Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 4 • August 2012


The invention of M. de Montgolfier has given such a shock to the French that it has restored vigor to the aged, imagination to the peasants and constancy to our women.

— A witticism of the first manned balloon flight (Paris, Nov. 21, 1783) reported by Simon Schama (FASEB J, May 2012)

(D&S: Sounds like something France could really use today, at least with respect to restoring vigor to the aged and imagination to its inhabitants.)

“Hydrogen Therapy” Update

Here we continue our ongoing series in which we follow the development of an emerging field of medical therapy in which hydrogen is used to treat diseases, especially those linked to oxidative stress or inflammation. The hydrogen is administered by being inhaled as gas, consumed in hydrogen dissolved in water or saline, or—the way we use it—by eating certain prebiotic foods that stimulate particular gut bacteria to produce hydrogen that circulates throughout the body, eventually being excreted by exhalation through the lungs. A growing number of studies involving animals or humans have shown promise for this simple to use and nontoxic treatment for such conditions as metabolic syndrome (diabetes), ischemia-reperfusion injury (as occurs in heart attacks and strokes), protection against radiation, cognitive impairment in senescence-accelerated mice, atherosclerosis in mouse models of the disease, hemorrhagic strokes, and protection against the development of Parkinson’s disease in animal models, to name some of the published research.

For those who want to read our initial introduction to this new, interesting field of medicine, you can access our article “Hydrogen Therapy” [See article in the June issue of Life Enhancement]. Briefly, hydrogen is a potent but selective antioxidant that scavenges the highly toxic hydroxyl radical (for which it is widely believed that there is no known endogenous protective mechanism) and peroxynitrite, a powerful oxidant that is created by the chemical combination of nitric oxide and superoxide in the body. Hydrogen has little effect, however, on reactive oxygen species such as superoxide and hydrogen peroxide that are important (at low concentrations) as signaling molecules; to scavenge these may not be desirable yet can occur when targeted by most antioxidants that cannot discriminate between different ROS.

Another advantage of hydrogen as an antioxidant is that it easily passes through membranes, reaches all tissues, and enters mitochondria where most of the reactive oxygen species are created and often escape control. Many antioxidants cannot easily enter mitochondria and do not provide much if any protection there. For that reason, there are scientists working on mitochondria-targeted antioxidants specifically for the purpose of overcoming this limitation. Hydrogen, however, is an antioxidant that is already able to enter mitochondria.

Incredibly, in a paper* new to us (though pretty old, having been published in 1969), the author notes that “[t]he presence of a high concentration of hydrogen (H2) in human flatus was first reported over 100 years ago.”**

Hydrogen Improves Obesity and Diabetes by Inducing FGF21 and Stimulating Energy Metabolism in Mice

A particularly interesting recent study in the field of hydrogen therapy is the one we describe here. Though this published paper1 appeared only last year, it represents early work in the attempt by scientists to discover mechanisms (other than its antioxidant and antiinflammatory effects) to explain hydrogen’s therapeutic benefits. It is the first paper that we know of reporting that hydrogen induces fibroblast growth factor 21 (FGF21) in db/db mice (obese because they lack leptin receptors) which, if verified, would be very exciting because FGF21 has been found to regulate energy metabolism. In rodents and rhesus monkeys with diet-induced or genetic obesity and diabetes, for example, systemic administration of FGF21 has been found to exert strong antihyperlipidemic and triglyceride- lowering effects and leads to body weight reduction.2

The researchers,1 knowing that oxidative stress is a major causative factor in diabetes, studed whether hydrogen (administered by dissolving hydrogen in the animals’ drinking water) might be beneficial in an animal model of diabetes, the db/db mouse which lacks leptin receptors. The mice were divided into three groups: the first group could drink water without hydrogen ad lib, the second group received drinking water 100% saturated in dissolved hydrogen (0.8 mmol/l) and the third group received drinking water with 10% of the saturated level of dissolved hydrogen (0.08 mmol/l). The mice in the third group began the experimental regimen at 6 weeks of age. The mice drinking the water with 10% or 100% saturated with hydrogen had modest but significant reductions in body weights at 18 weeks of age as compared with the controls (drinking water containing no hydrogen). Body fat was also substantially lower in the mice consuming water 100% saturated with hydrogen. The authors reasoned that, “[s]ince the consumed amounts and volumes of diet and water did not differ among groups, it is suggested that H2 [hydrogen] consumption stimulates energy metabolism to suppress the gain of fat and body weights.”1

The researchers further found that plasma levels of glucose and insulin were significantly reduced in the 100% hydrogen in water administered group and triglycerides were reduced in both the 100% and 10% hydrogen in water-administered groups. The authors examined the effects of genes involved in the regulation of gluconeo­genesis and found that FGF21, which contributes to the regulation of energy metabolism, had increased mRNA expression in the liver after hydrogen administration. Thus, the authors conclude, “the induction of hepatic [liver] FGF21 contributes to the lowering effect on plasma glucose and triglyceride levels.” Moreover, they found that the “H2-drinking db/db mice consumed more O2, 10%, and produced more CO2, 10%, than db/db mice without H2-water during both night and day.” This suggests that hydrogen consumption stimulated energy metabolism in the mice.

As we noted at the start, these are newly reported findings and we certainly hope to see follow up that attempts to replicate and extend this work. As we mentioned, FGF21 is a potent metabolic regulator, which has been reported to activate AMPK (a major metabolic energy sensor and master regulator of metabolic homeostasis) and SIRT1 (a putative longevity gene), in adipocytes (fat cells) that results in enhanced mitochondrial oxidative function (as indicated by increased oxygen consumption).2

FGF21 is also reported to regulate the activity of PPARgamma, which is the key mediator of the physiologic and pharmacologic actions of thiazolidinediones (a major class of antidiabetic drugs, such as Pioglitazone).3 In a commentary4 accompanying a very recent paper, new data were described suggesting that FGF21 promotes the “browning” of white fat (i.e., inducing white fat to take on the properties of thermogenic brown fat) by enhancing “PPARgamma coactivator 1alpha activity, potentially through inducing its post-translational modifications.”4 The commentary to the paper4 notes that “circulating FGF21 concentration also increases in overweight patients with various features of the metabolic syndrome, potentially hinting at the existence of an obesity-induced FGF-21 resistant state,”(see also 4b,4c) although the authors point out that this hypothetical FGF-21 resistant state is debated.

Improved Outcome in Hemorrhagic Strokes in Mice Inhaling Hydrogen Gas

Two recent papers describe the results of short periods of inhaling hydrogen gas in mouse models of hemorrhagic stroke. In the first paper,5 an intracerebral hemorrhage (ICH) was induced by injecting bacterial collagenase into the right basal ganglia of anesthetized CD1 male mice. As expected, the mice had brain edema and impaired functional performance. The 30 animals were divided into controls (which breathed room air), a group treated with hydrogen inhalation for one hour and then tested at 24 hours after ICH for neurological deficits (including tests for beam balance and wire hanging) and brain edema, and a group treated with 2 hours of hydrogen inhalation and tested at 72 hours after ICH for the same parameters.

Hydrogen leaves the body rapidly, mostly via exhalation through the lungs. Hence, a one hour or even two hour inhalation of hydrogen would not be around very long. It is remarkable to us that they found improvements in the experimental animals: ICH caused a significant increase in water content (edema) of the ipsilateral basal ganglia of all collagenase-injected animals. one hour of hydrogen inhalation resulted in a significant decrease in brain water content vs. room air treated animals, while the animals that had two hours of hydrogen inhalation showed no significant effect on brain water content (the authors offered no explanation for this discrepancy, but the small numbers of animals in the study may have been responsible). At 72 hours, the animals treated with one hour of hydrogen inhalation showed only a tendency (that is, the difference was not statistically significant) towards reducing brain water content. Similarly, the one hour hydrogen inhalation resulted in attenuation of the ICH-induced neurological deficits when measured at 24 hours after ICH, but showed only a tendency (not statistically significant) toward an improvement in the animals breathing hydrogen for two hours and examined at 72 hours.

In the other study,6 researchers conducted a similar experiment, this time with 137 adult male Sprague-Dawley rats. The scientists in the second study6 included one of the same authors, John H. Zhang, of the other study;5 it was a year later and Dr. Zhang had apparently become the director of the lab during that period. The rats had subarachnoid hemorrhages induced by endovascular perforation while under general anesthesia. The animals breathed 2.9% hydrogen gas for two hours after perforation. Brain edema and blood-brain barrier disruption that resulted from the hemorrhage was significantly improved at 24 hours but not at 72 hours. They also observed amelioration of oxidative stress injury in lipids, proteins, and DNA. After seeing the results of their first study, you have to wonder why they did not increase the period of time during which the animals were breathing hydrogen. As it is, they did two very similar experiments and got about the same result, very short term improvements.

References

* Levitt. Production and excretion of hydrogen gas in man. NEJM 281(3):122-127 (1969)
** Ruge E. Beitrage, zur Kenntniss der Darmgase, Chem Zentrabl 7:347-351 (1862).
1. Kamimura et al. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity 19(7):1396-1403 (2011).
2. Chau et al. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci USA 107(28):12553-8 (2010).
3. Dutchak et al. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones. Cell 148:556-67 (2012).
4. Canto and Auwerx. FGF21 takes a fat bite. Science 336:675-6 (2012).
4b. Fisher et al. Obesity is an FGF21 resistant state. Diabetes 59:2781-9 (2010).
4c. Domouzoglou and Maratos-Flier. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr 93(suppl):901S-5S (2011).
5. Manaenko et al. Hydrogen inhalation is neuroprotective and improves functional outcomes in mice after intracerebral hemorrhage. In: Zhang and Colohan, eds. Intracerebral Hemorrhage Research, Acta Neurochinurgica Supplementum, Vol. 111, Springer-Verlag/Wien 2011 DOI: 10.1007/978-3-7091-0693-8_30
6. Zhan et al. Hydrogen gas ameliorates oxidative stress in early brain injury after subarachnoid hemorrhage in rats. Crit Care Med 40(4):1-6 (2012).

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