Overview and Scope of the Book
Molecular Hydrogen for Medicine: The Art of Ancient Life Revived by Yuh Fukai (2020) is a comprehensive and critical exploration of the emerging medical field known as Molecular Hydrogen Medicine (MHM). The book bridges fundamental science, evolutionary biology, and clinical research to present molecular hydrogen (H2) as a novel therapeutic and preventive agent with broad physiological effects. It synthesizes decades of experimental, clinical, and historical data to elucidate hydrogen’s unique properties, mechanisms of action, and potential applications across a wide spectrum of diseases, including cancer-related oxidative stress and inflammation.
The author, a physicist by training, aims to provide a rigorous, interdisciplinary guide that contextualizes molecular hydrogen within the history of life on Earth, its biochemical roles, and its translational potential in modern medicine. The book is intended for researchers, clinicians, and advanced students interested in oxidative stress biology, antioxidant therapies, and innovative medical interventions, especially those related to chronic diseases, neurodegeneration, ischemia-reperfusion injury, and metabolic disorders.
Part I: What is Molecular Hydrogen Medicine?
This section introduces Molecular Hydrogen Medicine as a new medical field leveraging the physiological actions of molecular hydrogen (H2) for therapeutic and preventive purposes. Unlike hydrogen chemically bound within biological molecules, molecular hydrogen gas or hydrogen-rich water is nearly absent naturally in the body, so external administration can induce significant biological effects.
The origin of MHM traces back to a landmark 2007 study by Ohsawa et al., which demonstrated that inhaled hydrogen gas selectively scavenges harmful hydroxyl radicals (•OH) in rat models of brain ischemia-reperfusion injury, reducing damage without affecting other reactive oxygen species (ROS) essential for cell signaling. Earlier sporadic reports, such as Dole et al. (1975), hinted at hydrogen’s biological effects on cancer and liver damage but were largely overlooked until this pivotal work.
Japanese research initially focused on “reduced water” generated by electrolysis, with anecdotal health claims but limited scientific validation. Ohta and Ohsawa’s group rigorously showed that molecular hydrogen selectively neutralizes hydroxyl radicals, penetrates all cellular organelles (unlike conventional antioxidants), and exerts antioxidant, anti-apoptotic, anti-inflammatory, anti-allergen, and metabolic regulatory effects.
Animal studies demonstrated that inhalation of 2–4% hydrogen gas significantly reduced ischemia-reperfusion injury in brain and liver models and improved outcomes in transplantation and acute inflammatory conditions. The book also situates MHM within evolutionary biology, proposing that hydrogen’s role in early life forms has been retained physiologically, providing a biochemical “memory” that modern medicine can harness.
The author emphasizes hydrogen’s high stability and prior classification as biologically inert, which delayed recognition of its medical potential. The section outlines hydrogen’s physiological effects, administration methods (inhalation, drinking, injection), clinical trials, and historical perspectives, setting the foundation for subsequent detailed discussions.
Development and Expansion of Molecular Hydrogen Medicine
Research has expanded beyond antioxidant effects to encompass anti-inflammatory, anti-allergen, and metabolic regulatory actions. Animal models reveal benefits in diverse conditions including ischemia-reperfusion injury of heart, brain, lung, and liver; organ transplantation; glaucoma; cataract surgery; acute skin diseases; sepsis; and metabolic syndrome.
Clinical trials, predominantly conducted in Japan, have explored hydrogen’s effects in acute myocardial infarction, cardiac arrest, stroke, neurodegenerative diseases (Parkinson’s, Alzheimer’s), diabetes, rheumatoid arthritis, dialysis, and periodontitis. For example, hydrogen inhalation improved survival and neurological outcomes in rat cardiac arrest models, while hydrogen-supplemented perfusates enhanced graft function and reduced inflammation in lung and liver transplantation models.
Hydrogen water has shown efficacy in reducing inflammation and oxidative stress in experimental peritonitis, sepsis, and radiation injuries. Its excellent safety profile facilitates clinical translation, though statistical significance and interpretation require cautious evaluation.
The historical context traces hydrogen’s discovery by Lavoisier in 1789, linking foundational chemical and physiological concepts to modern MHM. The book highlights the evolution of understanding respiration as combustion and hydrogen’s fundamental role in life.
Therapeutic and Preventive Effects of Molecular Hydrogen
Hydrogen’s therapeutic effects extend beyond initial expectations. In acute peritonitis models, oral hydrogen water improved survival and reduced inflammatory markers, suggesting adjunctive use with antibiotics. Hydrogen water accelerated wound healing in oral mucosa and mitigated radiation-induced damage in multiple tissues, including lungs, skin, bone marrow, and testis.
In metabolic syndrome, hydrogen water improved fat and sugar metabolism, reduced obesity, liver fat, blood glucose, insulin, and complications such as erectile dysfunction and retinopathy. It also suppressed arteriosclerosis in animal models.
Neurologically, hydrogen water alleviated memory impairment and cognitive decline in models of stress, aging, Alzheimer’s, and Parkinson’s disease, preventing neurodegeneration and abnormal movements induced by toxins.
In lung diseases, hydrogen reduced oxidative stress, inflammation, apoptosis, and neutrophil infiltration in acute lung injury models induced by hyperoxia, burns, hemorrhagic shock, lipopolysaccharide, and drug toxicity. It suppressed NF-κB activation and autophagy markers, ameliorated cigarette smoke-induced COPD, and mitigated lung injury from anti-cancer drugs without compromising efficacy.
Preventive effects include pre-administration of hydrogen water reducing severity of irradiation damage and Parkinson’s disease models, as well as improving survival in drug-induced sepsis when started days before induction.
Origins of Fatigue and Aging
The book discusses fatigue as resulting from accumulation of superoxide anions (ROS) during metabolism and exercise exceeding antioxidant capacity. Hydrogen water intake mitigates physical and mental fatigue and improves autonomic and cognitive functions, supported by animal and human studies.
Aging is attributed primarily to accumulated ROS damage causing organ dysfunction. Hydrogen water may slow aging by reducing oxidative damage, as demonstrated in mouse models.
Current State and Clinical Trials of Molecular Hydrogen Medicine
By 2018, over 700 papers documented physiological and medical effects of hydrogen, with rapid growth since 2007. The Japanese Society for Medical and Biological Research on Molecular Hydrogen (established 2016) and the International Society for Hydrogen Medicine and Biology (established 2017) promote research and clinical applications.
Animal studies cover cardiovascular, neurological, cancer, ocular, hepatic, pulmonary, metabolic, muscular, and dermatological diseases. Human clinical trials, though fewer, are increasing and face challenges including ethical considerations, large sample sizes, and rigorous placebo-controlled designs.
Major clinical trial results include:
- Cardiac Arrest and Acute Myocardial Infarction: Trials at Keio University demonstrated that hydrogen gas inhalation during hypothermia therapy reduces ischemia-reperfusion injury, improves neurological outcomes, and is safe with appropriate protocols. A large-scale nationwide trial (HYBRID Research Group) is ongoing.
- Stroke: Hydrogen gas inhalation suppressed infarct progression and improved functional outcomes, possibly by protecting dying brain cells and enhancing stem cell regeneration.
- Neurodegenerative Diseases: In Parkinson’s disease, saturated hydrogen water slowed disease progression in a double-blind trial. Alzheimer’s disease patients showed symptom improvement and MRI evidence of nerve fiber regeneration with hydrogen gas inhalation, though larger trials are needed.
- Rheumatoid Arthritis: Hydrogen water consumption improved symptoms, especially in early-stage patients, likely by reducing ROS-mediated inflammation.
- Blood Dialysis: Hydrogen-enriched dialysis solution improved kidney function and reduced mortality by 41% over 5 years in a large trial, possibly by repairing blood damage during dialysis.
- Cataract Surgery: Hydrogen-dissolved irrigation solution reduced corneal endothelial cell damage during phacoemulsification.
- Periodontitis: Hydrogen water reduced periodontal pocket depth and increased antioxidant capacity, with implications for systemic diseases linked to periodontitis.
- Radiation Injuries: Hydrogen water reduced oxidative stress and improved quality of life in liver cancer patients undergoing radiotherapy, and may protect against chronic radiation-induced cardiovascular disease.
- COVID-19 Pneumonia: A Chinese trial showed that inhalation of a 66% H2/33% O2 gas mixture improved respiratory symptoms and disease severity, likely by mitigating cytokine storm inflammation.
The author cautions that many trials are preliminary or small-scale, mechanisms remain under investigation, and safety protocols are essential due to hydrogen’s flammability.
Part 3: From the Front-Line of Research – Interviews and Insights
This section presents interviews with leading researchers and clinicians involved in molecular hydrogen research. Early animal experiments demonstrated that low-concentration (2%) hydrogen gas inhalation effectively suppressed brain ischemia-reperfusion injury, with higher concentrations less effective, highlighting dose-dependent effects.
Clinical applications began early in cardiopulmonary arrest patients and ophthalmology, with hydrogen-enriched perfusion solutions used during cataract surgery. Hydrogen water showed significant benefits in arteriosclerosis, Parkinson’s disease, sepsis, atopic dermatitis, and chronic nephropathy animal models.
Research at Tokyo Metropolitan Institute of Gerontology focuses on aging-related diseases, exploring optimal administration routes and mechanisms beyond hydroxyl radical scavenging, including gene expression modulation via Nrf2.
Clinical studies include diabetic patients consuming hydrogen water, with ongoing data analysis. Cautions include unknown side effects in infants and pregnant women, and recommendations to use reliable hydrogen water sources promptly.
Hydrogen gas inhalation is under clinical trial for post-cardiac arrest syndrome at Keio University Hospital, combined with hypothermia therapy. This is the first large-scale human trial evaluating hydrogen inhalation efficacy.
Neurosurgery experience highlights advances in brain imaging and stem cell research, with early hydrogen therapy showing encouraging results in severe cases including acute cutaneous erythema and stroke secondary symptoms. Alternative clinical approaches for multifactorial neurodegenerative diseases like Alzheimer’s show promise due to hydrogen’s multifunctional effects.
Part 4: Physiological Effects of the Hydrogen Molecules
Hydrogen molecules enter the body via inhalation or drinking hydrogen water, rapidly distributing through blood to organs including brain, liver, and kidney within minutes. Hydrogen crosses the blood-brain barrier and cell membranes due to its small size and lipophilicity, concentrating in lipophilic cell membranes more than hydrophilic cytoplasm. It is excreted mainly by exhalation shortly after administration.
Endogenous hydrogen is produced by intestinal bacteria and exhaled in small amounts. Human exposure to low concentrations of hydrogen is common and safe, as evidenced by submarine and space station environments. Clinical studies report no harmful effects from hydrogen inhalation or hydrogen water consumption, though caution is advised for infants and pregnant women.
Mechanisms of action include:
- Direct scavenging of hydroxyl radicals (•OH): Hydrogen selectively neutralizes the highly reactive and toxic hydroxyl radical, reducing oxidative stress. However, due to low concentration and slower reaction rates compared to other biomolecules, direct scavenging alone cannot explain all observed effects.
- Nrf2/HO-1 pathway activation: Hydrogen activates the transcription factor Nrf2, which regulates antioxidant and anti-inflammatory gene expression, including heme oxygenase-1 (HO-1). This pathway contributes to protection against oxidative injury and broad physiological effects beyond direct radical scavenging.
- Modulation of intestinal microbiota: Hydrogen-producing gut bacteria contribute to endogenous hydrogen levels. Hydrogen administration suppresses bacterial translocation, maintains microbiota balance, and modulates immune responses, which may open new therapeutic avenues.
Animal studies show hydrogen administration improves survival in sepsis models by maintaining normal microbiota composition and reducing intestinal injury and oxidative stress. The synergistic action of microbiota and innate immune pathways is crucial for hydrogen’s effects.
The author notes that chronic diseases like Alzheimer’s and Parkinson’s involve complex, long-term lesion accumulation, and animal model results may not directly extrapolate to humans due to variability in microbiota and immune activity.
Part 5: Some Fundamental Properties of Hydrogen and Water
Hydrogen’s solubility in water at 20°C is approximately 1.6 ppm, about one-thirtieth that of oxygen by weight but nearly half the number of molecules due to hydrogen’s lower molecular mass. Hydrogen escapes readily from water exposed to air, causing hydrogen water to lose concentration over time.
Water’s unique properties arise from hydrogen bonding, which is weaker than covalent bonds but forms transient clusters enabling rapid migration of hydrogen and hydroxide ions. These hydrogen bonds underpin water’s high heat capacity, boiling point, and density anomalies.
Hydrogen atoms and molecules exhibit quantum tunneling, allowing migration through biological materials without thermal activation. This tunneling depends on hydrogen’s low mass and low energy barriers. Hydrogen molecules (H2) are small, chemically stable, and can diffuse rapidly into cells and organelles, unlike heavier isotopes such as deuterium (D2), which tunnel less effectively and have reduced biological activity.
The Grotthuss mechanism describes proton transfer in water via successive hydrogen bonding and rearrangement of water molecules, explaining the high mobility of H+ and OH− ions. This early 19th-century concept anticipated modern ion theory and is fundamental to understanding hydrogen’s behavior in biological systems.
Part 6: Preparation, Handling, and Usage of Hydrogen
Hydrogen administration methods include oral intake of hydrogen gas or hydrogen water and intravenous infusion of hydrogen-rich solutions. Optimal dosing and protocols remain undefined, and hydrogen’s small molecular size makes it difficult to contain, requiring strict quality control.
Hydrogen gas inhalation allows higher doses but poses explosion risks above 4% concentration, and legal restrictions limit high-pressure gas use in hospitals. Hydrogen storage alloys offer safer hydrogen sources by reversible absorption and desorption at moderate pressures.
Electrolysis of water is a common method for continuous hydrogen gas production, with commercial devices mainly for personal use. Hydrogen water for medical use can be prepared by permeation through plastic membranes into sterile sealed bags, suitable for clinical applications such as hemodialysis.
Simple bubbling methods achieve ~1 ppm hydrogen concentration but are unsuitable for sterile medical use. Molecular hydrogen is not yet approved as a drug or supplement in Japan, though personal use is considered safe due to lack of side effects.
Hydrogen water differs from carbonated water in solubility and loss characteristics. Aluminum containers are preferred for hydrogen water storage due to extremely low hydrogen permeability, whereas plastics and metals like steel and copper have higher permeability.
Three main methods to produce hydrogen water supplements are:
- Electrolysis of water producing ~2 ppm hydrogen, with concerns about electrode deterioration and contamination.
- Chemical reaction of metallic magnesium with water producing hydrogen and magnesium hydroxide, yielding up to ~1.6 ppm hydrogen.
- Use of hydrogen storage alloys releasing hydrogen gas dissolved into water, yielding 1.0–1.4 ppm hydrogen.
Freshly prepared hydrogen water is preferable due to gradual hydrogen loss. Purity and safety of reaction products must be carefully considered.
Part 7: Functions of Heavy Water in Living Organisms
Heavy water (D2O), containing the hydrogen isotope deuterium, differs from normal water (H2O) in physical and biological properties. Early studies showed heavy water inhibits growth and germination in plants and yeast, with toxic effects in small animals appearing at 20–25% concentration, including agitation, convulsions, tumors, and death above 30%.
Heavy water impairs sugar metabolism, hematopoiesis, and reproductive functions, and slows or halts cell division, including in human cancer cells. These effects arise from isotope effects on hydrogen bonding (stronger in deuterium) and quantum tunneling (slower in deuterium), affecting biochemical reaction chains.
Medical applications focus on organ preservation in transplantation, where heavy water stabilizes cytoskeletal proteins, inhibits calcium overload, and promotes ATP production during cold storage. Modified preservation solutions containing ~30% heavy water (e.g., Dsol) significantly improve viability and function of cold-preserved organs in animal models compared to standard University of Wisconsin (UW) solution.
Dsol reduces infarcts, fibrosis, protease activation, calcium overload, and improves ATP recovery and organ function after reperfusion. Challenges remain in scaling to large animal organs and reducing costs, as current methods dilute 99.9% heavy water to 30% inefficiently.
Expanding heavy water use to myocardial protection during artificial heart-lung machine use and food preservation could promote mass production and cost reduction. Safety concerns about deuterium accumulation in food require precise analysis methods.
Recent advances in induced pluripotent stem (iPS) cells and autophagy research are relevant to transplant medicine. iPS cells offer potential for regenerative therapies, while autophagy may be linked to organ preservation mechanisms, as suggested by increased ATP levels in deuterated preservation solutions.
Transplant and regenerative medicine may coexist and complement each other in the future. The section also recounts the historical naming of deuterium and its isotopes.
Part 8: The Future of Molecular Hydrogen Medicine
Molecular Hydrogen Medicine has progressed from foundational animal studies to accumulating human clinical data, focusing initially on diseases lacking effective treatments. As mechanisms and efficacy become clearer, MHM may expand to diseases with existing therapies, potentially replacing some conventional drugs due to lower cost and fewer side effects.
This evolution poses challenges to pharmaceutical companies, as hydrogen treatments are difficult to patent and require minimal equipment, reducing commercial incentives. Government involvement and health policy support are crucial to advance research and clinical application.
MHM holds promise to address rising healthcare costs and aging populations by providing affordable, safe, and effective treatments.
Part II: Tracing the History of Life and Hydrogen
This part situates molecular hydrogen within the evolutionary history of life on Earth, emphasizing its primordial role and ongoing physiological relevance.
Chapter 9: The Genesis of Life in the World of Hydrogen, Eons Ago
Life originated approximately 4 billion years ago in anoxic primitive oceans under harsh conditions. Deep-sea hydrothermal vents emitted hydrogen, hydrogen sulfide, methane, and metals, providing energy and materials for early life. Early organisms were thermophilic, autotrophic prokaryotes (archaea and bacteria) utilizing hydrogen as an energy source via hydrogenase enzymes.
Anaerobic hydrogen-utilizing organisms persisted for about 2 billion years until atmospheric oxygen rose. Hydrogenase enzymes evolved to adapt to increasing oxygen. Anaerobic organisms remain widespread underground and in various environments, carrying evolutionary memory of the hydrogen era.
Recent fossil evidence supports the hydrothermal vent hypothesis for life’s origin.
Chapter 10: Drastic Changes of Living Organisms in the Oxygen Age
Oxygen appeared in the atmosphere about 2.7 billion years ago, produced by photosynthetic cyanobacteria forming stromatolites. Rising oxygen levels enabled evolution of aerobic organisms capable of efficient ATP production via aerobic respiration, involving hydrogen and water biochemistry.
Incorporation of mitochondria into eukaryotic cells was key to energy efficiency, enabling larger, multicellular organisms and complex tissues. The Cambrian Explosion (~550 million years ago) saw rapid diversification of animals. Plants and animals colonized land following ozone layer formation and skin adaptations.
Biomolecules such as proteins and DNA rely on hydrogen bonds for 3D structure and function. Aerobic organisms developed defense systems against ROS, including superoxide dismutase enzymes. The evolutionary legacy of the hydrogen age remains embedded in biological molecules and processes.
Chapter 11: Since the Appearance of Humans
Humans appeared late in the oxygen age; oxygen metabolism enabled rapid evolution but introduced harmful ROS. Molecular hydrogen, produced by intestinal bacteria, exerts physiological effects and is considered part of ancestral biochemical machinery from the hydrogen age.
Human body composition retains traces of ancient ocean chemistry, with water (~60% of body) containing hydrogen and oxygen in ~2:1 ratio, similar to seawater. Essential metals are concentrated in the body for enzyme function and cellular activity.
Water and oxygen circulate extensively via blood, with oxygen transported by hemoglobin and stored by myoglobin. The discovery of aquaporins (water channel proteins) revolutionized understanding of water transport across membranes. Aquaporins facilitate rapid, selective water movement; hydrogen molecules uniquely permeate membranes freely despite strict regulation of other substances.
Reactive oxygen species (ROS) include about 20 types, some physiological but many damaging in excess. Key ROS are superoxide anion (O2•−), hydroxyl radical (•OH), hydrogen peroxide (H2O2), and singlet oxygen (¹O2). Superoxide anion is abundant and moderately reactive, eliminated by superoxide dismutase (SOD). Hydroxyl radical is highly reactive and toxic, damaging DNA, proteins, and lipids.
Living organisms balance ROS via enzymatic antioxidants (SOD, catalase, glutathione peroxidase) and non-enzymatic antioxidants (vitamins C, E, carotenoids). Mammals rely on dietary antioxidants, but excessive supplementation may be harmful. ROS are implicated in 90% of non-pathogenic diseases. Selective removal of hydroxyl radicals is challenging; molecular hydrogen administration offers a unique approach.
“Memories” of the hydrogen age persist in biology: some organisms show enhanced activity in hydrogen environments; plants grow better with elevated CO2; prokaryotes originally freely exchanged hydrogen and other gases; hydrogen influx and efflux remain largely free through evolution. Intestinal microbiota produce hydrogen, which is absorbed and circulates systemically, contributing to physiological effects.
The discovery of molecular hydrogen’s medical effects represents a re-recognition of ancestral biochemical functions. The chapter references key works on aquaporins, origins of life, and ROS biology.
Strengths and Notable Features
- The book offers a uniquely interdisciplinary perspective, integrating physics, chemistry, biology, medicine, and evolutionary history to elucidate molecular hydrogen’s role.
- It provides detailed summaries of animal and human clinical studies, including mechanisms, administration methods, and safety considerations.
- Historical context enriches understanding of hydrogen’s fundamental biological significance.
- Interviews with leading researchers provide practical insights and highlight ongoing challenges and future directions.
- Discussion of heavy water’s physiological effects and applications in organ transplantation adds depth to hydrogen isotope biology.
- Emphasis on molecular hydrogen’s selective scavenging of hydroxyl radicals addresses a critical gap in antioxidant therapy.
Limitations and Cautions
- Many clinical trials cited are preliminary, small-scale, or lack long-term follow-up; larger, rigorous studies are needed to confirm efficacy and safety.
- Exact molecular mechanisms remain incompletely understood, with multiple pathways likely involved.
- Hydrogen gas administration requires strict safety protocols due to flammability and explosion risks.
- Variability in individual microbiota and immune responses complicates extrapolation from animal models to humans.
- Heavy water applications face cost and scalability challenges.
- Antioxidant supplementation must be balanced; indiscriminate elimination of ROS can be detrimental.
Relevance to Cancer and Related Diseases
The book discusses molecular hydrogen’s potential to mitigate oxidative stress and inflammation, key contributors to cancer initiation, progression, and treatment side effects. Hydrogen’s selective scavenging of hydroxyl radicals may protect normal tissues during radiotherapy and chemotherapy, as shown in radiation injury models and cataract surgery. Its anti-inflammatory and metabolic regulatory effects may also influence cancer-related systemic conditions such as metabolic syndrome and immune dysregulation.
While direct anticancer effects are not the primary focus, hydrogen’s role in reducing oxidative damage and improving tissue resilience may complement conventional cancer therapies and supportive care.
Potential Utility in This Database
This book serves as a valuable reference for clinicians, researchers, and caregivers interested in novel antioxidant therapies and integrative approaches to oxidative stress-related diseases, including cancer. It provides a thorough scientific foundation for understanding molecular hydrogen’s physiological actions, clinical trial evidence, and practical considerations for administration and safety.
Its evolutionary and biochemical context enriches comprehension of hydrogen’s unique role, while the inclusion of heavy water applications broadens the scope to organ preservation and transplantation medicine. The detailed discussion of clinical trials, including those related to neurodegeneration, cardiovascular disease, and radiation injury, offers insights relevant to supportive oncology care.
Overall, the book supports informed evaluation of molecular hydrogen as a complementary therapeutic option and encourages further research and clinical exploration.
