (2012).

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