Effervescent H₂ Magnesium tabs by Drink HRW and Natural Wellness Now: The most comprehensive and efficacious anti-aging supplement on the market

Abstract

Following the seminal research article on molecular hydrogen published in Nature Med (2007), research on molecular hydrogen as a therapeutic agent has exploded. In recent years, the number of peer reviewed publications has doubled year on year, leading to now over 1000 unique articles citing evidence of beneficial effects in over 170 disease models across every organ in the human body.

For years the intricate pharmacokinetics and mechanisms of action of molecular hydrogen eluded research efforts however, recent discoveries and publications have elucidated some of the diverse functions in which H2 is a key player. H2 has the potential to be a product with the ability to impact all demographics, with unique marketing and formulations targeting specific sub groups. From natural health and sports science to science based anti aging, H2 therapy can be impactful.

Previous challenges facing H2 as a commercial product have delayed the market from growing at the rate of research in this area. While ongoing research is a necessity, delivering an affordable and user-friendly product to consumers in a manner that offers lucrative margins to distribution is paramount. Previous commercial goods have lacked elements, or included stipulations restraining their mass appeal: for example, complicated preparation, foul taste, high cost or lack of efficacy.

Drink HRW offers a unique opportunity for custom formulations and white label distribution channels bringing to market our patent-pending methodology of “super-saturation” in open containers of water by utilising maximized dissolution kinetics.

Introduction

Drink HRW was founded in Q2 of 2015 and for 13 months the company objective was solely focused on R&D and optimisation of formulations. After nearly 2000 iterative adjustments, the first commercial grade product was identified in Q2 of 2016, with accompanying patent applications.

Utilizing a special military grade of magnesium with a custom blend of excipients, the research team at Drink HRW has fine tuned the process to engineer clouds of “hydrogen nano-bubbles”

that are relatively stable in water for extended periods without the need for external pressurization. Drink HRW offers a suite of custom formula options, all delivering at minimum, full saturation of H2 (with additional benefits such as flavouring or synergy with other ingredients), and up to 6x the saturation limits of H2 other commercial products struggle to achieve. We also have a corporate objective to achieve this while maintaining affordability and simplicity of use. In addition to delivering the highest concentrations of H2 commercially available in the most convenient manner, Drink HRW effervescent H2 magnesium tablets also deliver a highly bioavailable magnesium supplement in the form of free magnesium ions in the water.

Dissolution Kinetics: Why our tablet is special

The observation that we were able to super saturate water without external pressure was a serendipitous discovery. We spent months attempting to falsify our hypothesis which generated more and more data to support the evidence of what the phenomenon: To quote Isaac Asimov “The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ but ‘That’s funny…’”

While maximizing the saturation of H2 in a closed container in as little time as possible, we discovered an interesting phenomenon. When the test container was opened, the water would ‘boil’ vigorously and if tested during the ‘boiling’ we could measure a hydrogen reading of 1.6 mg/L. However, if tested seconds later when the water had become ‘white’ we could consistently measure 3.5-4 mg/L. This reading was confusing, as PSI readings of the containers were consistent with a reading of 3.5-4 mg/L, however if it was stabilized and dissolved the water would not boil and read 1.6 mg/L and then turn white with a higher reading.

Like the rest of the commercial industry, as well as the researchers preparing H2, we were fixated on only half of the story, Henry’s Law. Henry’s Law tell us how much gas will dissolve in an aqueous solution at equilibrium. Henry’s Law was the limit to our understanding of H2 saturation, or more importantly the dosage and concentrations of H2 delivered to the user.

Through our observations regarding the ‘white water’ and several others, we were able to identify another factor: Le Chateliers principle. Le Chateliers principle talks about how when the pressure, heat or other factors in a system rise, reactions will increase or decrease in an attempt to reach equilibrium.

What this means for H2-creating-tablet science is that by dropping our newly-created quick-reacting tablet in a closed bottle, we were in effect dramatically increasing the pressure in the system in a very short time. The reaction was slowing to a stop, leaving unreacted magnesium in suspension. Once the pressure was released, the remaining unreacted magnesium created a rush of H2- enough to sparge (or ‘push out’) the super-saturated contents. Fortunately, this lead to our second discovery: by controlling the rate of reaction through pressure, we are able to create nanobubbles which follow different physics. Due to the specifically formulated reaction and conditions of speed, nanobubbles, dissolution kinetics, etc. the H2 concentration in water can be upwards of 4 mg/L rather than the 1.6 mg/L typically allowed as per Henry’s Law. This finding allowed us to fine tune formulations and create an approach that

creates a cloud of nano-bubbles from the instant the water and tablet touch. By creating a cloud full of nano-bubbles, we are able to utilize both the effects of Henry’s Law by increasing the internal pressure of the water, and then Le Chateliers by ‘trapping’ remaining unreacted Mg in suspension to act as a reserve tank as the pressure releases. What this means is that as the cloud of nano bubbles forms, 4 mg/L of H2 is circulating inside the water. Unreacted magnesium is transiently trapped in suspension, and for every molecule of H2 that escapes the surface from coalescing into larger bubbles- or is diffused into cells internally- an equal amount of magnesium reacts to take its place.

On top of strong patent application filings, our technologies are further strengthened by extreme modifications needed for each individual ingredient. Exact milling of components is needed to produce precise particle shape and size. Our mixing protocol alone is a 27-step procedure. The Drink HRW team brings over 2000 formula adjustments, refined manufacturing and constant product improvement with the goal of attaining the maximal experience.

Gene Signalling

Inflammation

Excessive levels of inflammation is believed to be one of the three most common precursors and driving forces of disease and premature death along with insulin resistance and oxidative stress. These three factors lead to a myriad of disease models, and contribute to premature aging at a cellular level. These stresses accelerate the shortening of our telomeres (needed for cell division) by either reducing our levels of telomerase, the enzyme required to extend our telomeres, or by causing a cascade of signals which reduce telomerase efficiency. ^{1234567891011}

While hydrogen administration does not directly eliminate inflammation it will down-regulate the production of pro inflammatory cytokines through various pathways when excess inflammation occurs which can promote a normal level of inflammation^{121314151617181920212223242526} Non steroidal anti inflammatorys (NSAIDS) typically used as a treatment for inflammation treat the symptoms of inflammation but not the underlying cause. In addition, they also have unwanted side effects including nephrotoxity (kidney damage) and GI trauma (ulcers). Other more powerful (prescription only) COX inhibitors and corticosteroids will completely eliminate inflammation which can be as hazardous as excess inflammation. Hydrogen can promote a healthy level of inflammation through regulation of our pro inflammatory cytokines.

Oxidative Stress

As one of the ‘main’ issues in disease indicators along with inflammation and insulin resistance, an imbalance of oxidative stress is a primary marker in the vast majority of diseases. Exogeneous

antioxidant supplementation has shown to lack efficacy at best in a recent meta analysis²⁷, and in some cases may prove harmful due to indiscriminately reducing necessary oxidative species while down regulating our endogenous production of antioxidants²⁸, even leading to an increase in prevalence of cancer.²⁹ Understandably, the ground breaking seminal article in Nature Med showing hydrogen acts as a selective antioxidant in only reducing the most cytotoxic hydroxyl radicals, the ‘bad oxidative species’ was met with considerable interest and an explosion in research.³⁰ Since this article, the exact mechanisms in which hydrogen works as an antioxidant have been further explored, with the realization that the most profound benefit is its ability to activate the Nrf2 pathway, regulating our bodies endogenous antioxidant productions of glutathione, catalase, super oxide dismutase, etc. protecting against oxidative damages and promoting a homeostatic antioxidant/oxidative stress balance.^313233343536 While other potent Nrf2 activators have come under criticism with the potential that the increased cholesterol levels in the liver associated with their administration may overshadow the benefits of increased antioxidant production³⁷, and perhaps more disturbing the evidence suggesting in some instances Nrf2 activation beyond homeostatic levels can promote cancerous tumours and decrease the effectiveness of chemotherapy³⁸³⁹. In constrast, hydrogen stands alone as a solution as it only promotes Nrf2 activation towards homeostatic balance of our ROS/Antioxidant system. It has also shown to lower our LDL or ‘bad’ cholesterols while promoting our HDL or ‘good’ cholesterol⁴⁰⁴¹⁴² , and also as both suppression of tumor growth ⁴³⁴⁴ while suppressing the negative side effects of cancer treatments without interfering with efficacy in two randomized clinical trials as well as rodent studies^45464748.

Through its attenuation of oxidative stress, hydrogen has shown to be an effective treatment in human studies of rheumatoid arthritis⁴⁹⁵⁰, Hepatitis B⁵¹, Parkinson’s Disease⁵², and many more.

Glucose Homeostasis and Insulin Sensitivity

In a tragic cyclical relationship that leads to, or dramatically increases the risk of, a plethora of diseases such as metabolic syndrome, diabetes, Alzheimer’s, cardiovascular disease, shortening of the telomeres and more, increased blood glucose leads to the formation of advanced glycation end products (AGEs) and insulin resistance. Insulin resistance and AGE crosslink formation further exacerbate the issue of blood glucose levels by decreased glucose absorption, leading to higher blood glucose levels, increased insulin resistance and further formations of AGEs.⁵³ Hydrogen has shown incredible promise in assisting both in healthy glucose levels as well as increasing insulin sensitivity in both animals and human studies of metabolic syndrome and diabetes- both types I and II.^{5455565758596061} One Type II diabetes drug, acarbose, may work in part by creating excess molecular hydrogen.⁶²⁶³  H2 acts as a protective shield to mitigate the damages and prevent this avalanche of symptoms from developing into chronic illness. While also profound for its’ neuroprotection, hydrogen has also shown to increase ghrelin secretion in mice⁶⁴, which is also needed for glucose metabolism.⁶⁵ Additionally, the highly bioavailable magnesium found in our tablets further adds to this protection. Magnesium is a cofactor of many enzymes involved in glucose metabolism such as its role in insulin action, and insulin stimulates magnesium uptake in insulin-sensitive tissues⁶⁶.

Hydrogen has also shown to positively impact body weight composition.⁶⁷

Neuroprotection, and a healthy mind

One of hydrogens greatest potentials is the exciting findings indicating it may act as a potential prophylactic neurodegenerative agent. Research on therapeutic Hydrogen has gathered considerable evidence demonstrating results in neurodegenerative diseases such as a 52 week human trial on mild cognitive impairment⁶⁸, Alzheimer’s⁶⁹⁷⁰ and Parkinson’s⁷¹⁷²⁷³, benefits in protection from cognitive impairment/decline^{747576777879808182}, rodent models on central nervous system diseases such as ALS⁸³  and MS⁸⁴, reduction of neuroinflammation⁸⁵⁸⁶ and recovery from stroke⁸⁷⁸⁸⁸⁹ and traumatic brain injuries⁹⁰. Hydrogen has also shown to induce secretion of ghrelin⁹¹ which has demonstrated neuroprotective capabilities.⁹²⁹³ On top of Hydrogen’s ability to protect against both long term deterioration in our brain, as well as acute injury, it has shown to positively effect mood, anxiety and depression both in rodent and human models,⁹⁴⁹⁵⁹⁶ as well as reducing autistic like behaviours in mice.⁹⁷

Senescent Cells, Anti-Apoptosis, Telomerase and the Mitochondria

Along with the vast list of benefits being explored for various markers associated with disease progression, hydrogen also has shown promise in protecting our cells and DNA from damage and aging at a fundamental level. The mitochondria function as our cells power plants, releasing ATP (adenosine triphosphate) for a source of chemical energy. When mitochondria ‘die’ or stop functioning, our lysosome is tasked with breaking them down. A challenge facing our evolved system is when mitochondria mutate internally and are able to escape detection from the lysosome. Internally mutated mitochondria escape lysosomal detection and releases damaging oxidative molecules, which are linked to apoptosis, or cellular death⁹⁸. Molecular hydrogen is a small enough molecule to pass right into the mitochondria and decrease hydroxyl radicals at the source, and has shown to be protective towards mitochondrial health and function^99100101102 while protecting against mitochondrial damaged and other damage induced cell apoptosis.^{103104105106107108109110111112113114115116} Hydrogen has also shown to be able to prevent cellular senescence¹¹⁷¹¹⁸, which is the phenomenon where cells stop dividing, increase telomerase activity¹¹⁹, the RNA containing protein that extends our telomeres and activate Sirt1^94120121 which is linked to extending lifespan in rodents¹²²¹²³.

Athletic Performance & Recovery

Hydrogen has received a considerable amount of research regarding its’ benefits for athletes. Studies have focused on decreasing healing time by speeding up healing of soft tissue injury, decreasing inflammation, and plasma viscosity¹²⁴, or rather proteins in our blood which coincide with inflammation. Hydrogen also helps by decreasing blood lactate levels leading to increased work completed before fatigue^125126127, over all peak performance¹²⁸ as well as potentially decreasing time needed for recovery¹²⁹. Hydrogen has shown to increase work capacity, time to exhaustion and VO2 max¹³⁰, decrease soreness post exercise when administered topically¹³¹, and regulate our redox to eliminate exercise induced oxidative stress without blunting gains^132133134.

Skin Health

While only a few articles exist on the potential benefits for H2 and skin health, these benefits include wrinkle reduction¹³⁵, atopic dermatitis¹³⁶¹³⁷, burn wounds¹³⁸, psoriasis and skin lesions both through topical and oral administration,¹³⁹¹⁴⁰ pressure ulcers¹⁴¹, as well as UV damage¹⁴² and erythematous skin

disease¹⁴³. Additionally, the tablet delivers ionic magnesium which has shown to be bioavailable through the skin not just for skin health, but absorption for whole body supplementation¹⁴⁴. While the tablet remains stoichiometrically alkaline due to the magnesium content, the momentary pH upon topical application falls in the 4.6-5pH range. This range is the precise range in which our skin naturally operates, and is optimal for our skins resident flora.¹⁴⁵

Acts as a Selective Antioxidant

One of the chronic challenges humanity is dealing with in longevity research is oxidative stress. Oxygen, so critical for life as we know it, wreaks havoc on our cells through certain oxygen free radicals. As our bodies age or become sick, these oxygen radicals increase and our health plummets into a downward spiral. In the beginning the Universe began with Hydrogen, so the realization that hydrogen is capable of supressing the most damaging oxidative radical, which if the suppression is done by reaction, the product becomes the essence of life, water, was not only a profound revelation which lead to an avalanche of research but truly poetic.

Magnesium

Magnesium is perhaps the most important- and the most deficient macro mineral in the human body, necessary in over 300 biological functions. It is estimated that nearly 90% of North Americans do not receive adequate magnesium from their diets, with an annual 4.5 million preventable deaths attributed to heart disease and stroke that may have been avoided through adequate magnesium intake through water source.¹⁴⁶ Many magnesium supplements offer poor bioavailability, such as the most common supplemental form magnesium oxide. One study suggests the average availability of magnesium oxide to be as low as 4%¹⁴⁷. In reality, depending on the strength of each individuals stomach acid, the bioavailability could be higher or even as low as zero. One of the results of our reaction is a powerful secondary benefit. The elemental magnesium first reacts creating with water creating magnesium hydroxide. Since hydroxide is a function of pH, our buffering acids are able to reduce the hydroxide dissociating it from the magnesium and leaving free magnesium ions in suspension. These magnesium ions will in turn be highly bioavailable, offering a fantastic source for this critical mineral.

Drink HRW Studies

Currently Drink HRW has provided product for one published human trial, positive effects of supplementation on VO2 max, exercise capacity and time to exhaustion in mid age overweight women in a 28 day double blind placebo controlled crossover design. This study was presented at the annual American College of Sports Medicine conference in 2018. Additionally, two completed trials are under peer review using Drink HRW tablets(acute supplementation, exercise, and 28 day for non alcoholic fatty liver disease). Further, Drink HRW has 2 other trials currently underway(post stroke, metabolic syndrome), and 3 more set to begin in 2019(topical for soft tissue injury, post concussion recovery, chronic fatigue syndrome). We at Drink HRW are always actively seeking public researchers interested in molecular hydrogen, willing to donate product and funds for increased testing.

References

1 Kordinas V, Ioannidis A, Chatzipanagiotou S. The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect? Saretzki G, ed. Genes. 2016;7(9):60. doi:10.3390/genes7090060.

2 Arai Y, Martin-Ruiz CM, Takayama M, et al. Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians. EBioMedicine. 2015;2(10):1549-1558. doi:10.1016/j.ebiom.2015.07.029.

3 Kordinas, V., Tsirpanlis, G., Nicolaou, C., et al. (2015). Is there a connection between inflammation, telomerase activity and the transcriptional status of telomerase reverse transcriptase in renal failure?. Cellular and Molecular Biology Letters, 20(2), pp. 222-236. Retrieved 10 Dec. 2017, from doi:10.1515/cmble-2015-0016

4 Najib Nassani, Georges Khayat, Issam Raad, Ying Jiang, Nada Alaaeddine, George Hilal, Telomerase as a potential marker for inflammation and cancer detection in bronchial washing: A prospective study, In Clinical Biochemistry, Volume 46, Issues 16–17, 2013, Pages 1701-1704, ISSN 0009-9120,

https://doi.org/10.1016/j.clinbiochem.2013.07.018. (http://www.sciencedirect.com/science/article/pii/S0009912013003512) Keywords: Bronchial aspiration; Lung cancer; Telomerase; Inflammation

5 Jurk, D., Wilson, C., Passos, J. F., Oakley, F., Correia-Melo, C., Greaves, L., … von Zglinicki, T. (2014). Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nature Communications, 5, [4172]. DOI: 10.1038/ncomms5172

6 -von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci 2002;27(7):339–344.

7 Oikawa S, Kawanishi S. Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett 1999;453(3):365-8

8 Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A,Erusalimsky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci 2004;117(Pt 11):2417-26

9 Fulsen Bozkus. Could serum levels of telomerase be considered as an oxidative stress marker in COPD? Telomere Telomerase 2016; 3: e1258. doi: 10.14800/tt.1258.

10 Ping F, Li Z, Lv K, et al. Deoxyribonucleic acid telomere length shortening can predict the incidence of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Journal of Diabetes Investigation. 2017;8(2):174-180. doi:10.1111/jdi.12555.

11 E.V. Plokhova, O.N. Tkacheva, D.U. Akasheva, I.D. Strazhesko, E.N. Dudinskaya, S.A. Boytsov; P3995 Advanced glycation end-products and telomere shortening contribute to cardiac aging: the relationship with myocardial strain, European Heart Journal, Volume 38, Issue suppl_1, 1 August 2017, ehx504.P3995, https://doi.org/10.1093/eurheartj/ehx504.P3995

12 Chen Y, Chen H, Xie K, et al (2015): H2 Treatment attenuated pain behavior and cytokine release through the HO-1/CO pathway in a rat model of neuropathic pain. Inflammation. 38:1835-1846

13 Gao Y, Yang H, Fan Y, et al (2016): Hydrogen-rich saline attenuates cardiac and hepatic injury in doxorubicin rat model by inhibiting inflammation and apoptosis. Mediators Inflamm, 2016; 2016: 1320365. doi: 10. 1155/2016/1320365. [Epub ahead of print].

14 Gharib B, Hanna S, Abdallahi OMS, et al (2001): Anti-inflammatory properties of molecular hydrogen: investigation on parasiteinduced liver inflammation. C R Acad Sci III,.324: 719-724.

15 Guo SX, Fang Q, You CG, et al (2015): Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation. J Transl Med, 13: 183.

161616 Kajiya M, Silva MJ, Sato K, et al (2009b): Hydrogen mediates suppression of colon inflammation induced by dextran sodium sulfate. Biochem Biophys Res Commun 386: 11-15.

17 Li J, Hong Z, Liu H, et al (2016a): Hydrogen-rich saline promotes the recovery of renal function after ischemia/reperfusion injury in rats via anti-apoptosis and anti-inflammation. Front Pharmacol, 2016 Apr 22;7; 106. doi; 10. 00106. eCollection 2016.

18 Liu L, Xie K, Chen H, et al (2014a): Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis. Brain Res, 2014 Sep 22. pii: S0006-8993(14)01251-7. doi: 10.1016/j.brainres. 2014. 09. 030. [Epub ahead of print].

19 Noda K, Tanaka Y, Shigemura N, et al (2012): Hydrogen-supplemented drinking water protects cardiac allografts from inflammationassociated deterioration. Transpl Int, 2012 Aug 14. doi: 10. 1111/j. 1432-

2227. 2012. 01542. x.

20 Shi Q, Chen C, Deng WH, et al (2016): Hydrogen-rich saline attenuates acute hepatic injury in acute necrotizing pancreatitis by inhibiting inflammation and apoptosis, involving JNK and p38 mitogen- activated protein kinase-dependent reactive oxygen species. Pancreas, 45: 1424-1431.

21 Spulber S, Edoff K, Hong L, et al (2012): Molecular hydrogen reduces LPS-induced neuroinflammation and promotes recovery from sickness behaviour in mice. PLoS One, 7: e42078.

22 Tian R, Hou Z, Hao S, et al (2016): Hydrogen-rich water attenuates brain damage and inflammation after traumatic brain injury in rats. Brain Res, 1637: 1-13.

23 Wang C, Li J, Liu Q, et al (2011a): Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neurosci Lett. 491: 127-132.

24 Wang X, Yu P, Yong Y, et al (2015): Hydrogen-rich saline resuscitation alleviates inflammation induced by severe burn with delayed resuscitation. Burns, 41: 379-85.

25 Xie K, Yu Y, Zhang Z, et al (2010b): Hydrogen gas improves survival rate and organ damage in zymosan- induced generalized inflammation model. Shock, 34: 495-501.

26 Xie K, Yu Y, Huang Y, et al (2012a): Molecular hydrogen ameliorates lipopolysaccharide-induced acute lung injury in mice through reducing inflammation and apoptosis. Shock. 37: 548-55.

27 Macpherson H, Pipingas A, Pase MP Multivitamin-multimineral supplementation and mortality: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2013 Feb; 97(2):437-44.

28Bjelakovic G¹, Nikolova D, Gluud C. Antioxidant supplements and mortality. Curr Opin Clin Nutr Metab Care. 2014 Jan;17(1):40-4. doi: 10.1097/MCO.0000000000000009.

29 KRISTELL LE GAL, MOHAMED X. IBRAHIM, CLOTILDE WIEL, VOLKAN I. SAYIN, MURALI K. AKULA, CHRISTIN KARLSSON, MARTIN G. DALIN, LEVENT M. AKYÜREK, PER LINDAHL, JONAS NILSSON, MARTIN

O. BERGO Antioxidants can increase melanoma metastasis in mice SCIENCE TRANSLATIONAL MEDICINE07 OCT 2015 : 308RE8 Antioxidants increase migration and invasion of human melanoma cells and accelerate metastasis in an endogenous mouse model of malignant melanoma.

30  Ohsawa I¹, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007 Jun;13(6):688-94. Epub 2007 May 7.

31 Diao M, Zhang S, Wu L, et al (2016): Hydrogen gas inhalation attenuates seawater instillation-induced acute lung injury via the Nrf2 pathway in rabbits. Inflammation 2016 Sep 5

32 Kawamura T, Wakabayashi N, Shigemura N, et al (2013): Hydrogen gas reduced hyperoxic lung injury vai the Nrf2 pathway in vivo. Am J Physiol Lung Cell Mol Physiol, 304: L646-L656.

33 Li Y, Xie K, Chen H, et al (2014): The role of Nrf2 in the hydrogen treatment for intestinal injury caused by severe sepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 26: 415-419. (in Chinese).

34 Liu L, Xie K, Chen H, et al (2014b): Role of Nrf2 in the protective effects of hydrogen against cerebral dysfunction in septic mice. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue, 26: 629-633. (in Chinese).

35 Tamaki N, Orihuela-Campos RC, Fukui M, et al (2016): Hydrogen-rich water intake accelerates oral palatal wound healing via activation of the Nrf2/antioxidant defense pathways in a rat model. Oxid Med Cell Long, 2016: Article ID 5679040.

36 Yu J, Zhang W, Zhang R, et al (2015): Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic cholangiocytes by activating Nrf2 expression. Toxicol Lett, 238: 11-19.

37 Barajas B, Che N, Yin F, Rowshanrad A, Orozco LD, Gong KW, Wang X, Castellani LW, Reue K, Lusis AJ, Araujo JA (Jan 2011). “NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection”. Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (1): 58–66.

38 DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, Mangal D, Yu KH, Yeo CJ, Calhoun ES, Scrimieri F, Winter JM, Hruban RH, Iacobuzio-Donahue C, Kern SE, Blair IA, Tuveson DA (Jul 2011). “Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis”. Nature. 475 (7354): 106–9.

39 Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nature reviews Cancer. 2012;12(8):10.1038/nrc3278. doi:10.1038/nrc3278.

40 Song G, Li M, Sang H, et al (2013): Hydrogen-rich water decrease serum low-density lipoprotein cholesterol levels and improves highdensity lipoprotein function in patients with potential metabolic syndrome. J Lipid Res, 2013 Apr 22.

41 Song G, Lin Q, Zhao H, et al (2015b): Hydrogen activates ATP-binding cassette transporter A1- dependent efflux ex vivo and improves high-density lipoprotein function in patients with hypercholesterolemia: A double-blinded, randomized, and placebo-controlled trial. J Clin Endocrinol Metab. 100: 2724-2733

42 Zong C, Song G, Yao S, et al (2012): Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet-fed hamsters. Metabolism, 61: 79

43 Runtuwene J, Amitani H, Amitani M, et al (2015): Hydrogen-water enhances 5-fluorouracil-induced inhibition of colon cancer. PeerJ, 3: e859; DOI 10.7717/peerj.859.

44 Dole M, Wilson FR, and Fife WP (1975): Hyperbaric hydrogen therapy: A possible treatment for cancer. Science, 190: 152-154.

45 Yang Q, Ji G, Pan R, Zhao Y, Yan P. Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy. Mol Clin Oncol. 2017;7(5):891-896.

46 Kang KM, Kang YN, Choi IB, Gu Y, Kawamura T, Toyoda Y, et al. Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors. Med Gas Res. 2011;1:11.

47 Nakashima-Kamimura N, Mori T, Ohsawa I, et al (2009): Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol, 64: 753-761

48 Zhao L, Zhou C, Zhang J, et al (2011): Hydrogen protects mice from radiation induced thymic lymphoma in BALB/c mice. Int J Bio Sci, 7: 297-300.

49 Ishibashi T, Sato B, Rikitake M, et al (2012): Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Med Gas Res, 2012

50 Ishibashi T, Sato B, Shibata S, et al (2014): Therapeutic efficacy of infused molecular hydrogen in saline on rheumatoid arthritis: A randomized, double-blind placebo-controlled pilot study. Int Immunopharmacol, 21: 468-473.

51 Xia C, Liu W, Zeng D, et al (2013): Effect of hydrogen-rich water on oxidative stress, liver function, and viral load in patients with chronic hepatitis B. Clin Trans Sci, 6: 372-375.

52 Yoritaka A, Takanashi M, Hirayama M, et al (2013): Pilot study of H2 therapy in Parkinson’s disease. A randomized double-blind placebo-controlled trial. Mov Disord, 28: 836-839

53 Vlassara H, Uribarri J. Advanced Glycation End Products  (AGE)  and  Diabetes:  Cause,  Effect,  or  Both? Current diabetes reports. 2014;14(1):453. doi:10.1007/s11892-013-0453-1.

54 Korovljev D¹, Trivic T¹, Drid P¹, Ostojic SM^2,3,4 Molecular hydrogen affects body composition, metabolic profiles, and mitochondrial function in middle-aged overweight women. Ir J Med Sci. 2017 May 30. doi: 10.1007/s11845-017-1638-4. [Epub ahead of print]

55 Li Y, Hamasaki T, Nakamichi N, et al (2011): Suppressive effects of electrolyzed reduced water on alloxan-induced apoptosis and type 1 diabetes mellitus. Cytotecnol, 63: 119-131

56 Kamimura N, Nishimaki K, Ohsawa I, et al (2011): Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity (Silver Spring), 19: 1396-1403

57 Kajiyama S, Hasegawa G, Asano M, et al (2008): Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res, 28: 137- 143.

58 Nakao A, Toyoda Y, Sharma P, et al (2010b): 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- 149.

59 Hashimoto M, Katakura M, Nabika T, et al (2011): Effects of hydrogen-rich water on abnormalities in a SHR.Cg-LeprCP/NDmcr rat – a metabolic syndrome rat model. Med Gas Res, 1: 26.

60 Song G, Li M, Sang H, et al (2013): Hydrogen-rich water decrease serum low-density lipoprotein cholesterol levels and improves highdensity lipoprotein function in patients with potential metabolic syndrome. J Lipid Res, 2013 Apr 22. [Epub ahead of print].

61 Wang QJ¹, Zha XJ, Kang ZM, Xu MJ, Huang Q, Zou DJ. Therapeutic effects of hydrogen saturated saline on rat diabetic model and insulin resistant model via reduction of oxidative stress. Chin Med J (Engl). 2012 May;125(9):1633-7.

62 Atsuko Tamasawa, Kazuki Mochizuki, Natsuyo Hariya, Miyoko Saito, Hidenori Ishida, Satako Doguchi, Syoko Yanagiya, Takeshi Osonoi, Hydrogen gas production is associated with reduced interleukin-1β mRNA in peripheral blood after a single dose of acarbose in Japanese type 2 diabetic patients, European Journal of Pharmacology, Volume 762, 2015, Pages 96-101, ISSN 0014-2999, https://doi.org/10.1016/j.ejphar.2015.04.051. (http://www.sciencedirect.com/science/article/pii/S0014299915004136)

63 Zhu JH, Zhang DQ, Chen WC. Managing ulcerative colitis by increasing hydrogen production via oral administration of Acarbose. Afr J Tradit Complement Altern Med. 2013;10(5):356-359. Published 2013 Aug 12.

64 Matsumoto A, Yamafuji M, Tachibana T, et al (2013): Oral ‘hydrogen water’ induces neuroprotective ghrelin secretion in mice. Sci Rep, 3: 3273. doi: 10. 1038. Srep03273.

65 Heppner KM, Tong J (July 2014). “Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions”. European Journal of Endocrinology. 171 (1): R21–32.

66 Junji Takaya, Hirohiko Higashino, Yohnosuke Kobayashi . Intracellular magnesium and insulin resistance . Magnesium Research. 2004;17(2):126-136.

Votre Email :

68 Nishimaki K¹, Asada T^2,3, Ohsawa I^1,4, Nakajima E², Ikejima C², Yokota T¹, Kamimura N¹, Ohta S^1,5.

Effects of Molecular Hydrogen Assessed byan Animal Model and

a Randomized Clinical Studyon Mild Cognitive Impairment. Curr Alzheimer Res. 2018 Mar 14;15(5):482- 492. doi: 10.2174/1567205014666171106145017.

69 Li J, Wang C, Zhang JH, et al (2010): 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

70 Wang C, Li J, Liu Q, et al (2011a): Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-κB activation in a rat model of amyloid-beta-induced Alzheimer’s disease. Neurosci Lett. 491: 127-132

71 Ito M, Hirayama M, Yamai K, et al. Drinking hydrogen water and intermittent hydrogen gas exposure, but not lactulose or continuous hydrogen gas exposure, prevent 6-hydorxydopamine-induced Parkinson’s disease in rats. Medical Gas Research. 2012;2:15. doi:10.1186/2045-9912-2-15.

72 Fu Y, Ito M, Fujita Y, et al (2009): Molecular hydrogen is protective against 6-hydroxydopamine- induced nigrostriatal degeneration in a rat model of Parkinson’s disease. Neurosci Lett, 453: 81-85

73 Fujita K, Seike T, Yutsudo N, et al (2009): 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: e7247

74 Gu Y, Huang C-S, Inoue T, et al. Drinking Hydrogen Water Ameliorated Cognitive Impairment in Senescence-Accelerated Mice. Journal of Clinical Biochemistry and Nutrition. 2010;46(3):269-276. doi:10.3164/jcbn.10-19.

75 Ge P, Zhao J, Li S, et al (2012): Inhalation of hydrogen gas attenuates cognitive impairment in transient cerebral ischemia via inhibition of oxidative stress. Neurol Res. 34: 187-194.

76 Li C, Hou L, Chen D, et al (2017): Hydrogen-rich saline attenuates isoflurane-induced caspase-3 activation and cognitive impairment via inhibition of isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. Am J Transl Res, 9: 1162- 1172.

77 Hou Z, Luo W, Sun X, et al (2012): Hydrogen-rich saline protects against oxidative damage and cognitive deficits after mild traumatic brain injury. Brain Res Bull, 88: 560-565.

78 Liu L, Xie K, Chen H, et al (2015): Protective effects of inhaled hydrogen gas on cognitive function in mice with sepsis-associated encephalopathy. DeZhonghua Yi Xue Za Zhi, 94:3179-3183.

79 Tian Y, Guo S, Zhang Y, et al (2016): Effects of hydrogen-rich saline on hepatectomy-induced postoperative cognitive dysfunction in old mice. Mol Neurobiol, 2016 Mar 19.

80 Zhou J, Chen Y, Huang GQ, et al (2012a): Hydrogen-rich saline reverses oxidative stress, cognitive impairment, and mortality in rats submitted to sepsis by cercal ligation and puncture. J Surg Res. 2012 Apr 1

81 Nagata, Kazufumi & Kamimura, Naomi & Mikami, Toshio & Ohsawa, Ikuroh & Ohta, Shigeo. (2008). Consumption of Molecular Hydrogen Prevents the Stress-Induced Impairments in Hippocampus- Dependent Learning Tasks during Chronic Physical Restraint in Mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 34. 501-8.

10.1038/npp.2008.95.

82 Takeuchi S, Nagatani K, Otani N, et al. Hydrogen improves neurological function through attenuation of blood–brain barrier disruption in spontaneously hypertensive stroke-prone rats. BMC Neuroscience. 2015;16:22. doi:10.1186/s12868-015-0165-3.

83  Zhang, Y., Li, H., Yang, C. et al. Treatment with Hydrogen-Rich Saline Delays Disease Progression in  a Mouse Model of Amyotrophic Lateral Sclerosis Neurochem Res (2016) 41: 770.

84Zhao, Ming et al. Hydrogen-rich water improves neurological functional recovery in experimental autoimmune encephalomyelitis mice Journal of Neuroimmunology , Volume 294 , 6 – 13

85 Liu L, Xie K, Chen H, et al (2014a): Inhalation of hydrogen gas attenuates brain injury in mice with cecal ligation and puncture via inhibiting neuroinflammation, oxidative stress and neuronal apoptosis. Brain Res, 2014 Sep 22. pii: S0006-8993(14)01251-7. doi: 10.1016/j.brainres. 2014. 09. 030.

86 Spulber S, Edoff K, Hong L, et al (2012): Molecular hydrogen reduces LPS-induced neuroinflammation and promotes recovery from sickness behaviour in mice. PLoS One, 7: e42078

87 Ono, Hirohisa et al. Hydrogen Gas Inhalation Treatment in Acute Cerebral Infarction: A Randomized Controlled Clinical Study on Safety and Neuroprotection

Journal of Stroke and Cerebrovascular Diseases , Volume 26 , Issue 11 , 2587 – 2594

• 88    Hirohisa Ono, Yoji Nishijima^†, Naoto Adachi^†, Masaki Sakamoto^†, Yohei Kudo^†, Kumi Kaneko^†, Atsunori Nakao and Takashi Imaokaet al A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level Medical Gas Research20122:21 https://doi.org/10.1186/2045-9912-2-21

© Ono et al.; licensee BioMed Central Ltd. 2012 Received: 4 January 2012 Accepted: 24 July 2012 Published: 23 August 2012

• 89  Hirohisa Ono^, Yoji Nishijima^†, Naoto Adachi^†, Shigekuni Tachibana^†, Shiroh Chitoku^†,

Shigeo Mukaihara^†, Masaki Sakamoto^†, Yohei Kudo^†, Jun Nakazawa^†, Kumi Kaneko^† and Hiroshi Nawashiro Improved brain MRI indices in the acute brain stem infarct sites treated with hydroxyl radical scavengers, Edaravone and hydrogen, as compared to Edaravone alone. A non-controlled study Medical Gas Research20111:12 https://doi.org/10.1186/2045-9912-1-12 © Ono et al; licensee BioMed Central

Ltd. 2011 Received: 16 March 2011 Accepted: 7 June 2011 Published: 7 June 2011

90 Dohi K, Kraemer BC, Erickson MA, et al. Molecular hydrogen in drinking water protects against neurodegenerative changes induced by traumatic brain injury. PLoS One. 2014;9(9):e108034. Published 2014 Sep 24. doi:10.1371/journal.pone.0108034

91 Matsumoto A, Yamafuji M, Tachibana T, Nakabeppu Y, Noda M, Nakaya H. Oral “hydrogen water” induces neuroprotective ghrelin secretion in mice. Scientific Reports. 2013;3:3273. doi:10.1038/srep03273.

92 Bayliss JA, Andrews ZB. Ghrelin is neuroprotective in Parkinson’s disease: molecular mechanisms of metabolic neuroprotection. Therapeutic Advances in Endocrinology and Metabolism. 2013;4(1):25-36. doi:10.1177/2042018813479645.

93 Dos Santos VV¹, Rodrigues AL, De Lima TC, de Barioglio SR, Raisman-Vozari R, Prediger RD. Ghrelin as a neuroprotective and palliative agent in Alzheimer’s and Parkinson’s disease. Curr Pharm

Des. 2013;19(38):6773-90.

94 Mizuno K, Sasaki AT, Ebisu K, et al. Hydrogen-rich water for improvements of mood, anxiety, and autonomic nerve function in daily life. Med Gas Res. 2018;7(4):247-255. Published 2018 Jan 22. doi:10.4103/2045-9912.222448

95 Zhang Y, Su WJ, Chen Y, et al. Effects of hydrogen-rich water on depressive-like behavior in mice. Sci Rep. 2016;6:23742. Published 2016 Mar 30. doi:10.1038/srep23742

96 Yasushi Satoh, Yoshiyuki Araki, Masashi Kashitani, Kiyomasa Nishii, Yasushi Kobayashi, Masanori Fujita, Shinya Suzuki, Yuji Morimoto, Shinichi Tokuno, Gentaro Tsumatori, Tetsuo Yamamoto, Daizoh Saitoh, Toshiaki Ishizuka; Molecular Hydrogen Prevents Social Deficits and Depression-Like Behaviors Induced by Low-Intensity Blast in Mice, Journal of Neuropathology & Experimental Neurology, Volume 77, Issue 9, 1 September 2018, Pages 827–836, https://doi.org/10.1093/jnen/nly060

97 Guo Qingjun, Yin Xi, Qiao Meng, Jia Yujiao, Chen Dandan, Shao Juan, Lebaron Tyler W., Gao Yuan, Shi Haishui, Jia Bin

Hydrogen-Rich Water Ameliorates Autistic-Like Behavioral Abnormalities in Valproic Acid-Treated Adolescent Mice Offspring Frontiers in Behavioral Neuroscience VOLUME=12 YEAR=2018 PAGES=170 https://www.frontiersin.org/article/10.3389/fnbeh.2018.00170 DOI=10.3389/fnbeh.2018.00170 ISSN=1662-5153

98 Terman A, Kurz T, Gustafsson B, Brunk UT. The Involvement of Lysosomes in Myocardial Aging and Disease . Current Cardiology Reviews. 2008;4(2):107-115. doi:10.2174/157340308784245801.

99 Cui Y, Zhang H, Ji M, et al (2014): Hydrogen-rich saline attenuates neuronal ischemia-reperfusion injury by protecting mitochondrial function in rats. J Sur Res, 2014 May 24. pii: S0022-4804(14)00529-0. doi: 10. 1016/j. jss. 2014. 05. 060.

100 Ito M, Ibi T, Sahashi K, et al (2011): Open-label trial and randomized, double-blind, placebo- controlled, crossover trial of hydrogenenriched water for mitochondrial and inflammatory myopathies. Med Gas Res, 1: 24

101 Li C, Hou L, Chen D, et al (2017): Hydrogen-rich saline attenuates isoflurane-induced caspase-3 activation and cognitive impairment via inhibition of isoflurane-induced oxidative stress, mitochondrial dysfunction, and reduction in ATP levels. Am J Transl Res, 9: 1162- 1172

102 Yoshida A, Asanuma H, Sasaki H, et al (2012): H2 mediates cardioprotection via involvements of KATP channels and permeability transition pores of mitochondria in dogs. Cardiovasc Drugs Ther, 26: 217-226 103 Liu Q, Li BS, Song YJ, et al (2016): Hydrogen-rich saline protects against mitochondrial dysfunction and apoptosis in mice with obstructive jaundice. Mol Med Rep, 4: 3588-3596

104 Cai J, Kang Z, Liu WW, et al (2008): Hydrogen therapy reduced apoptosis in neonatal hypoxia- ischemia rat model. Neurosci Lett, 441: 167-172

105 Gao Y, Yang H, Fan Y, et al (2016): Hydrogen-rich saline attenuates cardiac and hepatic injury in doxorubicin rat model by inhibiting inflammation and apoptosis. Mediators Inflamm, 2016; 2016: 1320365. doi: 10. 1155/2016/1320365.

106 Guo SX, Fang Q, You CG, et al (2015): Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation. J Transl Med, 13: 183.

107 Hong Y, Shao A, Wang J, et al (2014): Neuroprotective effect of hydrogen-rich saline against neurologic damage and apoptosis in early brain injury following subarachnoid hemorrhage: Possible role of the Akt/GSK3βsignaling pathway. PLoS ONE, 9: e96212. doi. 10. 1371.

108 Huang CS, kawamura T, Peng X, et al (2011a): Hydrogen inhalation reduced epithelial apoptosis in ventilator-induced lung injury via a mechanism involving nuclear factor-kappa B activation. Biochem Biophys Res Commun, 408: 253-258

109 Jiang H, Yu P, Qian DH, et al (2013): Hydrogen-rich medium suppresses the generation of reactive oxygen species, elevates the Bcl- 2/Bax ratio and inhibits advanced glycation end product-induced apoptosis. Int J Mol Med, 31: 1381-1387.

110 Li J, Hong Z, Liu H, et al (2016a): Hydrogen-rich saline promotes the recovery of renal function after ischemia/reperfusion injury in rats via anti-apoptosis and anti-inflammation. Front Pharmacol, 2016 Apr 22;7; 106. doi; 10. 00106. eCollection 2016.

111 Li J, Ge Z, Fan L, et al (2017): Protective effect of molecular hydrogen on steroid-induced osteonecrosis in rabbits via reducing oxidative stress and apoptosis. BMC Musculoskelet Disord, 18: 58 112 Liu Q, Li BS, Song YJ, et al (2016): Hydrogen-rich saline protects against mitochondrial dysfunction and apoptosis in mice with obstructive jaundice. Mol Med Rep, 4: 3588-3596

113 Liu YQ, Liu YF, Ma XM, et al (2015): Hydrogen-rich saline attenuates skin ischemia/reperfusion induced apoptosis via regulating Bax/Bcl-2 ratio and ASK-1/JNK pathway. J Plast Reconstr Aesthet Surg. 68:e147-156

114 Shi Q, Chen C, Deng WH, et al (2016): Hydrogen-rich saline attenuates acute hepatic injury in acute necrotizing pancreatitis by inhibiting inflammation and apoptosis, involving JNK and p38 mitogen- activated protein kinase-dependent reactive oxygen species. Pancreas, 45: 1424-1431

115 Yonamine R, Satoh Y, Kodama M, et al (2013): Co-administration of hydrogen gas as part of the carrier gas mixture suppresses neuronal apoptosis and subsequent behavioral deficits caused by neonatal exposure to sevoflurane in mice. Anesthesiology, 118: 105-113

116 Yang Y, Li B, Liu C, et al (2012): Hydrogen-rich saline protects immunocytes from radiation-induced apoptosis. Med Sci Monit. 18: BR144-148

117 Hara F, Tatebe J, Watanabe I, et al (2016): Molecular hydrogen alleviates cellular senescence in endothelial cells. Cric J, 80: 2037-2046

118 Han AL, Park SH, and Park MS (2017): Hydrogen treatment protects against cell death and senescence induced by oxidative damage. J Microbiol Biotechnol, 27: 365-371

119 Robert Settineri, Jin Ji, Chunlan Luo, Rita R. Ellithorpe, Gonzalo Ferreira de Mattos, Steven Rosenblatt, James LaValle, Antonio Jinenez, Shigeo Ohta, Garth L. Nicolson. Effects of Hydrogenized Water on Intracellular Biomarkers for Antioxidants, Glucose Uptake, Insulin Signaling and SIRT 1 and Telomerase Activity. American Journal of Food and Nutrition. Vol. 4, No. 6, 2016, pp 161-168

120 Xing Z, Pan W, Zhang J, et al (2017): Hydrogen rich water attenuates renal injury and fibrosis by regulation transforming growth factor-β induced Sirt1. Biol Pharm Bull, 40: 610-615.

121 Qi LS, Yao L, Liu W, et al (2015): Sirtuin type 1 mediates the retinal protective effect of hydrogen-rich saline against light-induced damage in rats. Invest Ophthalmol Vis Sci, 56: 8268-8269.

122 Mitchell SJ, Martin-Montalvo A, Mercken EM, et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell reports. 2014;6(5):836-843. doi:10.1016/j.celrep.2014.01.031.

123 Mitchell SJ, Martin-Montalvo A, Mercken EM, Palacios HH, Ward TM, Abulwerdi G, Minor RK, Vlasuk GP, Ellis JL, Sinclair DA, Dawson J, Allison DB, Zhang Y, Becker KG, Bernier M, de Cabo R (2014). “The                              SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet”. Cell Rep. 6 124Sergej M. Ostojic, Boris Vukomanovic, Julio Calleja-Gonzalez & Jay R. Hoffman Effectiveness of Oral and Topical Hydrogen for Sports-Related Soft Tissue Injuries Postgraduate Medicine Vol. 126 , Iss. 5,2014

125 Aoki K, Nakao A, Adachi T, Matsui Y, Miyakawa S. Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes. Medical Gas Research. 2012;2:12. doi:10.1186/2045-9912-2-12.

126 Ostojic, Sergej M. Serum Alkalinization and Hydrogen-Rich Water in Healthy Men Mayo Clinic Proceedings , Volume 87 , Issue 5 , 501 – 502

127 Sergej M. Ostojic & Marko D. Stojanovic Hydrogen-Rich Water Affected Blood Alkalinity in Physically Active Men Research in Sports Medicine Vol. 22 , Iss. 1,2014

128 Da Ponte A, Giovanelli N, Nigris D, Lazzer S. Effects of hydrogen rich water on prolonged intermittent exercise. J Sports Med Phys Fitness 2017 Apr 26. DOI: 10.23736/S0022-4707.17.06883-9

129 P.Drid^abT.Trivic^aC.Casals^cS.Trivic^dM.Stojanovic^abS.M.Ostojic^ab Is molecular hydrogen beneficial to enhance post-exercise recovery in female athletes? Science & Sports Volume 31, Issue 4, September 2016, Pages 207-213

130 Ostojic, Sergej, M.; Korovljev, Darinka; Stajer, Valdemar; Javorac, Dejan

28-Days Hydrogen-Rich Water Supplementation Affects Exercise Capacity in Mid-Age Overweight Women: 2942 Board #225 June 1 330 PM – 500 PM

Medicine & Science in Sports & Exercise: May 2018 – Volume 50 – Issue 5S – p 728–729

doi: 10.1249/01.mss.0000538402.25953.d2

131 Takuji Kawamura ¹ ; Yuko Gando ; Masaki Takahashi ; Reira Hara ; Katsuhiko Suzuki ; Isao Muraoka Effects of hydrogen bathing on exercise-induced oxidative stress and delayed-onset muscle soreness Japanese Journal of Physical Fitness and Sports Medicine 2016;65(3):297-305

132 Yue-Peng Sun, Liang Sun Selective protective effect of hydrogen water on free radical injury of athletes after high-intensity exercise. Biomedical Research 2017; 28 (10): 4558-4561 ISSN 0970-938X 133 Shibayama, Yudai & Takeuchi, Kaito & Dobashi, Shohei & Koyama, Katsuhiro. (2017). Hydrogen-rich Water Modulates Redox Status Repeated Three Consecutive Days Of Strenuous Exercise.: 3298 Board

#203 June 2 3. Medicine & Science in Sports & Exercise. 49. 941. 10.1249/01.mss.0000519562.97355.a8.

134 Nogueira, Jonatas & Passaglia, Patricia & Mota, Clarissa & M. Santos, Bruna & E. Batalhão, Marcelo &

C. Carnio, Evelin & G.S. Branco, Luiz. (2018). Molecular hydrogen reduces acute exercise-induced

inflammatory and oxidative stress status. Free Radical Biology and Medicine. 129. 10.1016/j.freeradbiomed.2018.09.028.

135 Shinya Kato, Yasukazu Saitoh, Keizou Iwai, Nobuhiko Miwa, Hydrogen-rich electrolyzed warm water represses wrinkle formation against UVA ray together with type-I collagen production and oxidative- stress diminishment in fibroblasts and cell-injury prevention in keratinocytes, In Journal of Photochemistry and Photobiology B: Biology, Volume 106, 2012, Pages 24-33, ISSN 1011-1344, https://doi.org/10.1016/j.jphotobiol.2011.09.006. (http://www.sciencedirect.com/science/article/pii/S1011134411002193)

Keywords: Hydrogen water; UV-A; Type-I collagen; Oxidative stress; Hydrogen water bathing; Wrinkle repression

136 Yoon YS, Sajo ME, Ignacio RM, et al (2014): Positive effects of hydrogen water on 2,4- dinitrochlorobenzene-induced atopic dermatitis in NC/Nga mice. Bio Pharm Bull, 2014; 37 (9): 1480-

1485.

137 Ignacio RM, Kwak HS, Yun YU, et al (2013b): The drinking effect of hydrogen water on atopic dermatitis induced by Dermatophagoides farina allergen in NC/Nga mice. Evid Based Complement Alternat Med, 2013, Article ID 538673, doi: 10.1155/2013/538673. Epub 2013 Nov 20.

138 Guo SX, Jin YY, Fang Q, et al (2015): Beneficial effects of hydrogen-rich saline on early burn-wound progression in rats. PLoS One. 10 (4):e0124897.

139 Ishibashi T, Ichikawa M, Sato B, et al (2015): Improvement of psoriasis-associated arthritis and skin lesions by treatment with molecular hydrogen: A report of three cases. Mol Med Rep, 2015 Apr 30. doi: 10.3892/mmr.2015.3707

140 Zhu Q, Wu Y, Li Y, et al. Positive effects of hydrogen-water bathing in patients of psoriasis and parapsoriasis en plaques. Sci Rep. 2018;8(1):8051. Published 2018 May 23. doi:10.1038/s41598-018- 26388-3

141 Li Q, Kato S, Matsuoka D, et al (2013): Hydrogen water intake via tube-feeding for patients with pressure ulcer and its reconstructive effects on normal human skin cells in vitro. Med Gas Res, 3:20.

142 Ignacio, R.M., Yoon, YS., Sajo, M.E.J. et al. The balneotherapy effect of hydrogen reduced water on UVB-mediated skin injury in hairless mice Mol. Cell. Toxicol. (2013) 9: 15

143 Ono H, Nishijima Y, Adachi N, et al. Hydrogen(H2) treatment for acute erythymatous skin diseases. A report of 4 patients with safety data and a non-controlled feasibility study with H2 concentration measurement on two volunteers. Med Gas Res. 2012;2(1):14. Published 2012 May 20. doi:10.1186/2045- 9912-2-14

144 Kass L, Rosanoff A, Tanner A, Sullivan K, McAuley W, Plesset M. Effect of transdermal magnesium cream on serum and urinary magnesium levels in humans: A pilot study. Song Y, ed. PLoS ONE. 2017;12(4):e0174817. doi:10.1371/journal.pone.0174817.

145 Lambers, H., Piessens, S., Bloem, A., Pronk, H. and Finkel, P. (2006), Natural skin surface pH is on average below 5, which is beneficial for its resident flora. International Journal of Cosmetic Science, 28: 359–370. doi:10.1111/j.1467-2494.2006.00344.x

146 Andrea Rosanoff The high heart health value of drinking-water magnesium Medical Hypotheses Volume 81, Issue 6, December 2013, Pages 1063-1065

147 Firoz M¹, Graber M Bioavailability of US commercial magnesium preparations. Magnes Res. 2001 Dec;14(4):257-62.