Safety & Health Benefits of Hydrogen Water – Nobel Prize Nominee, Dr. GARTH NICOLSON
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Molecular Hydrogen water effects on Mild Cognitive Impairment
Abstract
Background:
Oxidative stress is one of the causative factors in the pathogenesis of neuro-degenerative diseases including mild cognitive impairment (MCI) and dementia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant.
Objective:
We assess the effects of drinking H2 hydrogen-water (water infused with hydrogen gas H2) on oxidative stress model mice and human subjects with MCI.
Methods:
Transgenic mice expressing a dominant-negative form of aldehyde dehydrogenase 2 were used as a dementia model. The mice with enhanced oxidative stress were allowed to drink hydrogen H2-water.
For a ran-domized double-blind placebo-controlled clinical study, 73 subjects with mild cognitive impairment MCI drank ~300 mL of hydrogen H2-water (H2-group) or placebo water (control group) per day, and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores were determined after 1 year.
Results:
In mice, drinking hydrogen H2-water decreased oxidative stress markers and suppressed the decline of memory impairment and neurodegeneration. Moreover, the mean lifespan in the hydrogen H2-water group was longer than that of the control group.’
In MCI subjects, although there was no significant difference between the hydrogen water H2- and control groups in ADAS-cog score after 1 year, carriers of the apolipoprotein E4 (APOE4) geno-type in the H2-group were improved significantly on total ADAS-cog score and word recall task score (one of the sub-scores in the ADAS-cog score).
Conclusion:
H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4 carriers with MCI.
1. INTRODUCTION
Oxidative stress is one of the causative factors in the pathogenesis of major neurodegenerative diseases including Alzheimer’s disease (AD), mild cognitive impairment (MCI), and Parkinson disease (PD) [1, 2]. Moreover, the genotype of apolipoprotein E4 (APOE4) is a genetic risk for AD, and the increased oxidative stress in the APOE4 carriers is considered as one of the modifiers for the risk [3].
To explore effective dietary antioxidants to mitigate age-dependent neurodegeneration, it may be useful to construct model mice in which AD phenotypes would progress in an age-dependent manner in response to oxidative stress. We constructed transgenic DAL101 mice expressing a polymorphism of the mitochondrial aldehyde dehydrogenase 2 gene (ALDH2*2) [4]. ALDH2*2 is responsible for a deficiency in ALDH2 activity and is specific to North-East Asians [5]. We reported previously that ALDH2 deficiency is a risk factor for late-onset AD in the Japanese population, [6] which was reproduced by Chinese and Korean studies in their respective populations [7, 8]. DAL101 mice exhibited a decreased ability to detoxify 4-hydroxy-2-nonenal (4-HNE) in cortical neurons, and consequently an age-dependent neurodegeneration, cognitive decline, and a shortened lifespan [4].
We proposed that molecular hydrogen (H2) has potential as a novel antioxidant, [9] and numerous studies have strongly suggested its potential for preventive and therapeutic applications [10–12]. In addition to extensive animal experiments, more than 25 clinical studies examining the efficacy of molecular hydrogen H2 have been reported, [11, 12] including double-blind clinical studies. Based on these studies, the field of hydrogen medicine is growing rapidly.
There are several methods to administer hydrogen H2, including inhaling hydrogen gas (H2-gas), drinking hydrogen H2-dissolved water (H2-water), and injecting hydrogen H2-dissolved saline (hydrogen-rich saline) [13]. Drinking hydrogen H2-water prevented the chronic stress-induced impairments in learning and memory by reducing oxidative stress in mice [14] and protects neural cells by stimulating the hormonal expression of ghrelin [15]. Additionally, injection of hydrogen-rich saline improved memory function in a rat model of amyloid-β-induced dementia by reducing oxidative stress [16]. Moreover, hydrogen inhalation during normoxic resuscitation improved neurological outcome in a rat model of cardiac arrest independently of targeted temperature management [17].
In this study, we examined whether drinking hydrogen H2-water could suppress aging-dependent memory impairment induced by oxidative stress in DAL101 mice. Next, in a randomized double-blind placebo-controlled study, we investigated whether H2-water could delay the progression of MCI as assessed by the scores on the Alzheimer’s Disease Assessment Scale-cognition sub-scale (ADAS-cog) [18, 19] from baseline at 1-year. We found a significant improvement in cognition at 1 year in carriers with the APOE4 genotype in the H2-group using sub- and total ADAS-cog scores.
2. MATERIALS AND METHODS
2.1. Ethical Approval and Consent to Participate
This animal study was approved by the Animal Care and Use Committee of Nippon Medical School. The methods were carried out in “accordance” with the relevant guidelines and regulations.
The clinical study protocol was approved by the ethics committees of University of Tsukuba, and registered in the university hospital medical information network (UMIN) as UMIN000002218 on July 17, 2009 at https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=history&action =list&type= summary&recptno= R000002-725&language=J.
Participants were enrolled from July 2009. All patients provided written informed consent prior to research investigations, which were conducted according to the Declaration of Helsinki and subsequent revisions.
2.2. Transgenic DAL101 Mice
Transgenic mice (DAL101) that express a transgene containing a mouse version of ALDH2*2 were constructed as described previously [4]. Since the number of mice used for each experiment was not consistent because of a breeding difficulty, the number of the mice used was specified. All mice were kept in a 12-hr light/dark cycle with ad libitum access to food and water. Examiners performed experiments in a blinded fashion. Since no significant decline was observed in cognitive impairment at the age of 18 months in wild-type mice with the same genetic background (C57BL/6), [4] the effects of hydrogen H2-water were not assessed in this study.
2.3. Hydrogen Water
For animal experiments, saturated hydrogen H2-water was prepared as described previously [14]. In brief, hydrogen H2 was dissolved in water under high pressure (0.4 MPa) to a supersaturated level, and the saturated H2-water was stored under atmospheric pressure in an aluminum bag with no headspace. As a control, H2-water was completely degassed by gentle stirring for one day. Mice were given water freely using closed glass vessels equipped with an outlet line containing two ball bearings, which kept the water from being degassed. The vessel was freshly refilled with H2-water 6 days per week at 2:00 pm. The hydrogen H2-concentration was still more than 0.3 mM on the next day.
For this clinical study, commercially available hydrogen H2-water was a gift from Blue Mercury, Inc. (Tokyo, Japan). The hydrogen H2-water (500 mL) was packed in an aluminum pouch with no headspace to maintain H2 concentration, and sterilized at 80°C for 30 min. The concentration of hydrogen H2 was measured using a hydrogen sensor (Unisense, Aarhus N, Denmark), and used if the value was more than 0.6 mM. Placebo water packed in an identical package (500 mL) was also provided by Blue Mercury Inc. This company played no role in collection of data, management, analysis, or interpretation of the data. One package with 500 mL of placebo or hydrogen H2-water per day was provided after showing previous empty packages, by which self-reported compliance rates in the intervention group were calculated as the volume of hydrogen H2-water at 1-year.
2.4. Measurement of Oxidative Stress
As an oxidative stress marker, 8-OHdG [20] was measured using urine samples, which were collected between 9:00 and 10:00 am as described previously [21], by using a competitive enzyme-linked immunoassay (New 8-OHdG check; Japan Institute for the Control of Aging, Shizuoka, Japan). The values were normalized by urinary creatinine concentration, which was assayed using a standard kit (Wako, Kyoto, Japan). As an additional oxidative stress marker in the brain, accumulated MDA was determined using a Bioxytech MDA-586 Assay Kit (Percipio Biosciences, CA, USA). Malondialdehyde(MDA)levels were normalized against protein concentrations.
2.5. Measurement of Memory Impairment: Object Recognition Task
Learning and memory abilities were examined using objection recognition task (ORT) [4]. A mouse was habituated in a cage for 4 h, and then two different-shaped objects were presented to the mouse for 10 min as training. The number of times of exploring and/or sniffing each object was counted for the first 5 min (Training test). The frequencies (%) in training test were considered as the backgrounds. To test memory retention after 1 day, one of the original objects was replaced with a novel one of a different shape and then times of exploration and/or sniffing was counted for the first 5 min (Retention test). When mice would lose learning and memory abilities, the frequencies of exploration and/or sniffing of each object should be equal (about 50%) in the training session, indicating that mice showed a similar interest in each object because of lack of memory for the objects. Learning and memory abilities were evaluated as the subtraction of the frequencies (%) in the retention test from each background (Training test).
2.6. Measurement of Memory Impairment: Passive Avoidance Task (PA)
The apparatus consisted of two compartments, one light and the other dark, separated by a vertical sliding door [22]. On day 1, we initially placed a mouse in the light compartment for 20 s. After the door was opened, the mouse could enter the dark compartment (mice instinctively prefer being in the dark). On day 2, the mouse was again placed in the light section to allow the mouse to move into the dark section. After the mouse entered the dark compartment, the door was closed. After 20 s, the mouse was given a 0.3 mA electric shock for 2 s. The mouse was allowed to recover for 10 s, and was then returned to the home cage. On day 3, 24h after the shock, the mouse was again placed in the light section with the door opened to allow the mouse to move into the dark section. We examined the latency time for stepping through the door. Learning and memory abilities were assessed as the subtraction of the latency times after the electric shock from each background (before).
2.7. Immunostaining of the Hippocampal CA1 Region
To examine neuronal loss and glial activation, the hippocampus region was stained with a pyramidal neuron-specific anti-NeuN antibody (clone A60; Merck Millipore, Darmstadt, Germany), an astrocyte-specific anti-glial fibrillary acidic protein (anti-GFAP) antibody (Thermo Scientific, MA, USA) or a microglia-specific anti-IbaI antibody (Wako). Mice were transcardially perfused to be fixed with 4% paraformaldehyde in phosphate-buffered saline (PBS) under anesthesia, and their brains were cryoprotected with 30% sucrose, and then frozen brain was sectioned at 8 μm thickness. After incubation with each primary antibody, sections were treated with secondary antibodies (Vector Laboratories, CA, USA) and their immunereactivity was visualized by the avidin-biotin complex method (Vector Laboratories).
2.8. Subjects of the Clinical Study
This study was a randomized, double-blind, placebo-controlled trial undertaken as a part of Tone project, an ongoing epidemiological study conducted in Tone Town, Ibaraki, Japan as described in detail previously [23, 24]. This town is located approximately 40 km northeast of central Tokyo and consists of 22 districts. The baseline survey of the Tone project included 1,032 participants in July 2009, and subjects of the present study were recruited from these participants.
Eligibility criteria are age 67 years or older, being able to give written informed consent for participation in the present study, with a diagnosis of MCI, being able to observe the following requirement: good compliance with water consumption; participation in the scheduled examinations for assessment; keeping a log-diary recording consumption of the water, with a modified Hachinski Ischemic score of 4 or less and a 15-item Geriatric Depression Scale score of 6 or less. In brief, 3 months before this clinical study, all participants underwent a group assessment which used a set of 5 tests that measured the following cognitive domains: attention; memory; visuospatial function; language; and reasoning as described previously [25]. Objective impairment in at least 1 cognitive domain based on the average of the scores on the neuropsychological measures within that domain and 1 SD cut-off using normative corrections for age, years of education, and sex.
Exclusion criteria were having “The Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV TR” criteria for dementing illnesses, a serious or unstable illnesses, a history within the past 5 years of serious infectious disease affecting the brain and/or malignant diseases, a history of alcohol or drug abuse or dependence (on DSM-IV TR) within the past 5 years, and receiving any types of anti-Alzheimer drugs and recent (within 4 weeks) initiation of medications that affect the central nervous system. When the score of Mini Mental State Examination (MMSE) [26] was less than 24, the subjects were excluded.
In this study, subjects were randomly assigned to either to an intervention group, who received H2-water every-day for 1 year, or a control group, who received placebo water. The allocation sequence was determined by computer-generated random numbers that were concealed from the investigators and subjects. Drs. Nakajima and Ikejima generated the random allocation sequence, enrolled participants, and assigned participants to interventions. Any participants and care providers were blindly masked.
In the original protocol, we planed to administer H2-water for 2 years and assess the secondary outcomes; however, we had to stop the project in 2011 by the Tsunami-disaster and could not obtained the 2-year data and secondary outcomes.
The APOE4 genotype was determined as described [25].
2.9. Statistical Considerations
All statistical analyses were performed by an academic biostatistician using SAS software version 9.2 (SAS Institute Inc, Cary, NC, USA). Results were considered significant at p < 0.05.
For the comparison of two groups in learning and memory abilities, and lifespans, unpaired two-tailed Student’s t-test was used for the comparison of H2-group with control group. For the other animal experiments, one-way analysis of variance (ANOVA) with Tukey-Kramer or Dunnett post hoc analysis was applied unless otherwise mentioned.
For the clinical trial, we planned to recruit a total of 120 patients, which would provide 90% power to detect an effect size of 0.6 using a two-sided test with a 5% significance level, but the actual sample size for the primary analysis was 73, leading to 70% power in the same setting. End-points were scores in the Japanese version of ADAS-cog at 1-year, and the changes were evaluated by Mann-Whitney’s U test (non-parametric analysis) as well as Student’s t-test (parametric analysis).
3. RESULTS
3.1. Hydrogen-water Reduced Oxidative Stress in DAL Mice
Male DAL101 mice were given H2– or control water to drink ad libitum from the age of 1 month, and continued until the age of 18 months. The H2-water DAL101 group showed a significant decrease in the level of an oxidative stress marker, urinary 8-hydroxy-2’-deoxyguanosine (8-OHdG)[20] at the age of 14months (Suppl. Fig. S1A). Moreover, DAL101 mice increased oxidative stress in the brain as measured by the level of MDA as an alternative oxidative stress marker, and H2-water showed a significant recovery of this increased level of MDA in DAL101 mice (Suppl. Fig. S1B).
3.2. Hydrogen Water Suppressed a Decline in Learning and Memory Impairment
We examined learning and memory abilities using ORT [4]. As described in MATERIALS AND METHODS, learning and memory abilities were evaluated as the subtraction of the frequency (%) in Retention test from each background (Training test). Mice were provided with control or H2-water from the age of 1 month. At the age of 14 months, the H2-group significantly memorized the original objects and showed the preference for the novel object more than the control group (Fig. 1A1A 14-month-old).
Hydrogen water prevented cognitive decline. H2-water was provided from the age of 1 month (A, C), and from the age of 8 months (B). The mice were subjected to the first objection recognition task (ORT) at the age of 14 months (A, B, 14-month-old) and the second ORT at the age of 18 months (A, B, 18-month-old).
The recognition indexes were obtained as the frequency (%) of exploring and/or sniffing the object that would be replaced or the novel one that had been replaced. ΔRecognition index (%) indicates the frequencies in Retention test of ORT after the subtraction of those in Training test (background). WT, wild-type; (DAL, H2-),
DAL101 mice drinking degassed control water; (DAL, H2+), DAL101 mice drinking hydrogen water. Data are shown as the mean ± SEM. n = 9, *p < 0.05, **p < 0.01 by Student’s t-test. (C) The mice were subjected to a passive avoidance task. Step-through latencies before and after the electric shock are obtained and ΔStep-through latency (s) indicates the subtraction of Step-through latencies after from before the electric shock. WT, wild-type (n = 10); DAL, H2-, DAL101 mice receiving degassed control water (n = 8); and DAL, H2+, DAL101 mice receiving H2-water (n = 8). Data are shown as the mean ± SEM. *p < 0.05.
At the age of 18 months, the mice were subjected to the second ORT, which can be done by using different objects at the age of 18 months [14]. The aged DAL101 mice drinking H2-water still significantly memorized the original objects and preferred the novel one more than the control group (Fig. 1A1A 18-month-old).
Next, to test the drinking effects of H2-water from the later stage, we started giving H2-water to male DAL101 mice at the age of 8 months instead of 1 month, and subjected to ORT at the age of 14 months (Fig. 1B1B 14-month-old) and the second ORT at the age of 18 months (Fig. 1B1B 18-month-old). Even when the mice began to drink at the age of 8 months, H2-water significantly suppressed the decline in the learning and memory abilities at the age of 18 months as well as at the age of 14 months (Fig. 1B1B).
Moreover, we subjected the mice to PA [22] at the age 18 months as an alternative method. One day after a 0.3 mA electric shock for 2 s was given, wild-type C57BL/6 mice memorized the shock as evaluated by the subtraction of the latency time (s) to re-enter the dark compartment from each background (Fig. 1C1C). The H2-water group significantly suppressed the decline in learning and memory more than the control group (Fig. 1C1C).
Thus, drinking hydrogen H2-water suppressed the learning and memory impairment in the oxidative stress mice.
3.3. Hydrogen-water Suppressed Neurodegeneration
To examine whether hydrogen H2-water could prevent neurodegeneration in aged DAL101 mice, we stained the hippocampus with a neuron-specific anti-NeuN antibody (Fig. 2A2A). Neurodegeneration was evaluated by glial activations using an anti-GFAP antibody and a microglia-specific anti-Iba-I antibody. Immune-positive cells per field of view (FOV) were counted in the CA1 region (Fig. 2B2B).
Hydrogen water suppressed neurodegeneration. (A) The hippocampal CA1 region was stained with antibodies against NeuN (a neuronal marker), GFAP (an astrocytic marker) or Iba-1 (a microglial marker) (Scale bars: 50 µm). Right panels show magnified images of the squares in the left panels (Scale bars: 10 µm). (B) Cells positive for anti-NeuN, anti-GFAP and anti-Iba-I antibodies per field of view (FOV) were counted in the CA1 region (n = 5). Data are shown as the mean ± SD. *p < 0.05, **p < 0.01 (wild-type vs DAL), #p < 0.05 (H2-water vs. control water in DAL).
The number of neurons was decreased in the control DAL101 group as the comparison with wild type group, and the H2-DAL101 group showed a trend in recovery of the decrease (Fig. 2A2A). As has been described previously, [4] the control DAL101 mice exhibited an increase in glial activation, and the H2-water group suppressed the enhanced glial activation in the CA1 region (Fig. 22, GFAP and Iba-I).
3.4. Hydrogen-water Extended the Average Lifespan of Mice
DAL101 mice showed a shorter lifespan, which has also been described previously [4]. To examine whether consumption of hydrogen H2-water attenuated the shortened lifespan, female DAL101 mice started drinking control or H2-water at the age of 1 month. Although hydrogen H2-water did not extend the maximum lifespan (Fig. 3A3A), hydrogen H2-water significantly extended the mean of lifespan of DAL101 mice (Fig. 3B3B).
Extension of the average lifespan by continuous drinking H2-water. (A) Kaplan-Meier curve representing the survival of female C57BL/6 mice (wild-type), female DAL101 mice drinking control water (control water) and H2-water (H2-water). (B) Each dot indicates the lifespan of each mouse. The bars indicate the average lifespan of each group. *p < 0.05 (p = 0.036) by Student’s t-test.
3.5. A Randomized, Placebo Controlled Clinical Study
Fig. (44) shows the profile on the recruitment, randomization, and follow-up of this study. A total of 81 subjects of the 1,032 participants were randomized; however, 3 in the control group and 5 in the intervention group were diagnosed as ineligible after randomization and not included in this analysis. Baseline characteristics and lifestyle factors were balanced between the study groups (Table 11). Random assignment was stratified by age of ~74 years and MMSE score of ~28 points. The average compliance rate of drinking water was estimated as 64% in both groups at 1-year, meaning the subjects drank 320 mL/day on the average. The mean total ADAS-cog scores in the H2– and control groups were 8.04 and 7.89, respectively, with no significance.
Table 1
Background characteristics of 73 subjects with mild cognitive impairment.
| Control (n=38) | Intervention (n=35) | |||
|---|---|---|---|---|
| Mean | SD or % | Mean | SD or % | |
| Woman * | 20 | (52.6%) | 19 | (54.3%) |
| Age (years) | 74.45 | 5.44 | 73.97 | 5.11 |
| Body mass index (kg/m2) | 23.55 | 2.59 | 23.19 | 4.08 |
| Systolic blood pressure (mmHg) | 131.26 | 12.35 | 135.14 | 13.31 |
| Diastolic blood pressure (mmHg) | 77.92 | 7.13 | 78.89 | 9.53 |
| Education (years) | 11.26 | 2.71 | 11.57 | 2.83 |
| Current alcohol drinker * | 19 | (50.0%) | 14 | (40.0%) |
| Current smoker * | 4 | (10.5%) | 5 | (14.3%) |
| Current exercise habit * | 27 | (71.1%) | 22 | (62.9%) |
| APOE4 carrier * | 6 | (15.7%) | 7 | (20.0%) |
| Family history * | 2 | (5.3%) | 2 | (5.7%) |
| Comorbidity * | ||||
| Hypertension | 15 | (39.5%) | 14 | (40.0%) |
| Diabetes mellitus | 4 | (10.5%) | 5 | (14.3%) |
| Dyslipidemia | 4 | (10.5%) | 4 | (11.4%) |
| Stroke | 2 | (5.3%) | 1 | (2.9%) |
| Depression | 1 | (2.6%) | 2 | (5.7%) |
| MMSE | 28.08 | 1.66 | 27.83 | 1.74 |
| ADAS-cog | 7.89 | 3.19 | 8.04 | 3.47 |
* indicates frequency (%).
After 1 year, no observable harms or unintended effects in each group were found, and there was a trend to improve total ADA-cog score both in the H2– and control-groups (Suppl. Table S1), probably because of interventions such as moderate exercise by the Tone project. Moreover, the subjects in the H2-group had more trends for the improvement than those in the control-groups although there was no significance (Suppl. Table S1). However, when we pay attention to score-changes in carriers of the APOE4 genotype, the total ADAS-cogs and word recall task scores (one of the sub-scores) significantly improved as assessed by the distribution of the score change in each subject (Fig. 55). In the APOE4 carriers, the hydrogen water H2-group significantly improved, whereas the control group slightly worsened. Moreover, Fig. (66) shows the score change of each subject as an alternative presentation. Although the subjects in the control group did not improved, six and five out of 7 subjects improved on the total ADAS score and word recall task scores, respectively, in the hydrogen water H2-group of the APOE4 carriers.
Distribution of changes of sub- and total-ADAS-cog score. Distribution of change of word recall task score (A), a sub-score of ADAS-cog, and (B) total ADAS-cogs score in APOE4 non-carriers (left) and APOE4 carriers (right). Each dot indicates the change of individual subjects. The difference between the H2- and control groups was significant in APOE4 carriers by a non-parametric analysis as well as a parametric analysis. (A) p = 0.036 (by Student’s t-test) and p =0.047 (by Mann-Whitney’s U test) and (B) p = 0.037 (by Student’s t-test) and p = 0.044 (by Mann-Whitney’s U test) for (A) and (B), respectively. Middle bars in lozenges indicate median values.
Changes in a sub-sore and total ADAS-cog score of each subject in the APOE4 carriers. Each line indicates the 1-year change in the word recall task score (A) and total ADAS-cog score (B) of a subject in the APOE4 carriers. * indicates p < 0.05 as shown in the legend of Fig. 5.
DISCUSSION
Age-dependent neurodegenerative disorders are involved in oxidative stress. In this study, we showed that drinking hydrogen H2-water suppressed the biochemical, behavioral, and pathological decline in oxidative stress mice. The score of ADAS-cog [18] is the most widely used general cognitive measure in clinical trials of AD [27, 28]. The ADAS-cog score assesses multiple cognitive domains including memory, language, praxis, and orientation. Overall, the ADAS-cog has proven successful for its intended purpose. The present clinical study shows that drinking hydrogen H2-water significantly improved the ADAS-cog score of APOE4 genotype-carriers.
We have previously showed that DAL101 mice show age-dependent neurodegeneration and cognitive decline and the shorten lifespan [4]. DAL101 mice exhibit dementia phenotypes in an age-dependent manner in response to an increasing amount of oxidative stress [4]. Oxidative stress enhances lipid peroxidation, leading to the formation of highly reactive α, β-unsaturated aldehydes, such as MDA and 4-HNE [29]. The accumulation of 4-HNE-adducted proteins in pyramidal neurons has been observed in the brains of patients with AD and PD [30]. The decline of ALDH2*2 ability failed to detoxify cytotoxic aldehydes, and consequently increases in oxidative stress [31].
Moreover, double-transgenic mice were constructed by crossing DAL101 mice with Tg2576 mice, which express a mutant form of human amyloid precursor protein (APP). They showed accelerated amyloid deposition, tau phosphorylation, and gliosis, as well as impaired learning and memory abilities. The lifespan of APP/DAL mice was significantly shorter than that of APP and DAL101 mice [32]. Thus, these model animals may be helpful to explore antioxidants that could be able to prevent age-dependent dementia. Indeed, a diet containing Chlorella showed mitigated effects on cognitive decline in DAL101 [33].
One of the most potent risk factors for AD is carrier status of the APOE4 genotype, and the roles of APOE4 on the progression of AD have been extensively examined from various aspects [34, 35]. APOE4 also increase the number of atherogenic lipoproteins, and accelerate atherogenesis [36]. The increased oxidative stress in APOE4 carriers is considered as one of the modifiers for the risk [3]. A combination of antioxidants improved cognitive function of aged subjects after 3 years, especially in APOE4 carriers [23]. This previous clinical result agrees with the present study. hydrogen H2 acts as an efficient antioxidant inside cells owing to its ability to rapidly diffuse across membranes [9]. Moreover, as a secondary anti-oxidative function, H2 seems to activate NF-E2-related factor 2 (Nrf2), [10] which reduces oxidative stress by expression a variety of antioxidant enzymes [37]. We reported that drinking hydrogen H2-water prevented arteriosclerosis using APOE knockout mice, a model of the spontaneous development of atherosclerosis accompanying a decrease in oxidative stress [38]. Thus, it is possible that drinking H2-water improves vascular damage by decreasing oxidative stress as a direct or indirect antioxidant, leading to the improvement of a demintia model and MCI subjects. In this study, we focused on the genotype of APOE-isoforms; however, the polymorphism of the APOE gene in the promoter region influences the expression of the APOE gene [39]. Thus, it will be important to examine the effect of hydrogen H2-water under this polymorphism.
For mitigating AD, significant attention has been given to regular, moderate exercise to help reduce the risk of dementia and prevent MCI from developing in aging patients [40 – 42]. Moderate exercise enhances energy metabolism and suppresses the expression of pro-inflammatory cytokines, [43] and protects vascular systems [40, 44, 45].molecular hydrogen H2 exhibits multiple functions by a decrease in the levels of pro-inflammatory cytokines and an increase in energy metabolism in addition to anti-oxidative roles. To exert multiple functions, molecular hydrogen H2 regulates various signal transduction pathways and the expression of many genes [10]. For examples,molecular hydrogen H2 protects neural cells and stimulates energy metabolism by stimulating the hormonal expression of ghrelin [15] and fibroblast growth factor 21, [21] respectively. In contrast, molecular hydrogen H2 relieves inflammation by decreasing pro-inflammatory cytokines [46]. Thus, the combination of these functions of molecular hydrogen H2 on anti-inflammation and energy metabolism-stimulation might prevent the decline in brain function, [10] both of which are improved by regular and moderate exercise. Thus, it is possible that the multiple functions of molecular hydrogen H2, including energy metabolism-stimulation and anti-inflammation, may contribute to the improvement of the dementia model and the MCI subjects.
As an alternative aspect, molecular hydrogen H2 suppresses the nuclear factor of activated T cell (NFAT) transcription pathway to regulate various gene expression patterns [47]. NFAT signaling is altered in AD and plays an important role in driving amyloid β-mediated neurodegeneration [48]. Moreover, the NFAT transcriptional cascade contributes to amyloid β synaptotoxicity [49]. Additionally, an active involvement of the NFAT-mediated signaling pathway in α-syn-mediated degeneration of neurons in PD [50]. Indeed, patients with PD improved by drinking molecular hydrogen H2-water as revealed by a double-blind, placebo-controlled clinical study, [51] and a larger scale of a clinical trial is under investigation [52]. Thus, the beneficial effects of molecular hydrogen H2 on the neurodegenerative diseases may be explained by the suppression of NFAT transcriptional regulation.
CONCLUSION
The present study suggests a possibility for slowing the progress of dementia by drinking molecular hydrogen H2-water by means of animal experiments and a clinical intervention study for APOE4 carriers; however, a longer and larger scale of trials will be necessary to clarify the effect of H2-water on MCI.
- PMC5872374
Current Alzheimer Research
Curr Alzheimer Res. 15(5): 482–492.
PMCID: PMC5872374
PMID: 29110615
Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment
Kiyomi Nishimaki,1 Takashi Asada,2,3,* Ikuroh Ohsawa,1,4 Etsuko Nakajima,2 Chiaki Ikejima,2 Takashi Yokota,1Naomi Kamimura,1 and Shigeo Ohta1,5,*
Copyright © 2018 Bentham Science Publishers
This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
This article has been cited by other articles in PMC.
Associated Data
ACKNOWLEDGEMENTS
We thank Blue Mercury, Inc. (Tokyo, Japan) for providing H2-water and placebo water, Ms. Hiroe Murakoshi for technical assistance and Ms. Suga Kato for secretarial work. Financial support for this study was provided by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23300257, 24651055, and 26282198 to S.O.; 23500971 and 25350907 to K.N.). Financial support for this study was provided by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23300257, 24651055, and 26282198 to S.O.; 23500971 and 25350907 to K.N.).
LIST OF ABBREVIATIONS
| APOE4 | Apolipoprotein E4 |
| MCI | Mild cognitive Impairment |
| ALDH2 | Aldehyde Dehydrogenase 2 |
| ADAS-cog | Alzheimer’s Disease Assessment Scale-cognitive subscale |
| AD | Alzheimer’s Disease |
| PD | Parkinson’s Disease |
| DAL101 | Dominant Negative Type 101 of the ALDH2 Mutant Polymorphism (ALDH2*2) |
| 4-HNE | 4-Hydroxy-2-nonenal |
| 8-OHdG | 8-Hydroxy-2’-deoxyguanosine |
| MDA | Malondialdehyde |
| ORT | Object Recognition Task |
| PA | Passive Avoidance Task |
| GFAP | Glial Fibrillary Acidic Protein |
| PBS | Phosphate-buffered Saline |
| ANOVA | One-way Analysis of Variance |
| CI | Confidence Interval |
| MMSE | Mini Mental State Examination |
| FOV | Field of View |
| APP | Amyloid Precursor Protein |
| Nrf2 | NF-E2-related Factor 2 |
| NFAT | Nuclear Factor of Activated T Cell |
SUPPLEMENTARY MATERIAL
Supplementary material is available on the publisher’s web site along with the published article.
Click here to view.(224K, pdf)
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The animal study was approved by the Animal Care and Use Committee of Nippon Medical School.
The human clinical study protocol was approved by the ethics committees of University of Tsukuba.
HUMAN AND ANIMAL RIGHTS
All animal research procedures followed were in accordance with the standards set forth in the eighth edition of Guide for the Care and Use of Laboratory Animals published by the National Academy of Sciences, The National Academies Press, Washington, D.C.).
All human material was obtained in accordance with the standards set forth in the Declaration of Helsinkiprinciples of 1975, as revised in 2008 (http://www.wma.net/en/10ethics/10helsinki/<http://www.wma.net/en/10ethics/10helsinki/>).
Consent for Publication
All the patients provided written informed consent priority to research investigations.
CONFLICT OF INTEREST
We declare that there is no actual and potential conflict of interest on this study. Although SO was a scientific advisor of Blue Mercury, Inc. (Tokyo, Japan) from 2,005 to 2,008, there was no involvement during this study.
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Molecular hydrogen (water) benefits/effects for METABOLIC SYNDROME
The objective of this study was to examine the effectiveness of molecular hydrogen rich water (1.5-2 L/day; molecular hydrogen concentration; 0.55-0.65 mM)) in an open label, 8-week study on 20 human subjects with potential metabolic syndrome.
Metabolic syndrome is characterized by cardiometabolic risk factors that include obesity, insulin resistance, hypertension and dyslipidemia. Oxidative stress is known to play a major role in the pathogenesis of metabolic syndrome.
The consumption of hydrogen rich water for 8 weeks resulted in a 39% increase (p<0.05) in antioxidant enzyme superoxide dismutase (SOD) and a 43% decrease (p<0.05) in thiobarbituric acid reactive substances (TBARS) in urine.
Further, subjects demonstrated an 8% increase in high density lipoprotein (HDL)-cholesterol and a 13% decrease in total cholesterol/HDL-cholesterol from baseline to week 4.
There was no change in fasting glucose levels during the 8 week study.
In conclusion, drinking molecular hydrogen rich water represents a potentially novel therapeutic and preventive strategy for metabolic syndrome.
-
diatomic molecular hydrogen H2- Water Products
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AlkaViva Vesta H2 water ionizer -
AlkaViva Athena H2 Water Ionizer purifier - Enjoy molecular hydrogen water from an entry level price top quality water ionizer
-
Melody-II-H2-water-ionizer-purifier-AlkaViva - Enjoy neutral pH water rich in molecular Hydrogen form AlkaViva IonPia H2 hydrogen water ionizer
molecular hydrogen water generator AlkaViva IonPia H2 668300
- enjoy UltraWater filtration, ionization and hydrogen generation via a NON electric UnderSink water ionizer at a decent price
-
Elita US 700 undersink water ionizer non electric – with magnesium, as used in sthis study - enjoy UltraWater filtration, ionization and hydrogen generation EVERYWHERE through a AlkaViva PHD pitcher
J Clin Biochem Nutr. 2010 Mar;46(2):140-9. doi: 10.3164/jcbn.09-100. Epub 2010 Feb 24.
Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study.
Heart, Lung and Esophageal Surgery Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15213, USA.
- PMID:20216947; https://www.ncbi.nlm.nih.gov/pubmed/20216947
Free PMC Article PMCID:PMC2831093
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831093/
Drinking hydrogen water enhances ENDURANCE and relieves psychometric FATIGUE: a randomized, double-blind, placebo-controlled study
-
- Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study
Abstract
Acute physical exercise increases reactive oxygen species in skeletal muscle, leading to tissue damage and fatigue. Molecular hydrogen (H2) acts as a therapeutic antioxidant directly or indirectly by inducing antioxidative enzymes.
Here, we examined the effects of drinking hydrogen H2 water (H2-infused water) on psychometric fatigue and endurance capacity in a randomized, double-blind, placebo-controlled fashion.
In Experiment 1, all participants(humans) drank only placebo water in the first cycle ergometer exercise session, and for comparison they drank either hydrogen H2 water or placebo water 30 min before exercise in the second examination.In these healthy non-trained participants (n = 99), psychometric fatigue judged by visual analogue scales was significantly decreased in the hydrogen H2 water group after mild exercise. When each group was divided into 2 subgroups, the subgroup with higher visual analogue scale values was more sensitive to the effect of hydrogen water H2.
In Experiment 2, trained participants (n = 60) were subjected to moderate exercise by cycle ergometer in a similar way as in Experiment 1, but exercise was performed 10 min after drinking hydrogen H2 water. Endurance/fatigue were significantly improved/relieved in the hydrogen water H2 group as judged by maximal oxygen consumption and Borg’s scale, respectively.
Taken together, drinking hydrogen H2 water just before exercise exhibited anti-fatigue and improved endurance effects.
- PMID:31251888
- DOI:10.1139/cjpp-2019-0059
- Can J Physiol Pharmacol. 2019 Jun 28:1-6. doi: 10.1139/cjpp-2019-0059. [Epub ahead of print]
Drinking hydrogen water enhances endurance and relieves psychometric fatigue: a randomized, double-blind, placebo-controlled study 1.
Author information
- 1 Department of Health and Sports Science, Nippon Medical School, Musashino, Tokyo 180-0023, Japan.
- 2 Fitness Club, Asahi Big S Mukogaoka, Kawasaki-city, Kanagawa pref. 214-0014, Japan.
- 3 Hydrogen Health Medical Laboratory, Co., Ltd., Arakawa-ku, Tokyo 116-0001, Japan.
- 4 Slovak Academy of Sciences, Centre of Experimental Medicine, Institute for Heart Research, Bratislava 84005, Slovak Republic.
- 5 Molecular Hydrogen Institute, Enoch, UT 84721, USA.
- 6Department of Neurology Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
Effects of hydrogen rich water on prolonged intermittent EXERCISE
BACKGROUND:
Recent studies showed a positive effect of hydrogen rich water (HRW) intake on acid-base homeostasis at rest. We investigated 2-weeks of hydrogen rich water HRW intake on repeated sprint performance and acid-base status during prolonged intermittent cycling exercise.
METHODS:
In a cross over single-blind protocol, 8 trained male cyclists (age [mean±SD] 41±7 years, body mass 72.3±4.4 kg, height 1.77±0.04 m, maximal oxygen uptake [V̇O2max] 52.6±4.4 mL·kg-1·min-1) were provided daily with 2 liters of placebo normal water (PLA, pH 7.6, oxidation/reduction potential [ORP] +230 mV, free hydrogen content 0 ppb) or hydrogen rich water HRW (pH 9.8, ORP -180 mV, free Hydrogen 450 ppb). Tests were performed at baseline and after each period of 2 weeks of treatment. The treatments were counter-balanced and the sequence randomized. The 30-minute intermittent cycling trial consisted in 10 3-minute blocks, each one composed by 90 seconds at 40% V̇O2max, 60 seconds at 60% V̇O2max, 16 seconds all out sprint, and 14 seconds active recovery. Oxygen uptake (V̇O2), heart rate and power output were measured during the whole test, while mean and peak power output (PPO), time to peak power and Fatigue Index (FI) were determined during all the 16 seconds sprints. Lactate, pH and bicarbonate (HCO3-) concentrations were determined at rest and after each sprint on blood obtained by an antecubital vein indwelling catheter.
RESULTS:
In the PLA group, PPO in absolute values decreased significantly at the 8th and 9th of 10 sprints and in relative values, ΔPPO, decreased significantly at 6th, 8th and 9th of 10 sprints (by mean: -12±5%, P<0.006), while it remained unchanged in hydrogen rich water HRW group. Mean power, FI, time to peak power and total work showed no differences between groups. In both conditions lactate levels increased while pH and HCO3- decreased progressively as a function of the number of sprints.
CONCLUSIONS:
Two weeks of hydrogen rich water HRW intake may help to maintain PPO in repetitive sprints to exhaustion over 30 minutes.
J Sports Med Phys Fitness. 2018 May;58(5):612-621. doi: 10.23736/S0022-4707.17.06883-9. Epub 2017 Apr 26.
Effects of hydrogen rich water on prolonged intermittent exercise.
Da Ponte A1,2, Giovanelli N3,4, Nigris D5, Lazzer S3,4.
Author information
1
Department of Medical and Biological Sciences, University of Udine, Udine, Italy – dott.daponte@gmail.com.
2
School of Sports Medicine, University of Udine, Udine, Italy – dott.daponte@gmail.com.
3
Department of Medical and Biological Sciences, University of Udine, Udine, Italy.
4
School of Sport Sciences, University of Udine, Udine, Italy.
5
Department of Laboratory Medicine, University of Udine, Udine, Italy.
PMID: 28474871 DOI: 10.23736/S0022-4707.17.06883-9
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diatomic molecular hydrogen H2- Water Products
Diatomic molecular hydrogen H2- Water Products
The benefits of diatomic molecular hydrogen-infused water are clear, and are covered in this article.
As the word gets out regarding diatomic molecular, hydrogen-infused water or H2 water more options are becoming available to create molecular hydrogen dizzolved in water . Some of these include:
- Electric Water Ionizers
- Molecular Hydrogen water Generators
- Non-electric water ionizers / non-electric water filters
- Magnesium/hydrogen Tablets and Powders for water
- Magnesium Sticks (including water bottles with magnesium sticks) Mg + 2H 2O -> Mg (OH) 2 +H 2
Electric Water Ionizers
Electric water ionizers are the most proven and convenient way to create diatomic molecular hydrogen – H2 dissolved in water and have a 30+ year track record of improvements/ patents in this regard.
An electric water ionizer, as a flow through device, produces molecular hydrogen H2 water on-demand; you turn it on and you can instantly enjoy molecular hydrogen H2 water at the ionized alkaline level you enjoy and select.
Electric water ionizers also offer other benefits such as alkaline ionized water or acidic ionized water, with selectable controls that enable you to use the water in various “functional” ways.
One added benefit is that, in the water ionization /electrolysis process, the levels of fluoride ions and chemical compounds such as nitrates, phosphates and cyanide are reduced as they get attracted towards the acid water side.
AlkaViva has test results from the University of Nevada at Reno documenting this benefit.
All AlkaViva electric water ionizers employ a patented technology that reverses the polarity of electrodes with every use, ensuring the electrode plates are maintained in a pristine condition and preserving their ability to generate therapeutic levels of diatomic molecular hydrogen – or H2 water.
Electric water ionizers, however, are not affordable for everyone or practical in all situations and there exist more affordable options.
Neutral Water with molecular hydrogen H2 Generators(electric)
There is a newer technology for diatomic molecular hydrogen – or H2 water appearing on the market that is a significant departure from both the electric water ionizers and the magnesium-based, non-electric methods that produce dissolved molecular hydrogen H2 in water
These electric moleclar hydrogen H2 water generators are designed to create dissolved molecular hydrogen H2 in neutral pH water. Until they are tested extensively in the market over time, their durability remains unproven but a definite plus is that they can make good levels of diatomic molecular hydrogen water.
AlkaViva is now also importing their own molecular hydrogen H2 water generators and will be carefully observing performance and reliability over time, since unlike Korea or Japan, there is such a wide range in water quality and conditions in the USA which impact long-term performance in regards to H2 infusion /generating diatomic molecular hydrogen water.
We will be recommending UltraWater filter pre-treatment because the two standard water filters (carbon and .01m water filters) are produced in Asia and while they offer a good reduction of microorganisms, offer limited water contaminant reduction.
The best diatomic molecular hydrogen water generators are flow through devices like electric water ionizers. Cheaper models are inconvenient, requiring you to pour a limited amount of water into a container and then wait while molecular hydrogen is infused into the water. These models also do not usually filter the water.
Non-electric water Ionizers /water Filters
There are healing natural water springs around the world. Among them, are places like Nordenau (Germany), Tlacote (Mexico) and Hita Tenryosui, Japan. Research has documented that these waters contain dissolved molecular hydrogen1-3 along with alkaline minerals. These water springs get their healing characteristics through contact with natural alkaline earth metals and minerals. It is important to note that the molecular hydrogen level in water from the best natural healing spring is well below the molecular hydrogen H2 water level possible from an average electric water ionizer.
If quality water filters are used in non-electric water ionizers, then contaminants will be removed while helpful minerals are allowed to pass through. This makes a clean, mineralized healthy water that is designed to imitate nature’s healing springs. Unfortunately, today’s tap water is nothing like the water from natural springs. It often contains a host of chemicals, heavy metals, pharmaceuticals, and other toxic substances, and it is an oxidizing agent.
Most countertop units that produce molecular hydrogen H2 water do not address the tap water contamination issue. Their water filters remove or reduce chlorine and some other contaminants (but not all).
One countertop filter stands out in regard to its water filtration capability. The Elita CT700 from AlkaViva not only makes diatomic molecular hydrogen water but also creates very clean, alkaline, ionized water. The Elita CT700 from AlkaViva incorporates proprietary USA-made UltraWater filtration technology. Independent, USA EPA, certified laboratory testing confirms that up to 99.9% of virtually all tap water contaminants (a total of 172 were tested) are removed with the UltraWater filtration technology.
What is significant about any non-electric countertop water ionizers is that they will give filtered, alkaline pH and ionized water on-demand. Equally significant is that they will NOT necessarily produce significant levels of molecular hydrogen H2 on-demand. This is because the amount of molecular hydrogen H2 water produced depends on how long the water stays in the water filter between uses. Reason is magnesium in these water filters requires a certain amount of contact time with water before it can transform into molecular hydrogen H2. Once you have poured a continuous stream of water or completed a few start and stops, from filling glasses or containers, the molecular hydrogen H2 water production falls off significantly. The level of molecular hydrogen H2 will ALWAYS be highest when the non electric water ionizer has been sitting for a period of time so that the water in it and magnesium can react – the longer the better – just like a stick.
Molecular Hydrogen producing magnesium Tablets and Powders
Another way of producing molecular hydrogen H2 water is from metallic magnesium in the form of tablets or powders. There are a number of these products on the market today. Some are formulated to dissolve in water, producing the molecular hydrogen H2 reaction in a container before you consume the molecular hydrogen water . Others are formulated to be ingested – with the molecular hydrogen H2 being produced in the stomach. Since these products consist mainly of a special form of magnesium – a mineral that most of us are lacking in the diet – it’s normally both safe and beneficial to ingest.
The preferred method to make molecular hydrogen water is to use a tablet that dissolves in water. Why? Molecular hydrogen H2 saturation levels can easily be tested and documented. Using Molecular Hydrogen H2 reagent drops, you can measure the amount of molecular hydrogen H2 produced.4 Testing is impossible when tablets or powders are ingested. Also, the beneficial research results that have been achieved from ingesting molecular hydrogen H2 have mainly come from studies where subjects consumed dissolved molecular hydrogen H2 in water.
Tablets create molecular hydrogen H2 water in approximately 20 minutes. Drop the tablet into an airtight bottle of water, and you’ll see the molecular hydrogen gas bubbles immediately form, infusing it with the powerful health properties of molecular hydrogen H2. In fact, such tablets currently produce the most potent concentration of molecular hydrogen H2 water. Everyone is different when it comes to taste, and some people report that various versions of the molecular hydrogen H2 generating tablets if magnesium have an unpleasant taste. You can add lemon juice or other flavoring without affecting the molecular hydrogen H2 concentration.
While it is true that molecular hydrogen H2 producing tablets dissolved in water can make very high levels of molecular hydrogen H2 saturation, it is equally true that inconsistent performance is a real problem. Molecular hydrogen is the smallest element occupying the first position on the periodic table. Molecular hydrogen is similarly the smallest molecule – and it’s a gas. molecular hydrogen wants to escape and will if not prepared in the right type of container. If the container is not completely airtight, filled all the way to the top, capped tightly and then allowed to sit for the correct amount of time, you will have wildly inconsistent results. If the preparation is botched it is entirely possible to have no molecular hydrogen H2 in the water.
AlkaViva’s H2Viva is a molecular hydrogen H2 tablet product that you dissolve in water and that has been verified to produce a consistent saturation level up to twice the amount or more than that of a new hydrogen stick and will do so in half the time. These are stronger, faster, more consistent and convenient – working any place you have drinking water and a container.
Tablets are an effective way to get good molecular hydrogen saturation – IF you have done everything correctly. There is no doubt they are an excellent way to get the benefits of molecular hydrogen H2 when you are traveling. Overall they are easy to use, very affordable, portable, and – if used properly – consistently produce a high saturation of molecular hydrogen H2 water.
But what about water filtration? This is why at least a NON electric water ionizer with a great UltraWater filter could come in handy
Magnesium Sticks
The idea that you could generate molecular hydrogen H2 in water from metallic magnesium reacting with water was first introduced in the late 1990’s. Magnesium sticks have been marketed since the early 2000s. You purchase the magnesium stick, drop it into a bottle filled with water and cap it. molecular hydrogen H2 is produced when water comes into contact with a reactive form of magnesium metal in the stick. The chemical reaction is:
Mg + 2H2O —> Mg(OH)2 + H2
After waiting a while, and if you’ve done everything correctly, you will have molecular hydrogen H2 dissolved in water. One issue with the sticks is they do not filter the water. Many manufacturers recommend they be used with bottled water only. At a minimum, you should be using properly filtered water.
Also, while they will produce varying levels of molecular hydrogen H2 saturation when new, molecular hydrogen water generating sticks are not as convenient as an electric water ionizer. You have to wait for the chemical reaction to take place in a limited amount of water. Worse, there is no consistency in how long it takes to create the molecular hydrogen H2. Plus there is no data on how long a magnesium stick is capable of producing significant amounts of molecular hydrogen H2. The bottom line is that they work – with some important caveats.
Summary
The explosion in published research, covering every organ and over 150 disease models, continues to demonstrate positive impacts on health and wellbeing with no contraindications of diatomic molecular hydrogen( water). With all these choices of ways to take advantage of the benefits of consuming molecular hydrogen (water), there is no reason not to! It seems clear to us, at least for now, that electric water ionizers are the most proven, easiest and most consistent way to get your daily molecular hydrogen water
Join the molecular hydrogen H2 water revolution and optimize your health and well-being! Experience more energy and mental clarity plus improve your athletic performance by giving your body the ability to naturally thrive. You have the best products to choose from at AlkaViva – we’ll help you find the right one for your budget and lifestyle!
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1.) ZHANG, J. Y., LIU, C., ZHOU, L., QU, K., WANG, R. T., TAI, M. H., LEI, J. C. W. L., WU, Q. F. and WANG, Z. X. (2012). A Review of Hydrogen as a New Medical Therapy. Hepato-Gastroenterology 59, 1026-1032.
2.) SHIRAHATA, S. A. N. E. T. A. K. A. (2002). Reduced water for prevention of diseases. Animal Cell Technology: Basic and Applied Aspects 12, 25-30.
3.) SHIRAHATA, S., HAMASAKI, T. and TERUYA, K. (2012). Advanced research on the health benefit of reduced water. Trends in Food Science and Technology 23, 124-131.
4.) TOMOKI SEO, RYOSUKE KUROKAWA AND BUNPEI SATO (2012) A convenient method for determining the concentration of hydrogen in water: use of methylene blue with colloidal platinum. Medical Gas Research 2012, 2:1
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Daily ingestion of alkaline electrolyzed water containing hydrogen influences HUMAN HEALTH, including GASTROINTESTINAL symptoms
Abstract
In Japan, alkaline electrolyzed water (AEW) apparatus have been approved as a medical device. And for the patients with gastrointestinal symptoms, drinking AEW has been found to be effective in relieving gastrointestinal symptoms. But some users of AEW apparatus do not have abdominal indefinite complaint. Little attention has been given to the benefit for the users which have no abdominal indefinite complaint. The object of this study is to evaluate the effect on health, including gastrointestinal symptoms, when a person without abdominal indefinite complaint, etc., drinks AEW on a daily basis. A double-blind, randomized controlled trial has been designed. Four-week period of everyday water drinking, PW drinking group: drink purified tap water as a placebo, AEW drinking group: drink alkaline electrolyzed water which made by electrolysis of purified tap water. Before the experiment and after the 4-week period of water drinking, Blood tests, physical fitness evaluations, and questionnaire evaluations is conducted. In this study, we did not specifically select patients with gastrointestinal symptoms. Sufficiently clear effect could not be confirmed. But the stools were more normal, and, as shown in the previous report, that drinking AEW is considered to contribute to intestinal normalization. In addition, when drinking AEW, a high proportion of the respondents said that they felt they were able to sleep soundly, and the proportion of subjects who answered that they felt good when awakening increased. The effect of reducing oxidative stress, thus allowing for improved sleep, was exhibited by drinking AEW containing hydrogen, which is considered to be an antioxidant substance. This research were approved by the Ethics Committee of the Osaka City University Graduate School of Medicine (No. 837) and were registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000031800) on March 22, 2018.
Keywords: alkaline electrolyzed water, gastrointestinal symptoms, hydrogen-dissolved water, physical fitness evaluations, questionnaire evaluations, functional beverage
Introduction
In Japan, water which is obtained on the cathode side by the electrolysis of tap water is called alkaline electrolyzed water (AEW) or reduced hydrogen water.1 Improvement of gastrointestinal symptoms by ingesting AEW has been confirmed by Japanese researchers. For example, Naito et al.2 reported the inhibitory effect of AEW ingestion on gastric mucosal disorder caused by aspirin, and Hayakawa et al.3reported the inhibitory effect of AEW ingestion on abnormal intestinal fermentation. Tashiro et al.4examined the effect of ingesting AEW or purified tap water (PW; as a placebo) at a rate of at 500 mL per day for 4 weeks in patients who had abdominal pain such as heartburn, stomach discomfort, abdominal bloating, diarrhea, constipation, etc., and reported that the results of the AEW group were superior to those of the placebo group.5,6 From these results, apparatus that produce AEW have been approved as medical devices by the Japanese Ministry of Health, Labour and Welfare. AEW is thought to be effective for functional gastrointestinal disorders.5
Since AEW is produced by electrolyzing water, hydroxide ions, which are alkaline in nature, are generated. Hydrogen molecules are also generated on the electrode surface and dissolved in water. Therefore, AEW is alkaline water containing hydrogen.1 In conventional efficacy studies, evaluations with respect to ingesting AEW have typically been conducted focusing on the alkalinity of the water.2,3,4,5 In recent years, however, the assumed effectiveness of the antioxidant effect of dissolved hydrogen on various diseases has been reported.7,8,9,10,11,12,13,14,15 Nevertheless, some users of AEW apparatus do not have any definite abdominal symptoms. In many cases, they are drinking AEW on a daily basis to improve their health, and many users also feel health benefits such as improvement in exercise capacity12. These may be thought to be due to the action of dissolved hydrogen. There have been no researched studies of these in detail. The object of this study is to evaluate the effect of daily ingestion of AEW on health, including gastrointestinal symptoms, in subjects without any definite abdominal symptoms.
Participants and Methods
Participants
Healthy men and women (20–60 years) who use the Osaka City Citizen Health Development Consultation Center were selected as test subjects to determine the health effect of daily AEW ingestion. It was aimed to clarify whether general subjects without gastrointestinal symptoms have another good effect besides gastrointestinal symptoms by drinking AEW which is good for gastrointestinal symptoms. We explained this purpose to the subjects and asked for research participation. Written informed consent was obtained from all subjects. All procedures used in this research were approved by the Ethics Committee of the Osaka City University Graduate School of Medicine (No. 837) and were registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000031800) on March 22, 2018. This study follows the Consolidated Standards of Reporting Trials (CONSORT) guidelines. A double-blind, randomized controlled trial has been designed, and the research design is shown in Figure 1.
Research design.
Note: PW: Purified tap water; AEW: alkaline electrolyzed water.
Subjects were randomly divided into two groups, with an AEW group (n = 30) and a PW group (n = 30). Blood tests, physical fitness evaluations, and questionnaire evaluations were conducted before the experiment was initiated. Subjects were provided with AEW apparatus1 that had been modified to produce only AEW or PW. They ingested 500 mL or more of freshly produced AEW or PW per day (they were required to ingest 200 mL immediately after awakening, and 300 mL or more during the rest of the day). After the end of the four-week period, blood tests, physical fitness evaluations, and questionnaire evaluations were conducted again to check whether the ingestion of AEW for four weeks had beneficial effects on the health of the subjects.
Blood sample/urinalysis
General blood test: Red blood cell count, white blood cell count, hemoglobin, hematocrit, and platelet count.
Blood biochemical examination: Total protein, albumin, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), γ-GTP, total cholesterol, high-density lipoprotein (HDL), cholesterol, low-density lipoprotein (LDL) cholesterol, neutral fat, uric acid, creatinine, and blood sugar.
Urinalysis: Urine sugar, urine protein, urine occult blood, and urine pH.
Physical measurements
Right/left grip strength, right/left leg muscle strength, vertical jump, whole body reaction time, standing time on one leg with eyes closed, sit-up, seated forward bend, and resting blood pressure.
Questionnaire variables
Gastrointestinal symptoms (stomachache, heartburn, heavy stomach, lower abdominal pain, bloated stomach), urinary frequency, condition of the stools (fecal properties and bowel movement), and physical condition (sleep quality and upon awakening).
Statistical analysis
In the blood data, the urinalysis and physical measurement values, the statistical significance of the average difference (before and after AEW, PW drinking) was analysed using a paired t-test (Statcel 4 Software [OMS Publishing, Saitama, Japan). The questionnaire data (before and after AEW, PW drinking) was analysed by the Wilcoxon signed-rank test using the same Statcel 4 software. Differences for which Pvalues of < 0.05 and < 0.01 were inferred as significant.
Results
Conditions of subjects and water quality
Subjects with abdominal symptoms such as heartburn, stomach discomfort, abdominal bloating, diarrhea, and constipation were used in the study previously performed.4,5 For the current study, subjects aged 20 to 69 years were randomly selected among medical checkup examinees who visited the Osaka City Citizen Health Development Consultation Center, and then divided into two groups. One group ingested PW while the other ingested AEW. Neither the subjects nor the experimenters knew which group the subjects belonged to. Figure 2 shows that no significant differences were found in dispersion of mean values and distribution values.
Age distribution of subjects.
Note: PW: Purified tap water; AEW: alkaline electrolyzed water.
Each subject was provided with an AEW apparatus that had been modified to either produce or not produce AEW, and asked to install it at their home. In order to verify the quality of the drinking water, the water produced by the apparatus was taken into aluminum containers and collected when the subjects came in for measurement. Figure 3 shows the water quality distribution of each drinking water.
Water quality distribution of two types of drinking water.
Note: PW: Purified tap water; AEW: alkaline electrolyzed water.
Because we selected subjects who live in or around Osaka City, the tap water from either the same or a nearby water source was used for the evaluation. For this reason, the tests have been conducted using water of equivalent quality and which shows little bias in the distribution of ions.
Regarding the water before and after the electrolysis, the pH was 7.6 ± 0.2 for the PW group, and 9.2 ± 0.2 for the AEW group. Dissolved hydrogen concentration was not measurable at the subjects’ houses because hydrogen easily escapes water. However, for non-electrolyzed and electrolyzed tap water from the same water source and using the same water apparatus, the hydrogen concentration was confirmed as 0 mg/L in the PW group and 0.2 mg/L for the AEW group for the characteristics of the device.
Comparison of hematological values
The hematological data of subjects in the PW group and the AEW group were compared before and after the four-week period, but no significant differences were observed in both groups. This is consistent with the contents of the previous report.5 However, the HDL cholesterol level, a newly measured value this time, of the AEW group showed a tendency to increase with P = 0.097, as shown in Figure 4.
Change in HDL cholesterol before and after drinking.
Note: (A) alkaline electrolyzed water (AEW) drinking group, (B) purified tap water (PW) drinking group. HDL: High-density lipoprotein.
Comparison of data related to physical abilities
For the seated forward bend, vertical jump, right/left grip strength, and sit-up, there was no significant difference before and after the 4-week period for both the PW group and the AEW group.
Regarding the whole body reaction time, no significant differences were observed before and after the 4-week period in the case of the PW group, as seen in Figure 5B. However, a significant difference (decrease) (P < 0.05) was observed in the AEW group, as seen in Figure 5A. As for standing time on one leg with eyes closed, longer times were observed in the AEW group (P = 0.09), as seen in Figure 6A.
Change in whole body reaction time before and after drinking.
Note: (A) Alkaline electrolyzed water (AEW) drinking group; (B) purified tap water (PW) drinking group.
Changes in the standing time on one leg with eyes closed before and after drinking.
Note: (A) alkaline electrolyzed water (AEW) drinking group, (B) purified tap water (PW) drinking group.
Questionnaire to subjects
As for the questionnaire items, we asked the subjects to provide answers in 3 to 5 points about gastrointestinal symptoms (Table 1), defecation and urination (Table 2), and physical condition (Table 3).
Table 1
Gastrointestinal symptoms
| Item | 1 | 2 | 3 | 4 |
|---|---|---|---|---|
| Stomachache | Not at all | Slightly | Quite a lot | Very much |
| Heartburn | Not at all | Slightly | Quite a lot | Very much |
| Heavy stomach | Not at all | Slightly | Quite a lot | Very much |
| Lower abdominal pain | Not at all | Slightly | Quite a lot | Very much |
| Bloated stomach | Not at all | Slightly | Quite a lot | Very much |
Note: Scoring 1 to 4, where: Not at all = 1, and Very much = 4.
Table 2
Defecation and urination
| Item | 1 | 2 | 3 | 4 | 5 |
|---|---|---|---|---|---|
| Uninary frequency | Very often | Often | Sometimes | Occasionally | Rarely |
| Fecal properties | Hard | Slightly hard | Normal | Slightly soft | Soft |
| Bowel movement | Very good | Good | Normal | Bad | Very bad |
Table 3
Physical conditionn
| Item | 1 | 2 | 3 |
|---|---|---|---|
| Sleep quality | Good | Neither nor | Bad |
| Waking up | Good | Neither nor | Bad |
Note: Scoring 1 to 3, where: Good = 1, and Bad = 3.
First, as seen in Figures 77 to to11,11, as for gastrointestinal symptoms, sufficiently clear effect could not be confirmed in this study. Next, as seen in Figure 12, the urinary frequency significantly increased in both groups, likely due to an increase in urine volume resulting from water ingestion. Regarding bowel movement, the stools slightly changed from slightly soft to normal or slightly hard, or from soft to normal (P < 0.05) in the AEW group, as can be seen in Figure 13A. There was no difference between subjects of the two groups who had answered that they were in “good” or “bad” physical condition.
Change in stomach ache before and after drinking.
Note: Left side: alkaline electrolyzed water (AEW), and right side: purified tap water (PW).
Change in bloated stomach before and after drinking.
Note: Left side: alkaline electrolyzed water (AEW), and right side: purified tap water (PW).
Change in urinary frequency before and after drinking.
Note: (A) Alkaline electrolyzed water (AEW) drinking group, and (B) purified tap water (PW) drinking group.
Changes in the condition of stools before and after drinking.
Note: (A) Alkaline electrolyzed water (AEW) drinking group, and (B) purified tap water (PW) drinking group.
Change in heartburn before and after drinking.
Note: Left side: alkaline electrolyzed water (AEW), and right side: purified tap water (PW).
Change in heavy stomach before and after drinking.
Note: Left side: alkaline electrolyzed water (AEW), and right side: purified tap water (PW).
Change in lower abdominal pain before and after drinking.
Note: Left side: alkaline electrolyzed water (AEW), and right side: purified tap water (PW).
Regarding sleep quality, there was a significant increase (P < 0.01) in the number of AEW group subjects who responded that they were able to sleep well, as shown in Figure 14A, and there was a significant increase (P < 0.05) in the number of subjects from the same group who said that they felt good upon awakening, as seen in Figure 15A.
Change in sleep quality before and after drinking.
Note: (A) Alkaline electrolyzed water (AEW) drinking group, and (B) purified tap water (PW) drinking group.
Changes in the state of getting up before and after drinking.
Note: (A) Alkaline electrolyzed water (AEW) drinking group, and (B) purified tap water (PW) drinking group.
Discussion
In Japan, AEW apparatus have been approved as medical devices, and ingesting AEW has been found to be effective in relieving gastrointestinal symptoms. A clinical evaluation of this effect was conducted with patients with gastrointestinal symptoms (heartburn, stomach discomfort, and abdominal symptoms such as abdominal bloating, diarrhea, and constipation).5
Antioxidant action by hydrogen and gastric acid neutralization by alkaline pH have been considered.6 In addition, recent studies have shown that the intestinal bacterial flora distribution changes. It seems that these are involved in the normalization of the gastrointestinal activity.11 However, for this study, patients with gastrointestinal symptoms were not specifically selected. As for these as well as the previous results, in general, there was no difference in the hematological values between the PW group and the AEW group.5 However, the newly measured HDL cholesterol value showed a tendency to increase with P = 0.097. The increase in HDL cholesterol by ingesting water containing hydrogen is reported by Gadek and colleagues.16 The effect of hydrogen can be considered to have had an effect in the AEW group this time as well.
As for gastrointestinal symptoms—which showed a significant difference during the previous study (significant improvement of abdominal symptoms and improvement of abnormal bowel movement)4,5—sufficiently clear effect could not be confirmed by this study because the subjects did not show gastrointestinal symptoms, and very few of them responded that they had abnormal abdominal symptoms and bowel movement before participating in this study. Therefore, we believe this is the reason the answers of the subjects were the same before and after their participation in the study.
However, with respect to bowel movement, the stools slightly changed from soft to normal or slightly hard, or from loose to normal in the AEW group. This reflects that the stools are more normal, and, as shown in the previous report, that ingesting AEW is considered to contribute to intestinal normalization.4,5,6Regarding items other than the gastrointestinal tract, a high proportion of the respondents said that they felt they were able to sleep well, and the proportion of subjects who answered that they felt good when awakening increased. Various studies on the relationship between the ingestion of antioxidant substances and the condition of sleep have been undertaken,17 and the effect of reducing oxidative stress, thus allowing for improved sleep quality, is exhibited by ingesting AEW containing hydrogen, which is considered an antioxidant substance.
Regarding sports performance, various reports on the effects of sleep on sports performance have concluded that willingly sleeping longer can lead to faster running, shortened reaction time, and improved motivation during practice and games.18 Improved sleep quality by ingesting AEW is, therefore, believed to help reduce fatigue, ensure appropriate endurance recovery, and improve overall sports performance.
The findings of this study indicate that ingesting AEW on a daily basis improves health and exercise capacity, even in healthy people who do not have gastrointestinal symptoms.
Footnotes
Funding: The study was supported by a grant from Matsushita Electric Works Co., Ltd. Home Appliances R&D Center (to HN).
Conflicts of interest
The corresponding author (YT) is a salaried employee of the Panasonic Corporation. One of the authors (SY) was a salaried employee of the Panasonic Corporation. This study does not alter our adherence to Medical Gas Research policies on sharing data and materials. Another authors (KI and HN) report no conflict of interest related to this manuscript.
Financial support
The study was supported by a grant from Matsushita Electric Works Co., Ltd. Home Appliances R&D Center (to HW).
Institutional review board statement
All procedures used in this research were approved by the Ethics Committee of the Osaka City University Graduate School of Medicine (No. 837) and were registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000031800) on March 22, 2018.
Declaration of participant consent
The authors certify that they have obtained participant consent forms. In the form, participant have given their consent for their images andother clinical information to be reported in the journal. The patients understand that their names and initials not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Reporting statement
This study follows the Consolidated Standards of Reporting Trials (CONSORT) guidelines.
Biostatistics statement
The statistical methods of this study were reviewed by the biostatistician of the Osaka City University, Osaka, Japan.
Copyright license agreement
The Copyright License Agreement has been signed by all authors before publication.
Data sharing statement
Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Study protocol and informed consent form will be available immediately following publication, without end date. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
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- Med Gas Res
- v.8(4); Oct-Dec 2018
- PMC6352572
Med Gas Res. 2018 Oct-Dec; 8(4): 160–166.
Published online 2019 Jan 9. doi: 10.4103/2045-9912.248267
PMCID: PMC6352572
PMID: 30713669
Daily ingestion of alkaline electrolyzed water containing hydrogen influences human health, including gastrointestinal symptoms
References
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Articles from Medical Gas Research are provided here courtesy of Wolters Kluwer — Medknow Publications
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- Ionized water uses(alkaline, neutral, acidic)
- Alkaline ionized water on long & short terms – RULES and WARNINGS of use / consumption & storage / bottling
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