ArticlePDF AvailableLiterature Review

A "philosophical molecule," hydrogen may overcome senescence and intractable diseases

  • MiZ Co. Ltd., Japan, Kanagawa


It has been revealed that the cause of senescence and diseases is associated with the reactive oxygen species “hydroxyl radicals” (·OH). Se-nescence and diseases may be overcome as long as we can scavenge •OH mostly produced in mitochondria. It is one and only one “molecular hydrogen” (H2) that can both penetrate into the mitochondria and scavenge the •OH. The H2 in the body can function in disease prevention and recovery. H2 gas is explosive so that a safe hydrogen inhaler has to be developed for home use. We would like to advocate the great use of H2.
© 2020 Medical Gas Research | Published by Wolters Kluwer - Medknow 47
Although modern medicine has evolved so far with stalling
rapidly in the 21st century, large walls hinder the development
of medicine. There are many diseases which cannot be cured
or healed by treatment based on “element reductionism.” The
element reductionism is associated with one treatment. Many
diseases are caused not by single factor abnormalities but by
multiple factors with various mechanisms. These multiple
factors may not have been elucidated in modern medicine.
However, we have recently developed how we can break
through these challenges. A key solution lies in using molecular
hydrogen (H2).
From a scientic standpoint, all activities of the molecules
can be called the exchange of electrons: “oxidation” and
“reduction.” From the viewpoint of the longevity of the
youth, oxidation means “senescence” while reduction does
“rejuvenation.” Life activity begins after the birth, and
immediately the oxidation proceeds. It means that “electrons
are deprived” to be oxidized. H2, supplying electrons, can
be said that the reducing agent “rejuvenated material.”
Senescence and diseases can be interpreted as oxidative
phenomenon, rejuvenation and recovery as reductive one.
The substance with oxidizing maximizes the phenomenon. In
this paper, we propose the possibility that H2 will overcome
the senescence and intractable diseases from the viewpoint of
mitochondrial oxidation and reduction.
What is the most potent oxidizing one? It is hydroxyl radicals
(•OH). About 90% of reactive oxygen species (ROS) are
generated in the mitochondria in the cells.1 The •OH have
been generated in large quantities almost all within the
mitochondria. Mitochondria are the organs that create the
energy ATP that is necessary for our life activities.
Mitochondrial functions can be compared to the boiler
of a steam locomotive. In the past, the term “boiler” as a
word for locomotive originated from the fact that the boiler
occupied most of the body of the locomotive. In the same way,
mitochondria are energy generating organs for life activities
that must be necessary for life. Locomotives run with fuel,
but in that case a large amount of soot, imperfect combustion
substance is generated. When energy conversion is performed,
the combustion efciency is not perfect without exception. In
the mitochondria, when converting the incorporated material
into energy, about a few percent of the imperfect combustion
substance are produced. The imperfect combustion materials
are ROS. There are a variety of ROS that can be used usefully.
If they are not necessary for life, metabolic system to scavenge
by the use of enzymes has been constructed. However, in the
mitochondria of the generated ROS, there is only •OH that
cannot be reduced by any means. The •OH is generated in
the mitochondria, and can cause oxidation, senescence and
diseases. Because •OH has the strongest oxidizing power,
and reacts with nucleic acids (DNA), lipids and proteins that
make up our bodies and destroy them. This vandalism is an
oxidative reaction. We do not know how to handle with •OH.
Antioxidants except H2 are not very effective especially
because of the impossibility into the cell and mitochondria. We
should scavenge the •OH that produces in the mitochondria.
Is there any substance that can scavenge it? It is H2 that can
solve the vandalism of •OH.
We have reported that drinking of H2 water produced in our
electrolytic cell released a pioneering study to inhibit oxidative
disorders in the liver of rats in 2005.2 This is the rst hydrogen
medicine paper in Japan. Two years later, a series of papers
A “philosophical molecule, hydrogen may overcome
senescence and intractable diseases
Shin-ichi Hirano1, *, Yusuke Ichikawa1, Ryosuke Kurokawa1, Yoshiyasu Takefuji2, Fumitake Satoh1
1 MiZ Company Limited, Kamakura, Japan
2 Faculty of Environment and Information Studies, Keio University, Fujisawa, Japan
*Correspondence to: Shin-ichi Hirano, DVM, PhD,
orcid: 0000-0002-8610-8922 (Shin-ichi Hirano)
It has been revealed that the cause of senescence and diseases is associated with the reactive oxygen species “hydroxyl radicals” (·OH). Se-
nescence and diseases may be overcome as long as we can scavenge •OH mostly produced in mitochondria. It is one and only one “molecular
hydrogen” (H2) that can both penetrate into the mitochondria and scavenge the •OH. The H2 in the body can function in disease prevention and
recovery. H2 gas is explosive so that a safe hydrogen inhaler has to be developed for home use. We would like to advocate the great use of H2.
Key words: Google; Amazon; Facebook; Apple; hydroxyl radicals; mitochondria; molecular hydrogen; oxidation; reactive oxygen species;
reduction; rejuvenation; senescence
doi: 10.4103/2045-9912.279983
How to cite this article: Hirano S, Ichikawa Y, Kurokawa R, Takefuji Y, Satoh F. A “philosophical molecule,” hydrogen may overcome se-
nescence and intractable diseases. Med Gas Res. 2020;10(1):47-49.
[Downloaded free from on Saturday, March 6, 2021, IP:]
Hirano et al. / Med Gas Res
Medical Gas Research ¦ March ¦ Volume 10 ¦ Issue 1
on H2 began to emerge from other research institutes.3 We
have reported the equipment to deliver H2 to the living body.4,5
H2 is capable to pass through all materials, because H2 is
the smallest molecule. Only H2 can pass through the cell
membrane and also pass the mitochondrial membrane, while
the other antioxidants cannot do that to scavenge the •OH. H2
has been reported to react with two kinds of strong ROS,3,6 i.e.,
•OH and peroxynitrite (ONOO-).7 However, it is reported that
H2 reacts with ONOO- somewhat.3 The reactivity of H2 with
•OH is high and quick. As observed from the production of
H2 in the body (gut),8,9 it is completely harmless for the body.
H2 does not interfere with the metabolic system. Rather, H2
can scavenge the waste, •OH in soot that has occurred in the
metabolic reaction, harmless and non-toxic. In conclusion, it
is only H2 that can penetrate into the mitochondria and can
also scavenge •OH (Figure 1). Thereby, the H2 in the body
can function in disease prevention and recovery.10-26 There is
a possibility of longevity of youth.
There are many diseases which we cannot treat well. The
massive fund-raising of Google, Amazon, Facebook and Apple
(GAFA) is continuing to discover the cure for those diseases.
Apple CEO Tim Cook said that in the future, if anybody asks
what Apple’s greatest contribution to humankind is “health”
will be his answer.27
The wasteful medical treatment is rampant in the modern
therapy. The medical expense increase of the nation is
spurred. As a solution, there is a “Choosing Wisely” in the
United States. This is a public organization in Philadelphia of
United States, the United States Internal Medicine Specialist
Certication Organization Foundation (ABIM Foundation)
becomes the epicenter, bundling the medical Society of the
United States, to announce a wasteful medical treatment. For
example, United States Clinical Oncology Society, United
States gastroenterological Society, United States Psychiatric
Society, United States Cardiology Association, United States
Obstetrics and Gynecology Society, United States Pediatrics
Association, etc., the world’s first medical Association
has presented themselves with “the medical act that seems
How should we overcome various problems including
medical problems and social problems? As mentioned in this
paper, we would like to propose a safe H2 medical use with
no adverse effects. H2 may be able to solve various problems
by combining with modern treatment or alone use in the
future. This proposal does not deny the modern medicine
indiscriminately. Especially in acute diseases, the modern
medical treatments are very effective certainly. However,
there are diseases due to chronic diseases and complex factors
that cannot be covered by modern medicine. Up to now there
are more than 600 papers regarding the use of H2, including
about 50 clinical trials papers. The use of H2 is indispensable
in the future, and we would like to advocate the promotion of
hydrogen medicine.
The authors are grateful to Ms. Yoko Satoh and Mr. Masatsugu Saitou
of MiZ Company Limited, and Dr. Goh Matsuo for their excellent
advices in writing this manuscript.
Author contributions
SH, YT and FS designed and wrote the manuscript. YI and RK sup-
ported this study by giving advice and revised the manuscript. All
authors read and approved the nal manuscript.
Conflicts of interest
The authors have no conicts of interests to declare.
Financial support
Copyright license agreement
The Copyright License Agreement has been signed by all authors
before publication.
Plagiarism check
Checked twice by iThenticate.
Peer review
Externally peer reviewed.
Open access statement
This is an open access journal, and articles are distributed under
Figure 1: “Molecular hydrogen” (H2) is the only molecule that can both enter the mitochondria and scavenge the hydroxyl radicals.
Note: Inhalation gas was prepared by mixing of H2 gas and air, where the H2 gas was produced by the electrolysis of water, and the concentration was controlled under
the detonation limit of the mixture of H2 gas and air (below 10% H2 concentration in the apparatus “Jobs-α").·OH: Hydroxyl radicals; PTSD: posttraumatic stress disorder.
[Downloaded free from on Saturday, March 6, 2021, IP:]
Medical Gas Research ¦ March ¦ Volume 10 ¦ Issue 1 49
Hirano et al. / Med Gas Res
the terms of the Creative Commons Attribution-NonCommercial-
ShareAlike 4.0 License, which allows others to remix, tweak, and
build upon the work non-commercially, as long as appropriate credit
is given and the new creations are licensed under the identical terms.
1. Zhang W, Hu X, Shen Q, Xing D. Mitochondria-specic drug release
and reactive oxygen species burst induced by polyprodrug nanoreac-
tors can enhance chemotherapy. Nat Commun. 2019;10:1704-1704.
2. Yanagihara T, Arai K, Miyamae K, et al. Electrolyzed hydrogen-sat-
urated water for drinking use elicits an antioxidative effect: a feeding
test with rats. Biosci Biotechnol Biochem. 2005;69:1985-1987.
3. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a thera-
peutic antioxidant by selectively reducing cytotoxic oxygen radicals.
Nat Med. 2007;13:688-694.
4. Kurokawa R, Seo T, Sato B, Hirano SI, Sato F. Convenient methods
for ingestion of molecular hydrogen: drinking, injection, and inhala-
tion. Med Gas Res. 2015;5:13.
5. Kurokawa R, Hirano SI, Ichikawa Y, Matsuo G, Takefuji Y. Prevent-
ing explosions of hydrogen gas inhalers. Med Gas Res. 2019;9:160-
6. Sano M, Suzuki M, Homma K, et al. Promising novel therapy with
hydrogen gas for emergency and critical care medicine. Acute Med
Surg. 2017;5:113-118.
7. Setsukinai Ki, Urano Y, Kakinuma K, Majima HJ, Nagano T. Devel-
opment of novel uorescence probes that can reliably detect reac-
tive oxygen species and distinguish specic species. J Biol Chem.
8. Levitt MD. Production and excretion of hydrogen gas in man. N Eng
J Med. 1969;281:122-127.
9. Shin W. Medical applications of breath hydrogen measurements.
Anal Bioanal Chem. 2014;406:3931-3939.
10. Dole M, Wilson FR, Fife WP. Hyperbaric hydrogen therapy: a pos-
sible treatment for cancer. Science. 1975;190:152-154.
11. Hirano Si, Aoki Y, Kurokawa R, et al. Hydrogen gas inhalation al-
leviates radiation-induced bone marrow damage in cancer patients.
https://ssrncom/abstract=3349228. Accessed by March 8, 2019.
12. Fontanari P, Badier M, Guillot C, et al. Changes in maximal perfor-
mance of inspiratory and skeletal muscles during and after the 7.1-
MPa Hydra 10 record human dive. Eur J Appl Physiol. 2000;81:325-
13. Cai J, Kang Z, Liu WW, et al. Hydrogen therapy reduces apoptosis in
neonatal hypoxia-ischemia rat model. Neurosci Lett. 2008;441:167-
14. Hayashida K, Sano M, Ohsawa I, et al. Inhalation of hydrogen gas
reduces infarct size in the rat model of myocardial ischemia-reperfu-
sion injury. Biochem Biophys Res Commun. 2008;373:30-35.
15. Xie K, Yu Y, Pei Y, et al. Protective effects of hydrogen gas on mu-
rine polymicrobial sepsis via reducing oxidative stress and HMGB1
release. Shock. 2010;34:90-97.
16. Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N. Effectiveness of
hydrogen rich water on antioxidant status of subjects with potential
metabolic syndrome-an open label pilot study. J Clin Biochem Nutr.
17. Nagatani K, Wada K, Takeuchi S, et al. Effect of hydrogen gas on
the survival rate of mice following global cerebral ischemia. Shock.
18. Xiang L, Tan JW, Huang LJ, et al. Inhalation of hydrogen gas re-
duces liver injury during major hepatotectomy in swine. World J
Gastroenterol. 2012;18:5197-5204.
19. Yoshida A, Asanuma H, Sasaki H, et al. H(2) mediates cardiopro-
tection via involvements of K(ATP) channels and permeability
transition pores of mitochondria in dogs. Cardiovasc Drugs Ther.
20. Yoritaka A, Takanashi M, Hirayama M, Nakahara T, Ohta S, Hattori
N. Pilot study of H2 therapy in Parkinson’s disease: a randomized
double-blind placebo-controlled trial. Mov Disord. 2013;28:836-
21. Hayashida K, Sano M, Kamimura N, et al. Hydrogen inhalation dur-
ing normoxic resuscitation improves neurological outcome in a rat
model of cardiac arrest independently of targeted temperature man-
agement. Circulation. 2014;130:2173-2180.
22. Homma K, Yoshida T, Yamashita M, Hayashida K, Hayashi M, Hori
S. Inhalation of hydrogen gas is benecial for preventing contrast-
induced acute kidney injury in rats. Nephron Exp Nephrol. 2015;doi:
23. Tamura T, Hayashida K, Sano M, et al. Feasibility and safety of
hydrogen gas inhalation for post-cardiac arrest syndrome- rst-in-
human pilot study. Circ J. 2016;80:1870-1873.
24. Matsuoka T, Suzuki M, Sano M, et al. Hydrogen gas inhalation in-
hibits progression to the “irreversible” stage of shock after severe
hemorrhage in rats. J Trauma Acute Care Surg. 2017;83:469-475.
25. Katsumata Y, Sano F, Abe T, et al. The effects of hydrogen gas in-
halation on adverse left ventricular remodeling after percutaneous
coronary intervention for ST-elevated myocardial infarction- rst
pilot study in humans. Circ J. 2017;81:940-947.
26. Tamaki I, Hata K, Okamura Y, et al. Hydrogen ush after cold stor-
age as a new end-ischemic ex vivo treatment for liver grafts against
ischemia/reperfusion injury. Liver Transpl. 2018;24:1589-1602.
27. CNBC. Tim Cook: Apple’s greatest contribution will be ‘about
health’. https://wwwcnbccom/2019/01/08/tim-cook-teases-new-ap-
ple-services-tied-to-health-carehtml. Accessed by January 8, 2019.
Received: August 26, 2019
Reviewed: August 28, 2019
Accepted: September 8, 2019
[Downloaded free from on Saturday, March 6, 2021, IP:]
... These methods of modern medicine are called the "elemental reductionist approach." 1,6,7 It subdivides the object of study from organ to cell, then to molecule, and finally to gene to identify the factors that most affect diseases. Drugs are designed to act on a single factor (e.g., enzymes, receptors, and genes) in order to ameliorate the diseases. ...
... Drugs are designed to act on a single factor (e.g., enzymes, receptors, and genes) in order to ameliorate the diseases. 1,6,7 In modern medicine, it is also said that there is a "one-to-one relationship" between the cause of a disease and its treatment. 1,6,7 However, many diseases are not caused by a single factor alone, but by multiple factors and a wide variety of mechanisms. ...
... 1,6,7 In modern medicine, it is also said that there is a "one-to-one relationship" between the cause of a disease and its treatment. 1,6,7 However, many diseases are not caused by a single factor alone, but by multiple factors and a wide variety of mechanisms. 1,6,7 Therefore, modern medicine may be called "rifle gun therapy" because it can target a single shot. ...
Full-text available
Most of the drugs used in modern medical treatments are symptomatic treatments and are far from being a cure for the diseases. The adverse effects are unavoidable in the drugs in modern medical treatments. Molecular hydrogen (H2) has a remarkable therapeutic effect on various diseases, and many clinical studies have reported that H2 has no adverse effects. Therefore, H2 is a novel medical gas that is outside the concept of modern medical treatment. H2, unlike drugs, works on the root of many diseases by scavenging the two kinds of strong reactive oxygen species, hydroxyl radical (·OH) and peroxynitrite (ONOO-). Since the H2 alleviates the root of diseases and can treat many diseases at the same time, the medical application of H2 may be called “machine gun therapy.” In this review, we demonstrated that the root of many diseases is based on ·OH-induced oxidative stress in the mitochondria, and at the same time, the root of chronic inflammation is also attributed to ·OH.
... The effects of H 2 are not limited to antioxidant activity, they also include anti-inflammatory, anti-apoptotic, and anti-allergic activities, improvements in lipid metabolism, and the regulation of gene expression and signal transduction (41,42). In mammalian cells, H 2 is an inactive molecule that has no metabolic system and does not react with biological substances; however, it reacts with ·OH, which is abundant in mitochondria (43). H 2 easily passes through the blood-brain barrier. ...
... It is the most potent oxidizing ROS and indiscriminately reacts with nucleic acids, lipids, and proteins. Since H 2 is a substance with excellent permeability to mitochondria, it may react with ·OH produced in mitochondria and convert it to water for detoxification (·OH + H 2 → H· + H 2 O) (41)(42)(43)(44)71). ...
... Since mitochondrial dysfunction plays a major role in abnormal energy metabolism in ME/CFS, our literature review suggested that H 2 gas may be an effective medical gas for the treatment of ME/CFS (58,59,62,63). More than 1,300 studies on H 2 have been reported to date, including ∼100 clinical trials, and research on the medical use of H 2 is being conducted worldwide (43). Since H 2 is produced by intestinal bacteria (89) and is recognized as a food additive in Japan, the U.S., and European Union (EU), and H 2 gas has been applied to the treatment of treat caisson disease (90), there are no safety issues associated with H 2 . ...
Full-text available
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction. There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism. The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired. Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species. Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects. Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS.
... This section will focus on the ROS that oxidize mtDNA in order to activate the NLRP3 inflammasome. ROS are mainly produced by mitochondria when there is an imbalance between the production of free radicals and the production of other reactive metabolites [11]. When the activity of excessive ROS produced exceeds that of antioxidant mechanisms in the body, oxidative stress can indiscriminately occur in different cells [11]. ...
... ROS are mainly produced by mitochondria when there is an imbalance between the production of free radicals and the production of other reactive metabolites [11]. When the activity of excessive ROS produced exceeds that of antioxidant mechanisms in the body, oxidative stress can indiscriminately occur in different cells [11]. Since this excessive stress on cellular organelles eventually leads to dysfunction, consequently triggering signals that lead to the onset of mibyou, it is extremely important to find a therapeutic agent that can selectively eliminate ROS in order to prevent this from occurring. ...
... Amongst the ROS produced in the living body, it is known that ·OH has the strongest oxidizing power, and thus partakes in the most significant damages via oxidative stress [11]. Living cells have enzymes that specifically scavenge other notable ROS, such as superoxide and hydrogen peroxide. ...
Full-text available
Mibyou, or pre-symptomatic diseases, refers to state of health in which a disease is slowly developing within the body yet the symptoms are not apparent. Common examples of mibyou in modern medicine include inflammatory diseases that are caused by chronic inflammation. It is known that chronic inflammation is triggered by the uncontrolled release of proinflammatory cytokines by neutrophils and macrophages in the innate immune system. In a recent study, it was shown that molecular hydrogen (H2) has the ability to treat chronic inflammation by eliminating hydroxyl radicals (�OH), a mitochondrial reactive oxygen species (ROS). In doing so, H2 suppresses oxidative stress, which is implicated in several mechanisms at the root of chronic inflammation, including the activation of NLRP3 inflammasomes. This review explains these mechanisms by which H2 can suppress chronic inflammation and studies its applications as a protective agent against different inflammatory diseases in their pre-symptomatic state. While mibyou cannot be detected nor treated by modern medicine, H2 is able to suppress the pathogenesis of pre-symptomatic diseases, and thus exhibits prospects as a novel protective agent.
... Molecular hydrogen (H2) is an antioxidant that can selectively scavenge ·OH, which is the most potent oxidant among ROS [12]. Among the homonuclear diatomic molecules (N2, O2, etc.) that can permeate the cell membrane, only H2 is able to scavenge ·OH, which is always generated inside of mitochondria [13,14]. It has been shown by literature that H2 in various animal models of inflammation may be based on mechanisms to inhibit mitochondrial oxidation and NLRP3 inflammasome activation [15][16][17][18][19][20][21][22][23]. ...
... In addition, because H2 itself is an inert substance and the reaction product of H2 and ·OH is a water molecule, it does not have any adverse effects on the living body, unlike drugs. In a recent paper, we proposed that H2 is the only molecule that can enter mitochondria and undergo a hydrogen withdrawal reaction with ·OH [13,14]. Thus, H2 is the only diatomic molecule that can enter mitochondria to protect cells from cytotoxicity caused by ·OH. ...
... However, previous papers supporting this mechanism have not shown that the ROS is ·OH itself. The most oxidatively produced ROS in mitochondria is ·OH [13,14]. Therefore, in this review, we hypothesized that the ·OH scavenging effects of H2 may lead to the suppression of NLRP3 activation through the inhibition of mtDNA oxidation (Figure 1). ...
Full-text available
Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mi-tochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mito-chondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).
... ROS are mainly generated in the mitochondria [40]. H 2 is the smallest molecule and therefore capable of passing through the mitochondrial membrane to neutralize •OH and ONOO − [41]. In addition, H 2 suppresses electron leakage in the electron transport chain (ETC), prevents superoxide generation in the mitochondrial complex I, rectifies the electron flow, and thus suppresses oxidative damage in the mitochondria [42]. ...
... Although modern medicine has evolved rapidly in the 21 st century, many significant questions still need to be addressed and many diseases still cannot be cured. As a "philosophical molecule," H 2 may overcome intractable diseases and ageing [41] and solve various problems via its use alone or synergistically with other therapies. Moreover, H 2 gas has demonstrated a safety profile in a number of research studies, which is pivotal for clinical trials. ...
Full-text available
Ageing is a physiological process of progressive decline in the organism function over time. It affects every organ in the body and is a significant risk for chronic diseases. Molecular hydrogen has therapeutic and preventive effects on various organs. It has antioxidative properties as it directly neutralizes hydroxyl radicals and reduces peroxynitrite level. It also activates Nrf2 and HO-1, which regulate many antioxidant enzymes and proteasomes. Through its antioxidative effect, hydrogen maintains genomic stability, mitigates cellular senescence, and takes part in histone modification, telomere maintenance, and proteostasis. In addition, hydrogen may prevent inflammation and regulate the nutrient-sensing mTOR system, autophagy, apoptosis, and mitochondria, which are all factors related to ageing. Hydrogen can also be used for prevention and treatment of various ageing-related diseases, such as neurodegenerative disorders, cardiovascular disease, pulmonary disease, diabetes, and cancer. This paper reviews the basic research and recent application of hydrogen in order to support hydrogen use in medicine for ageing prevention and ageing-related disease therapy.
... In addition, because H 2 itself is an inert substance and the reaction product of H 2 and ·OH is a water molecule, and the production of H 2 in the intestine, adverse effects caused by H 2 has not been observed in many clinical studies [4][5][6][7][8]. In a recent paper, we proposed that H 2 is the only molecule that enters the mitochondria and undergoes a hydrogen withdrawal reaction from the ·OH [18]. Thus, H 2 is a molecule entering the mitochondria that can protect cells from cytotoxicity caused by ·OH. ...
... Since H 2 is arguably a molecule essential for the survival of life, we proposed in the recent paper that H 2 is a "philosophical molecule" [18]. ...
Full-text available
Hydrogen (H 2) is promising as an energy source for the next generation. Medical applications using H 2 gas can be also considered as a clean and economical technology. Since the H 2 gas based on electrolysis of water production has potential to expand the medical applications, the technology has been developed in order to safely dilute it and to supply it to the living body by inhalation, respectively. H 2 is an inert molecule which can scavenge the highly active oxidants including hydroxyl radical (·OH) and peroxynitrite (ONOO −), and which can convert them into water. H 2 is clean and causes no adverse effects in the body. The mechanism of H 2 is different from that of traditional drugs because it works on the root of many diseases. Since H 2 has extensive and various effects, it may be called a "wide spectrum molecule" on diseases. In this paper, we reviewed the current medical applications of H 2 including its initiation and development, and we also proposed its prospective medical applications. Due to its marked efficacy and no adverse effects, H 2 will be a next generation therapy candidate for medical applications.
... Since hydrogen is the smallest diatomic molecule, it can easily permeate mitochondrial membranes to react with these hydroxyl radicals and prevent cells from oxidative stress without any side effects. 6 Hydrogen has clinical benefits in many diseases, including neurological diseases, cardiovascular diseases, respiratory diseases, diabetes, liver and metabolic syndrome. More than 1000 papers have been published on the medical applications of hydrogen, including over 90 reports of human clinical trials. ...
Full-text available
Intestinal bacteria can be classified into “beneficial bacteria” and “harmful bacteria.” However, it is difficult to explain the mechanisms that make “beneficial bacteria” truly beneficial to human health. This issue can be addressed by focusing on hydrogen-producing bacteria in the intestines. Although it is widely known that molecular hydrogen can react with hydroxyl radicals, generated in the mitochondria, to protect cells from oxidative stress, the beneficial effects of hydrogen are not fully pervasive because it is not generally thought to be metabolized in vivo. In recent years, it has become clear that there is a close relationship between the amount of hydrogen produced by intestinal bacteria and various diseases, and this report discusses this relationship.
... For example, in cigarette smoke (CS)-induced emphysema, hydrogen significantly decreased phosphorylated histone H2AX and 8-hydroxy-2'-deoxyguanosine (8-OHdG), which are markers of oxidative DNA damage (Suzuki et al., 2017). As a "philosophical molecule," hydrogen may be used for the treatment of intractable diseases and aging (Hirano et al., 2020). ...
Molecular hydrogen exerts biological effects on nearly all organs. It has anti-oxidative, anti-inflammatory, and anti-aging effects and contributes to the regulation of autophagy and cell death. As the primary organ for gas exchange, the lungs are constantly exposed to various harmful environmental irritants. Short- or long-term exposure to these harmful substances often results in lung injury, causing respiratory and lung diseases. Acute and chronic respiratory diseases have high rates of morbidity and mortality and have become a major public health concern worldwide. For example, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. An increasing number of studies have revealed that hydrogen may protect the lungs from diverse diseases, including acute lung injury, chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary arterial hypertension, and pulmonary fibrosis. In this review, we highlight the multiple functions of hydrogen and the mechanisms underlying its protective effects in various lung diseases, with a focus on its roles in disease pathogenesis and clinical significance.
... Unlike conventional medications, H2 has no side effects and is effective in treating many diseases caused by oxidative stress and chronic inflammation [11][12][13]. In a recent paper, we reported that H2 is the only molecule capable of mitochondrial translocation with ·OH scavenging ability [14]. H2 has clinical benefits for many diseases, including neurological diseases [15][16][17], cardiovascular diseases [18,19], respiratory diseases [20,21], diabetes [22], liver and metabolic syndrome [23,24]. ...
Full-text available
While many antitumor drugs have yielded unsatisfactory therapeutic results, drugs are one of the most prevalent therapeutic measures for the treatment of cancer. The development of cancer largely results from mutations in nuclear DNA, as well as from those in mitochondrial DNA (mtDNA). Molecular hydrogen (H2), an inert molecule, can scavenge hydroxyl radicals (·OH), which are known to be the strongest oxidizing reactive oxygen species (ROS) in the body that causes these DNA mutations. It has been reported that H2 has no side effects, unlike conventional antitumor drugs, and that it is effective against many diseases caused by oxidative stress and chronic inflammation. Recently, there has been an increasing number of papers on the efficacy of H2 against cancer and its effects in mitigating the side effects of cancer treatment. In this review, we demonstrate the efficacy and safety of H2 as a novel antitumor agent and show that its mechanisms may not only involve the direct scavenging of ·OH, but also other indirect biological defense mechanisms via the regulation of gene expression.
... These papers have led to global research on the medical applications of H 2 . We recently showed that although H 2 is an inactive substance, compared to other antioxidants, it is the only molecule with mitochondrial permeability and an ability to reduce •OH, which is promising for future medical applications [9,10]. Selective •OH scavengers may have potential medical applications as radioprotective agents. ...
Full-text available
Although ionizing radiation (radiation) is commonly used for medical diagnosis and cancer treatment, radiation-induced damages cannot be avoided. Such damages can be classified into direct and indirect damages, caused by the direct absorption of radiation energy into DNA and by free radicals, such as hydroxyl radicals (�OH), generated in the process of water radiolysis. More specifically, radiation damage concerns not only direct damages to DNA, but also secondary damages to non-DNA targets, because low-dose radiation damage is mainly caused by these indirect effects. Molecular hydrogen (H2) has the potential to be a radioprotective agent because it can selectively scavenge �OH, a reactive oxygen species with strong oxidizing power. Animal experiments and clinical trials have reported that H2 exhibits a highly safe radioprotective effect. This paper reviews previously reported radioprotective effects of H2 and discusses the mechanisms of H2, not only as an antioxidant, but also in intracellular responses including anti-inflammation, anti-apoptosis, and the regulation of gene expression. In doing so, we demonstrate the prospects of H2 as a novel and clinically applicable radioprotective agent.
Full-text available
Abstract: Background: Radiotherapy for cancer patients is one of the useful methods; however, it not only impairs the targeted tumor tissues but also damage the normal surrounding tissues. Intensity modulated radiation therapy (IMRT) for cancer patients has been recently performed to alleviate the adverse effects, but reducing bone marrow damage is limited in the patients with multiple tumor lesions and large irradiation volume. Molecular hydrogen (H2) was recently reported as a preventive and therapeutic antioxidant that selectively scavenges hydroxy radical (*OH) and peroxynitrite (ONOO-). This observational study aims to examine whether H2 gas treatment improves IMRT radiation-induced bone marrow damage in cancer patients. Methods: The patients with end stage of cancer were received IMRT once per day for 1 to 4 weeks except Saturday and Sunday. After each IMRT, the patients of control group (n = 7) were housed in health care chamber (HCC, mild hyperbaric oxygen chamber) for 30 minutes, and the patients of H2 group (n = 16) were also housed in HCC and received 5% H2 gas for 30 minutes once per day. Radiation-induced bone marrow damage was evaluated by hematological examination of peripheral blood obtained before and after IMRT. Results: IMRT with HCC therapy significantly reduced white blood cells (WBC) and platelets (PLT) respectively, but not red blood cells (RBC), hemoglobin (HGB) and hematocrit (HT). In contrast, H2 gas treatment significantly alleviates reducing effects of WBC and PLT respectively. There was no difference in anti-tumor effects between the two groups. Interpretation: Our study demonstrated that H2 gas inhalation therapy significantly alleviates IMRT radiation-induced bone marrow damage without compromising anti-tumor effects. These results suggest that H2 gas treatment would be a strategy for reducing IMRT bone marrow damage in cancer patients.
Full-text available
Production and excretion of hydrogen (H2) gas in human was reported in 1969, since then it has been regarded as non-toxic molecule. For preventive and therapeutic medical uses, a possible treatment for cancer was reported and another article was published on how H2 acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. A variety of H2 gas inhalers have been available in the market for hospital and home uses. However, H2 is odorless and flammable or explosive ignited by static electricity. We have examined the safety of a variety of H2 gas concentrations from the viewpoint of flammability and explosion. We have also measured concentrations of H2 gas inhalers in the market respectively. This paper also details how to control H2 gas concentration for preventing explosions.
Full-text available
Cancer cells exhibit slightly elevated levels of reactive oxygen species (ROS) compared with normal cells, and approximately 90% of intracellular ROS is produced in mitochondria. In situ mitochondrial ROS amplification is a promising strategy to enhance cancer therapy. Here we report cancer cell and mitochondria dual-targeting polyprodrug nanoreactors (DT-PNs) covalently tethered with a high content of repeating camptothecin (CPT) units, which release initial free CPT in the presence of endogenous mitochondrial ROS (mtROS). The in situ released CPT acts as a cellular respiration inhibitor, inducing mtROS upregulation, thus achieving subsequent self-circulation of CPT release and mtROS burst. This mtROS amplification endows long-term high oxidative stress to induce cancer cell apoptosis. This current strategy of endogenously activated mtROS amplification for enhanced chemodynamic therapy overcomes the short lifespan and action range of ROS, avoids the penetration limitation of exogenous light in photodynamic therapy, and is promising for theranostics.
Full-text available
It has been reported that hydrogen gas exerts a therapeutic effect in a wide range of disease conditions, from acute illness such as ischemia–reperfusion injury, shock, and damage healing to chronic illness such as metabolic syndrome, rheumatoid arthritis, and neurodegenerative diseases. Antioxidant and anti-inflammatory properties of hydrogen gas have been proposed, but the molecular target of hydrogen gas has not been identified. We established the Center for Molecular Hydrogen Medicine to promote non-clinical and clinical research on the medical use of hydrogen gas through industry–university collaboration and to obtain regulatory approval of hydrogen gas and hydrogen medical devices ( Studies undertaken by the Center have suggested possible therapeutic effects of hydrogen gas in relation to various aspects of emergency and critical care medicine, including acute myocardial infarction, cardiopulmonary arrest syndrome, contrast-induced acute kidney injury, and hemorrhagic shock.
Full-text available
Background: Hydrogen gas inhalation (HI) reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model of acute myocardial infarction (AMI). We designed a prospective, open-label, rater-blinded clinical pilot study in patients experiencing ST-elevated MI (STEMI).Methods and Results:The 20 patients with an initial diagnosis of STEMI were assigned to either an HI group (1.3% H2with 26% oxygen) or a control group (26% oxygen). There were no HI-related severe adverse events. In the full analysis set, the cardiac salvage index as evaluated using cardiac magnetic resonance imaging at 7 days after primary percutaneous coronary intervention (PCI), showed no significant between-group difference (HI: 50.0±24.3%; control: 60.1±20.1%; P=0.43). However, the improvement from day 7 in the HI group was numerically greater than that in the control group in some of the surrogate outcomes at 6-month follow-up, including the LV stroke volume index (HI: 9.2±7.1 mL/m(2); control: -1.4±7.2 mL/m(2); P=0.03) and the LV ejection fraction (HI: 11.0%±9.3%; control: 1.7%±8.3%; P=0.11). Conclusions: The first clinical study has shown that HI during PCI is feasible and safe and may also promote LV reverse remodeling at 6 months after STEMI. The study was not powered to test efficacy and a further large-scale trial is warranted. (Clinical trials registration: UMIN00006825).
Full-text available
Background: Hydrogen gas inhalation (HI) ameliorates cerebral and cardiac dysfunction in animal models of post-cardiac arrest syndrome (PCAS). HI for human patients with PCAS has never been studied.Methods and Results:Between January 2014 and January 2015, 21 of 107 patients with out-of-hospital cardiac arrest achieved spontaneous return of circulation. After excluding 16 patients with specific criteria, 5 patients underwent HI together with target temperature management (TTM). No undesirable effects attributable to HI were observed and 4 patients survived 90 days with a favorable neurological outcome. Conclusions: HI in combination with TTM is a feasible therapy for patients with PCAS.
Full-text available
Molecular hydrogen (H2) is clinically administered; however, in some hospitals, H2 is given to patients without consideration of its safe use. In the present study, we prepared convenient and safe devices for the drinking of super-saturated H2 water, for intravenous drip infusion of H2-rich saline, and for the inhalation of H2 gas. In order to provide useful information for researchers using these devices, the changes in H2 concentration were studied. Our experimental results should contribute to the advance of non-clinical and clinical research in H2 medicine.
Cold storage (CS) remains the gold standard for organ preservation worldwide, though it is inevitably associated with cold-ischemia/warm-reperfusion injury (IRI). Molecular hydrogen (H2 ) is well-known to have anti-oxidative properties, however, its unfavorable features, i.e. inflammability, low solubility, and high tissue/substance permeability, have hampered its clinical application. To overcome such obstacles, we developed a novel reconditioning method for donor organs, named HyFACS (hydrogen flush after cold storage), just an end-ischemic H2 -flush directly to donor organs ex vivo, and herein report its therapeutic impact against hepatic IRI. Whole liver grafts were retrieved from Wistar rats. After 24-hour CS in UW solution, livers were cold-flushed with H2 -solution (1.0ppm) via portal vein (HyFACS-PV), or hepatic artery (HyFACS-HA), or both (HyFACS-PV+HA). Functional integrity and morphological damages were then evaluated by 2-hour oxygenated reperfusion at 37°C. HyFACS significantly lowered portal-venous pressure, transaminase, and HMGB-1 release compared to vehicle-treated controls (P<0.01). Hyaluronic-acid clearance was significantly higher in HyFACS-PV and -PV+HA than in the others (P<0.01), demonstrating the efficacy of PV route to maintain sinusoidal endothelia. In contrast, bile production and LDH leakage therein were both significantly improved in HyFACS-HA and -PV+HA (P<0.01), representing the superiority of arterial route to attenuate biliary damage. Consistently, electron microscopy revealed sinusoidal ultra-structures were well-maintained by portal HyFACS, while microvilli in bile canaliculi were well-preserved by arterial flush. As an underlying mechanism, HyFACS significantly lowered oxidative damages, thus improving GSH/GSSG ratio in liver tissue. Conclusion: HyFACS significantly protected liver grafts from IRI by ameliorating oxidative damages upon reperfusion, in the characteristic manner with its route of administration. Given its safety, simplicity, and cost-effectiveness, end-ischemic HyFACS may be a novel pre-transplant conditioning for cold-stored donor organs. This article is protected by copyright. All rights reserved.
Background: Mortality of hemorrhagic shock primarily depends on whether or not the patients can endure the loss of circulating volume until radical treatment is applied. We investigated whether hydrogen (H2) gas inhalation would influence the tolerance to hemorrhagic shock and improve survival. Methods: Hemorrhagic shock was achieved by withdrawing blood until the mean arterial blood pressure reached 30-35 mm Hg. After 60 minutes of shock, the rats were resuscitated with a volume of normal saline equal to four times the volume of shed blood. The rats were assigned to either the H2 gas (1.3% H2, 26% O2, 72.7% N2)-treated group or the control gas (26% O2, 74% N2)-treated group. Inhalation of the specified gas mixture began at the initiation of blood withdrawal and continued for 2 hours after fluid resuscitation. Results: The survival rate at 6 hours after fluid resuscitation was 80% in H2 gas-treated rats and 30% in control gas-treated rats (p < 0.05). The volume of blood that was removed through a catheter to induce shock was significantly larger in the H2 gas-treated rats than in the control rats. Despite losing more blood, the increase in serum potassium levels was suppressed in the H2 gas-treated rats after 60 minutes of shock. Fluid resuscitation completely restored blood pressure in the H2 gas-treated rats, whereas it failed to fully restore the blood pressure in the control gas-treated rats. At 2 hours after fluid resuscitation, blood pressure remained in the normal range and metabolic acidosis was well compensated in the H2 gas-treated rats, whereas we observed decreased blood pressure and uncompensated metabolic acidosis and hyperkalemia in the surviving control gas-treated rats. Conclusions: H2 gas inhalation delays the progression to irreversible shock. Clinically, H2 gas inhalation is expected to stabilize the subject until curative treatment can be performed, thereby increasing the probability of survival after hemorrhagic shock.
Background: The present study aimed at investigating the effect of a novel antioxidant, hydrogen (H2) gas, on the severity of contrast-induced acute kidney injury (CIAKI) in a rat model. Methods: CIAKI was induced in rats by intravenous injection of a contrast medium, Ioversol, in addition to reagents inhibiting prostaglandin and nitric oxide synthesis. During the injection of these reagents, the rats inhaled H2 gas or control gas. Results: One day after the injection, serum levels of urea nitrogen were significantly lower in H2 gas-inhaling CIAKI rats (17.6 ± 2.3 mg/dl) than those in control gas-treated CIAKI rats (36.0 ± 7.3 mg/dl), although they both were elevated as compared to untreated rats (14.9 ± 0.9 mg/dl). Consistently, creatinine clearance in H2 gas-treated CIAKI rats was higher than that in control gas-treated counterparts. Renal histological analysis revealed that the formation of proteinaceous casts and tubular necrosis was improved by H2 gas inhalation. Mechanistic analyses showed that inhalation of H2 gas significantly reduced renal cell apoptosis, expression of cleaved caspase 3, and expression of an oxidative stress marker, 8-hydroxydeoxyguanosine, in injured kidneys. Conclusion: Results suggest that H2 gas inhalation is effective in ameliorating the severity of CIAKI in rats by reducing renal cell apoptosis and oxidative stress. © 2015 S. Karger AG, Basel.