In supplemental trigger-form …

Hydrogen Slows Aging
By disarming the hydroxyl radical
and the potent oxidant peroxynitrite

By Will Block

CONTINUED FROM PART I


A low concentration of hydrogen in
drinking water of experimental mice
reduced oxidative stress induced by
the toxin and significantly decreased
a marker of DNA damage, and a
marker of lipid peroxidation, as
compared to controls.


Hydrogen Protects Against Dopaminergic Cell Loss

Parkinson’s disease model rodents were “treated” with a toxin that induces a Parkinson’s disease-like condition by damaging or killing dopaminergic neurons in the nigrostriatal area of the brain. (Fujita, 2009)

The study reported that a low concentration of hydrogen in drinking water of experimental mice reduced oxidative stress induced by the toxin and significantly decreased a marker of DNA damage, and a marker of lipid peroxidation, as compared to controls.

The researchers reported that “[t]he effects of H2 water were dose-dependent, with a maximal effect at a much lower concentration (0.08 ppm) than saturated concentration of H2 (1.5 ppm).” (Emphasis added.)


“[T]he effects of H2 water were
dose-dependent …”


Hydrogen Protects Against Parkinson’s Disease

In another study, nigrostriatal degeneration was induced by the neurotoxin 6-hydroxydopamine in Parkinson’s disease model rats. (Fu, 2009)

Researchers found hydrogen in water (~50% saturated) prevented both the development and progression of nigrostriatal degeneration as compared to rats’ drinking water containing no dissolved hydrogen gas.

The researchers found protective effects of both pre- and post-treatment of the neurotoxin-exposed rats to prevent dopaminergic cell loss.

Breath Hydrogen Correlated with Satiety

In another study, researchers examined the effect of including indigestible carbohydrates in the evening meal of healthy human subjects on glucose tolerance, inflammatory markers, and satiety in the next day’s breakfast. (Nilsson, 2008)

Breath hydrogen was measured as an indicator of fermentation of indigestible carbohydrates by colonic bacteria. Furthermore, the researchers found that fewer calories were eaten.

Determining Normal Flatus Production

There have been studies (though not many) on the normal production of flatus in humans.

In one such study, scientists report that on a fiber-free diet (a liquid diet that contained no complex polysaccharides), hydrogen was almost absent from the flatus as compared to their normal diet—less than 3% of the amount produced on their normal diets. (Tomlin, 1991)


Researchers found hydrogen in water
(~50% saturated) prevented both the
development and progression of
nigrostriatal degeneration.


The production of hydrogen in the gut by resident bacteria may contribute significantly to how dietary fiber provides important health benefits, such as reducing the risk of colon cancer and cardiovascular disease.


Fewer calories were eaten.


Calculating Total Flatus I

To measure flatus, a study was conducted with five men and five women, all healthy, aged 19-25 years. (Tomlin, 1991)

Flatus gas was collected by means of a flexible gas impermeable rubber tube held in place with surgical tape or the subject’s underwear. The other end of the tube was connected to a plastic T-connector that was attached to a laminated gas bag impermeable to gas diffusion.

The patency of the gas collection device was determined by having two volunteers wearing the device and having the lower parts of their bodies submerged in warm water for an hour during which time observers checked for leaks (bubbling) and that gas was collected in the bags.

Calculating Total Flatus II

Gas was collected separately overnight, for the fiber-free liquid diet, as well as for a 24-hour period following test meals consisting of 200 g of baked beans in tomato sauce.


The patency of the gas collection
device was determined by having two
volunteers wearing the device and
having the lower parts of their bodies
submerged in warm water for an
hour during which time observers
checked for leaks (bubbling) and that
gas was collected in the bags.


Detailed instructions (which we will not go into here) were given to subjects as to how to proceed when they needed to defecate. The authors note that the liquid diet was sipped through a straw, resulting in some air swallowing, another complication of the determination.

And so, in this way, the scientists got measurements for the production of flatus by healthy young people. Of course, it could all be done again (not with the same subjects, of course) for getting measurements of flatus produced by subjects consuming inulin-containing diets. (Tomlin, 1991)

Another simpler way to determine how much hydrogen is generated by colon bacteria is to measure breath hydrogen, as the hydrogen generated in the colon is eventually mostly excreted from the body in the lungs. You would still need to account for hydrogen taken up by gut bacteria for their own use. As the authors note, slower passage of gas through the colon allows more time for bacterial use of fermentation gases.

Protection by Hydrogen Against Radiation

The damage caused by radiation is largely a result of hydroxyl radicals and hydrogen is a potent scavenger of hydroxyl radicals.

Studies have reported protection by hydrogen against radiation injury.

One study explained that “[t]he gastrointestinal tract is one of the most susceptible organs to radiation. As low as 1 Gy [a unit of absorbed radiation] of radiation induces a dramatic increase in apoptosis [programmed cell death] in mouse small intestinal crypt within 3-6 hours after exposure, predominantly in the stem cell region.” (Qian, 2010)

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Hydrogen-rich saline water protected against gamma radiation to cultured lymphocytes and the gastrointestinal tract in mice. Plasma SOD (superoxide dismutase) and GSH (glutathione) concentrations were significantly higher at 12 hours after irradiation in the hydrogen group.

The breakdown product of damaged DNA at 12 hours of irradiation in the hydrogen group was significantly lower compared to controls.

More Radiation Protection

In another radiation study, hydrogen-rich water was tested and found to protect the heart from damage by ionizing radiation in mice. (Qian, 2010) The authors found decreased myocardium degeneration, decreased myo­cardium malondialdehyde, decreased 8-hydroxy­deoxy­guanosine levels, and increased levels of endogenous antioxidants in the mouse hearts.


Hydrogen might be a useful
prophylactic under conditions where
you may be exposed to radiation.


Thus, hydrogen might be a useful prophylactic under conditions where you may be exposed to radiation. However, it is probably NOT a good idea to use hydrogen at the same time you are receiving irradiation therapy for cancer because of the risk that treatment effects (the desired toxicity of the radiation to cancer cells) would be reduced.

Molecular Hydrogen and Radioprotection

A new paper (Chuai, 2012) describes work on radioprotective potential of hydrogen. In human intestinal epithelial 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.


Cell survival fractions were increased
by hydrogen treatment.


The authors also found that when hydrogen was administered by intraperitoneal injection in model mice, testicular injury was inhibited, supporting that H2 directly reduced hydroxyl radicals.


Testicular injury was inhibited.


Moreover, hydrogen protected against radiation fibrotic damage in cardiac myocytes (heart muscle cells) and pulmonary alveoli.

A human study cited by the researchers found consumption of hydrogen improved 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.

How Much Hydrogen is Enough?

The prior paper 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),* the amount possibly reaching the concentration required to exert selective antioxidant effects.


* 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.


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.”

A few papers have tested H2, but not as an antioxidant. Most of the papers investigated other mechanisms, such as its use as a gaseous signaling molecule like NO, CO and H2S.


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.”


A paper was cited that reported an assay of DNA microarrays in the livers of rats after 4 weeks of drinking hydrogen-enriched water. That paper reported 548 upregulated genes and 695 downregulated genes; of those, genes for oxidoreduction-related proteins were enriched in the up-regulated groups. (Nakai, 2011)


Genes for oxidoreduction-related
proteins were enriched in the up-
regulated groups.


Hydrogen Protects Against Exercise-Induced Muscle Fatigue

In another study, ten young male soccer players were given either hydrogen-rich water or placebo water for one-week interval, in a crossover study. (Aoki, 2012) The impact of 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, oxidative stress and creatine kinase in the peripheral blood was measured.

“… peak torque of [hydrogen-rich water] didn’t decrease at early phase. There was no significant change in blood oxidative injury markers...or creatine kinase after exercise.” “Adequate hydration with hydrogen-rich water pre-exercise reduced blood lactate levels and improved exercise-induced decline of muscle function.”

Hydrogen via fermentation by intestinal microbiota wouldn’t (unlike hydrogen in water) provide water for hydration (which has a value during vigorous exercise), but water for hydration can be easily obtained and consumed — it is the hydrogen that requires a special source.

Hydrogen for Brain Trauma, Stroke and Neonatal Hypoxia-Ischemia

A 2012 paper (Eckermann, 2012) 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 … Hydrogen may serve as an adjunct treatment for neurological disorders.”


Most antioxidants are not able to
enter the mitochondria, where much
of the generation of ROS (reactive
oxygen species) takes place. They are
unable to target ROS in
mitochondria, and that mitochondria-
targeted antioxidants are, therefore,
needed.


Hydrogen May Protect Against Mitochondrial Diseases

One of the problems in lifespan studies is that most antioxidants are not able to enter the mitochondria, where much of the generation of ROS (reactive oxygen species) takes place. In fact, proponents of the mitochondrial theory of aging propose that antioxidants have not generally been very effective in lifespan studies precisely because they are unable to target ROS in mitochondria, and that mitochondria-targeted antioxidants are, therefore, needed.

Hydrogen may be a good way to overcome that problem as it easily enters mitochondria.

The use of hydrogen “to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases” was recently proposed. (Ohta, 12012) Patients with mitochondrial disorders treated with hydrogen demonstrated possible improvements.


Hydrogen may be a good way to
overcome that problem as it easily
enters mitochondria.


Hydrogen Enters Mitochondria

Once again, most antioxidants are not able to enter the mitochondria, where much ROS (reactive oxygen species) is generated.


Most antioxidants are not able to
enter the mitochondria, where much
ROS (reactive species) is
generated.


In fact, proponents of the mitochondrial theory of aging (Harman, Part II) propose that antioxidants have not generally been very effective in lifespan studies because they are unable to target ROS in mitochondria and that mitochondria-targeted antioxidants are needed.

Hydrogen may be a good way to overcome that problem as it easily enters mitochondria.

Improved Septic Shock Survival

Multiple organ dysfunction syndrome (MODS) is a disease in which there is progressive deterioration of multiple organs, as occurs in patients with severe sepsis, septic shock, shock, multiple trauma, severe burns, or pancreatitis.


MODS is said to be the leading cause
of death in critically ill patients.


MODS is said to be the leading cause of death in critically ill patients.

In a mouse model of MODS, the mice were given the toxin zymosan, derived from the cell wall of the yeast Saccharomyces cerevisiae, which can lead to life-threatening systemic inflammation. The mice inhaled 2% hydrogen for 60 minutes at 1 and 6 hours.

The 14-day survival rate of the injected mice improved from 10% (no hydrogen treatment) to 70% (hydrogen inhalation).


The 14-day survival rate of the
injected mice improved from 10%
(no hydrogen treatment) to 70%
(hydrogen inhalation).


As well, the zymosan-injected hydrogen-treated mice had significantly reduced damage markers, decreased levels of oxidative products, increased activities of antioxidant enzymes (such as superoxide dismutase), and reduced levels of early and late pro-inflammatory cytokines in serum and in tissue.

Hydrogen Improves Obesity

Hydrogen induces fibroblast growth factor 21 (FGF21) in mice that are obese because they lack leptin receptors. (Chau, 2010)


Hydrogen induces fibroblast growth
factor 21 (FGF21).


FGF21 regulates energy metabolism in several species, where it exerts strong anti-hyperlipidemic and triglyceride-lowering effects and leads to body weight reduction.


FGF21 exerts strong anti-
hyperlipidemic and triglyceride-
lowering effects and leads to body
weight reduction.


Knowing that oxidative stress is a major causative factor in diabetes, researchers gave hydrogen to mice, through drinking water that was 10% or 100% saturated. (Kamimura, 2011)

The researchers reported modest but significant reductions in body weight at 18 weeks of age as compared with the controls.

Body fat was also substantially lower in the mice consuming water that was 100% saturated with hydrogen, as were levels of insulin and glucose. 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.” FGF21 levels were induced, and stimulated energy levels in the mice.


Body fat was also substantially lower.



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Hydrogen Mitochondrial Origination Hypothesis

The hydrogen hypothesis is a model that describes a possible way in which the mitochondrion arose as an endosymbiont within a prokaryote (an archaea), giving rise to a symbiotic association of two cells from which the first eukaryotic cell could have arisen: (Martin, 1998)

1. The host that acquired the mitochondrion was a prokaryote, a hydrogen-dependent archaea, possibly similar in physiology to a modern methanogenic archaea, which uses hydrogen and carbon dioxide to produce methane.


A hot spring at Yellowstone National Park, among the first location where archaea were discovered.
2. The future mitochondrion was a facultatively anerobic eubacterium, which produced hydrogen and carbon dioxide as byproducts of anaerobic respiration.

3. A symbiotic relationship between the two started, based on the host's hydrogen dependence (anaerobic syntrophy).

Hydrogen Hypothesis (Con’t)

The hypothesis differs from many alternative views within the endo­symbiotic theory framework.

These views suggest that the first eukaryotic cells evolved a nucleus but lacked mitochondria, the latter arising as a eukaryote engulfed a primitive bacterium that eventually became the mitochondrion.


The first eukaryotic cells evolved a
nucleus but lacked mitochondria.


The hydrogen hypothesis attaches significance to hydrogenosomes and provides a rationale for their common ancestry with mitochondria.


The hydrogen hypothesis attaches
significance to hydrogenosomes.


Hydrogenosomes are anaerobic mitochondria that produce ATP by generally converting pyruvate into hydrogen, carbon dioxide and acetate. Examples from modern biology are known where methanogens cluster around hydrogenosomes within eukaryotic cells.

Most theories within the endosymbiotic theory framework do not address the common ancestry of mitochondria and hydrogenosomes.


Most theories within the
endosymbiotic theory framework do
not address the common ancestry of
mitochondria and hydrogenosomes.


Hydrogen Hypothesis (Con’t)

The hydrogen hypothesis provides a straightforward explanation for the observation that eukaryotes are genetic chimeras (a single organism that is composed of two or more different populations of genetically distinct cells) with genes of archaeal and eubacterial ancestry.


Eukaryotes are genetic chimeras with
genes of archaeal and eubacterial
ancestry.


This would imply that archaea and eukarya split after the modern groups of archaea appeared. Most theories within the endosymbiotic theory framework predict that some eukaryotes never possessed mitochondria.


The hydrogen hypothesis predicts that
no primitively mitochondrion-lacking
eukaryotes ever existed.


The hydrogen hypothesis predicts that no primitively mitochondrion-lacking eukaryotes ever existed.


Hydrogen was not only there at the
beginning of time, it was there (and
played an active role) at the
beginning of complex life.


In other words, hydrogen was not only there at the beginning of time, it was there (and played an active role) at the beginning of complex life.


Hydrogen is coming home to roost,
not because of failure but because of
success!


WHAT’S THE BIG DEAL?

If the hydrogen hypothesis is correct, hydrogen was instrumental in the creation of eukaryotes, the cells of which are responsible for complex life such as ourselves.

If this is true, hydrogen extends the life of eukaryotes, and may extend our lives as well.

Hydrogen is coming home to roost, not because of failure but because of success!

Hydrogen Scavenges the Highly Toxic Hydroxyl Radical


LEM1610overlapping274.jpg
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In summary, 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 (ROS) such as superoxide and hydrogen peroxide that are important (at low concentrations) as signaling molecules


Hydrogen has little effect on reactive
oxygen species (ROS) 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.

Hydrogen Reaches All Tissues

Another advantage of hydrogen as an antioxidant is that it easily passes through membranes, reaches all tissues, and readily 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 is an antioxidant that is
already able to enter mitochondria.


Hydrogen, however, is an antioxidant that is already able to enter mitochondria.

References


The life extension scientists who made hydrogen therapy feasible are Durk Pearson & Sandy Shaw®
  • Delzenne et al. Impact of inulin and oligofructose on gastrointestinal peptides. Br J Nutr. 93 Suppl 1: S157-61 (2005).
  • Fu et al. Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci Lett. 453:81-5 (2009).
  • Fujita et al. Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. PLoS One. 4(9):e7247 (2009).
  • Fujita et al. Therapeutic effects of hydrogen in animal models of Parkinson’s disease. Parkinsons Dis. 2011:307875-83 (2011).
  • Fukuda et al. Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. Biochem Biophys Res Commun. 361:670-4 (2007).
  • Gu et al. Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. J Clin Biochem Nutr. 46:269-76 (2010).
  • Hanaoka et al. Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide. Med Gas Res. 1:18-26 (2011).
  • Hayashida et al. Inhalation of hydrogen gas reduces infarct size in the rat model of myocardial ischemia-reperfusion injury. Biochem Biophys Res Commun. 373:30-5 (2008).
  • Hong et al. Hydrogen as a selective antioxidant: a review of clinical and experimental studies. J Int Med Res. 38:1893-1903 (2010).
  • Ito et al. Degree of polymerization of inulin-type fructans differentially affects number of lactic acid bacteria, intestinal immune functions, and immunoglobulin A secretion in the rat cecum. J Agric Food Chem. 59:5771-8 (2011).
  • Janes et al. Anti-superoxide and anti-peroxynitrite strategies in pain suppression. Biochim Biophys Acta. [online computer file] 1822:815-21 (2012).
  • Kajiyama et al. Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 28:137-43 (2008).
  • Kaur et al. In vitro batch fecal fermentation comparison of gas and short-chain fatty acid production using “slowly fermentable” dietary fibers. J Food Sci. 76(5):H137-42 (2011).
  • Liu et al. Hydrogen saline offers neuroprotection by reducing oxidative stress in a focal cerebral ischemia-reperfusion rat model. Med Gas Res. 1:15-24 (2011).
  • Nagata et al. Consumption of molecular hydrogen prevents the stress-induced impairments in hippocampus-dependent learning tasks during chronic physical restraint in mice. Neuropsychopharmacology. 34:501-8 (2009).
  • Nakao et al. Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome—an open label pilot study. J Clin Biochem Nutr. 46:140-9 (2010).
  • Ndengele et al. Cyclooxygenases 1 and 2 contribute to peroxynitrite-mediated inflammatory pain hypersensitivity. FASEB J. 22:3154-64 (2008).
  • Nilsson et al. Including indigestible carbohydrates in the evening meal of healthy subjects improves glucose tolerance, lowers inflammatory markers, and increases satiety after a subsequent standardized breakfast. J Nutr. 138:732-9 (2008).
  • Ohsawa et al. Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem Biophys Res Commun. 377:1195-8 (2008).
  • Ohsawa et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 13(6):688-94 (2007).
  • Ohta. Molecular hydrogen is a novel antioxidant to efficiently reduce oxidative stress with potential for the improvement of mitochondrial diseases. Biochim Biophys Acta. 1820:586-94 (2012).
  • Ohta. Recent progress toward hydrogen medicine: potential of molecular hydrogen for preventive and therapeutic applications. Curr Pharm Des. 17:2241-52 (2011).
  • Ong et al. Manipulation of dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms in irritable bowel syndrome. J Gastroenterol Hepatol. 25(8):1366-73 (2010).
  • Piche et al. Colonic fermentation influences lower esophageal sphincter function in gastroesophageal reflux disease. Gastroenterology. 124:894-902 (2003).
  • Qian et al. Radioprotective effect of hydrogen in cultured cells and mice. Free Radic Res. 44(3):275-82 (2010).
  • Qian et al. The potential cardioprotective effects of hydrogen in irradiated mice. J Radiat Res. 51:741-7 (2010).
  • Rideout et al. Excretion of major odor-causing and acidifying compounds in response to dietary supplementation of chicory inulin in growing pigs. J Anim Sci. 82:1678-84 (2004).
  • Rumessen and Gudmand-Hoyer. Fructans of chicory: intestinal transport and fermentation of different chain lengths and relation to fructose and sorbitol malabsorption. Am J Clin Nutr. 68:357-64 (1998).
  • Salvemini et al. Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med. 51:951-66 (2011).
  • Shimouchi et al. Effect of dietary turmeric on breath hydrogen. Dig Dis Sci. 54:1725-9 (2009).
  • Sun et al. Hydrogen-rich saline protects myocardium against ischemia/reperfusion injury in rats. Exp Biol Med. 234:1212-9 (2009).
  • Tomlin et al. Investigation of normal flatus production in healthy volunteers. Gut. 32:665-9 (1991).
  • Xie et al. Hydrogen gas improves survival rate and organ damage in zymosan-induced generalized inflammation model. Shock.­ 34(5):495-501 (2010).
  • Xie et al. Protective effects of hydrogen gas in murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. Shock. 34:90-97 (2010).
  • Yeo et al. Antinociceptive effect of CNS peroxynitrite scavenger in a mouse model of orofacial pain. Exp Brain Res. 184(3):435-8 (2009).
  • Zheng et al. Hydrogen-rich saline protects against intestinal ischemia-reperfusion injury in rats. Free Radic Res. 43(5):478-84 (2009).


Will Block is the publisher and editorial director of Life Enhancement magazine.

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