The chemistry. The papers. The tablet.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW supports healthy blood sugar levels is supported by more than 10 human clinical studies, most of them being randomized, double-blinded, placebo-controlled studies. The duration of the studies was between 4 and 24 weeks involving approximately 300 subjects that were administered HRW daily at a dose of ≈ 1 to \> 11 mg per day. These clinical studies clearly demonstrate that in subjects with normal blood glucose levels (e.g., 70 to 100 mg/dL; 3.9 to 5.6 mM), HRW neither increased nor decreased glucose levels. However, in subjects with elevated glucose levels (e.g., \>120 mg/dL; \> 6 mM), HRW treatment significantly decreased blood glucose levels. For example, a study involving 60 individuals with metabolic syndrome was conducted to evaluate the effect of HRW ingestion (\> 11 mg/day) for 24 weeks on glucose levels. The trial was randomized, double-blinded, and placebo-controlled. The findings showed that the HRW group experienced a ≈ 15% mean reduction in glucose levels (from 122 mg/L at baseline to 103 mg/L at 24-week follow-up), while the placebo group saw a slight increase of ≈ 2% in glucose levels (from 124 mg/dL at baseline to 126.4 mg/dL at 24-week follow-up). Additionally, the study found a significant reduction (p \< 0.001) of approximately 12% in hemoglobin A1c (HbA1c). These results indicate a shift from the upper to the lower range of prediabetic criteria.

Another human study evaluated the effects of 28-day intake of hydrogen-rich water (HRW) on Homeostasis Model Assessment (HOMA2) outcomes and body composition in a cohort of physically inactive overweight men and women. The authors reported that drinking HRW was superior to placebo to increase insulin sensitivity (for up to 11.1%; p \< 0.05), and tended to reduce body fat at 28-day follow-up more as compared to placebo (- 4.2% vs. 0.6%; p = 0.09). The results of this trial nominate HRW as a possible nutritional strategy to improve insulin sensitivity in overweight inactive population.

In addition to the clinical studies, many animal studies demonstrate a profound and impressive effect of HRW lowering elevated glucose levels. Some animal data indicate that the effects of HRW are comparable to a 20% caloric restriction, as well as to the anti-diabetic drug pioglitazone and metformin. Finally, this claim is also supported by some in vitro mechanistic data that indicates that HRW can promote GLUT4 translocation in myocytes and adipocytes. In addition, HRW seemed to decrease the absorption of glucose in intestinal cells, which may also explain reduced blood glucose levels.

In conclusion, the evidence indicates that this claim is substantiated. In our opinion there is supportive scientific evidence that indicates that HRW may decrease excess levels of blood glucose but will not decrease glucose levels below normal healthy ranges. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical, animal, and cell culture in vitro studies.

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Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “supports the maintenance of healthy blood lipids” is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies. Many of these studies used tablets of this formulation. For example, a 24-week study in subjects with metabolic syndrome found that daily ingestion of HRW resulted in nearly a 10% reduction in total cholesterol (TC). This resulted in a favorable decrease to the TC to high-density lipoprotein-cholesterol (HDL) ratio and triacylglycerol (TAG) to HDL ratio of 7.2% and 22.9%, respectively.

Similarly, an 8-week RDBPC crossover study with a 12-week washout period found significant decreases in small dense low-density lipoprotein-cholesterol (sdLDL), electronegative charge-modified LDL, and a strong trend of decreased oxidized LDL (oxLDL) with HRW (1 mg/day) in subjects with type 2 diabetes or impaired glucose tolerance. Another 24-week RDBPC parallel study in elderly subjects found that HRW tended to decrease total cholesterol by 6.67% and had a stronger tendency to reduce LDL levels, with a 12.5% decrease in the TC to HDL ratio. In patients with NAFLD a RDBPC study found that HRW (\> 4 mg/day) for 8 weeks tended to increase HDL cholesterol and prevent the rise in TAG levels over two months as compared to placebo. HRW administration was associated with an 8% increase in HDL, and a 13% decrease in the TC/HDL ratio from baseline to week 4, as well as an improved function of HDL, a decrease in serum TC and LDL, especially among smokers.

Another RDBPC crossover study found that HRW significantly reduced TAG and tended to reduce TC. A 2023 metanalysis on seven high quality studies involving 256 participants concluded that HRW can significantly reduce TC, LDL, and TAG (p = 0.01) with small to moderate effects.

In addition to the clinical studies, this claim is also supported by many animal studies. For example, in a streptococci-induced diabetic mouse model fed a high fat diet, it was found H2 administration prevented the significant increase in TC, TG and LDL, and lowered their levels even more than the control. There are many similar animal studies, some of which indicate the effects of HRW are as effective as the anti-lipidemic drug simvastatin.

Mechanistically, the cholesterol regulating effects of HRW may be related to a variety of factors. For example, in mice HRW induced fibroblast growth factor 21, which is a hepatic hormone that stimulates energy metabolism. Additionally, using DNA microarrays, researchers identified 548 upregulated and 695 downregulated genes in the liver following a 4-week treatment of HRW. Further analysis using Gene Ontology indicated that the upregulated genes were significantly enriched with genes responsible for oxidoreduction-related proteins, such as hydroxymethylglutaryl CoA reductase.

These animal and clinical studies demonstrate that HRW may increase HDL, and decrease LDL, TC, and TAC in subjects with dyslipidemia. In less dyslipidemic individuals, HRW may prevent the decrease in HDL and attenuate the age or diet-induce increase in LDL, TC, and TAC.

In conclusion, the evidence indicates that the claim that HRW supports the maintenance of healthy blood lipids is substantiated. In our opinion there is supportive scientific evidence that indicates that HRW may attenuate blood lipids outside of the desired range but will not decrease or increase their levels outside of normal healthy ranges. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical, animal, and cell culture in vitro studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “supports healthy blood pressure” is supported by several randomized, double-blinded, placebo-controlled (RDBPC) human clinical studies. Many of these studies used tablets of this formulation. For example, a 24-week RDBPC study in 60 subjects with metabolic syndrome found that daily ingestion of HRW reduced the circulating angiotensin-converting enzyme by 5.3%. This was associated with a decrease in both systolic and diastolic blood pressure by approximately 15 and 14 mmHg, respectively. The average blood pressure levels were reduced from pre-hypertension to the normal range (from 127/83 mmHg at baseline to 112/70 mmHg at the follow-up).

An 8-week observational study conducted in subjects with potential metabolic syndrome found a non-significant trend in the reduction of systolic and diastolic blood pressure with HRW intake. Similarly, in an 8-week randomized, double-blind, placebo-controlled study, it was observed that HRW intake (\> 4 mg/day) tended to decrease pre-hypertensive systolic blood pressure by 2 mmHg in patients with non-alcoholic fatty liver disease (NAFLD). Additionally, in a single-blinded study, 4 hours of daily inhalation of hydrogen gas (0.2-0.4%) for two weeks significantly decreased systolic blood pressure from ≈152 mmHg to 147 mmHg, and nighttime diastolic blood pressure decreased by 2.7 ± 6.5 mmHg. The study also reported significant reductions in angiotensin II, aldosterone, and cortisol levels, as well as a lower aldosterone-to-renin ratio in plasma.

However other studies show no significant change in blood pressure, particularly in the normotensive population. These findings suggest that HRW intake may not result in hypotension. This is also indicated in other clinical studies where the baseline blood pressure was already within the normal range, but has more of a tendency to reduce elevated blood pressure.

Finally, in a 24-week observational study, 21 subjects who were switched from standard hemodialysis (HD) to HD with hydrogen gas (240 µM) experienced significant decreases in blood pressure at 3 and 6 months of follow-up. The post-dialysis blood pressure levels were reduced from 148/71 mmHg to 131/67 mmHg.

In addition to the clinical studies, a number of animal studies have also demonstrated that H2 can lower high but not normal blood pressure.

In conclusion, the evidence indicates that the claim that HRW supports healthy blood pressure is substantiated. In our opinion there is supportive scientific evidence that indicates that HRW may attenuate elevated blood pressure outside of the desired range but will not result in hypotension. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “supports cardiovascular health” is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies. Many of these studies used tablets of this formulation. For example, in a DBPC 8-week crossover study in 36 subjects, HRW (1 mg/day) tended to non-significantly decrease homocysteine levels by 5.3%.

Ingestion of high-concentration HRW may maintain optimal function of the endothelial vasculature. A randomized controlled trial of 34 healthy subjects revealed that compared to baseline, ingestion of HRW (3.5 mg) resulted in a 19.9% ± 41.6% increase in flow-mediated dilation of the brachial artery, whereas it slightly decreased in the placebo group.

An open-labeled, single-blinded, controlled trial of 20 subjects found that H2 treatment (1.3% inhalation) following percutaneous coronary intervention led to greater improvements in several parameters. At the 6-month follow-up there was an increase in left ventricle (LV) stroke volume and ejection fraction compared to control group.

In addition to the mentioned human clinical studies, many animal studies also provide support to this claim. For example, six months of HRW prevented development of atherosclerosis in apoE-/- knockout mice. Compared to other studies, HRW appeared to be more effective than folic acid, vitamin E, iron, and alpha-lipoic acid.

In apoE-/- knockout mice fed a high fat diet, hydrogen-rich saline (HRS) reduced apoB, TNFa, IL-6. HRS also decreased vessel wall infiltration of macrophages and induced the hepatic scavenger receptor class B type 1, ATP-binding cassette transporters. HRS also decreased the lipid deposition on the arterial wall of the aorta. Moreover, two-week consumption of HRW by diet-induced obese mice with chronic cardiovascular conditions resulted in elevated eNOS activation in the myocardium and adipose tissue, especially BAT. This led to significant dilation of arterioles and capillaries, which subsequently provided cardioprotective effects. Additionally, HRW improved cardiac hypertrophy, shortened the width of cardiomyocyte, and restored left ventricular function.

Finally, in an experiment using mice with diabetes induced by streptozotocin, HRW was observed to have a considerable effect in reducing cardiac hypertrophy and fibrosis, as well as regulating the overexpression of collagen I and III. Importantly, HRW decreased oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis.

Important, part of the substantiation of this claim relies upon the known relationship between hyperglycemia, dyslipidemia, and hypertension with impaired cardiovascular health. It has been demonstrated that HRW may support healthy glucose levels, blood lipid profiles, and normal blood pressure. Additionally, there exists a strong relationship between excessive chronic inflammation and oxidative stress with cardiovascular dysfunction. This document also provides support for the claims that HRW may support a healthy redox homeostasis and inflammatory response. Therefore, in our opinion, we believe that these supported claims provide substantiation that HRW may support cardiovascular health.

In conclusion, the evidence indicates that the claim that HRW supports cardiovascular health is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. Evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “supports healthy body weight and body composition” is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies. Some of these studies used tablets of this formulation. For example, an improved body composition from HRW (\>11 mg/day) was observed in a 24-week randomized, double-blinded, placebo-controlled study comprising 60 subjects with metabolic syndrome. Subjects in the HRW group had reductions in their BMI (28.92 ± 4.8 kg/m2 vs 28.2 ± 4.9 kg/m2), waist-hip circumference, and experienced a ≈1.7 kg decrease in body mass. In a RDBP crossover (two weeks) study in ten middle-aged overweight women, HRW administration (≈3.3 mg/day) for 4 weeks resulted in a significant reduction body fat by 1.4%, and arm fat index by 5.7%. There was also a strong trend of reduced arm circumference (p = 0.09), waist-to-hip ratio (p = 0.07), and body mass (p = 0.16). Similar effects have been observed in other clinical studies. However, in subjects with a normal BMI (e.g., 18.5 to 24.9 kg/m2), HRW may not have any BMI-decreasing effect.

In addition to the human clinical studies, many animal studies also support this claim. For example, H2 administration prevented the weight gain induced by DM and high fat diet. In a diabetes mouse model with obesity, HRW for three months significantly suppressed fat and weight gain. Mechanistically, HRW induced fibroblast growth factor 21, which is a hepatic hormone that stimulates energy metabolism. Mice in the HRW group consumed 10% more oxygen than the control group.

In conclusion, the evidence indicates that the claim that HRW supports healthy body weight and body composition is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “supports the maintenance of healthy redox” is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies. Many of these studies used tablets of this formulation. For example, several studies have investigated the effects of hydrogen-rich water (HRW) on oxidative stress markers. One 24-week double-blind, placebo-controlled study on metabolic syndrome subjects (n= 60) showed improved redox status through increased levels of vitamins C and E, decreased TBARS, MDA and diene conjugate levels. Another open-label study on subjects with potential metabolic syndrome showed 43% decreased urinary TBARS, a trend of decreased 8-OHdG, and 39% increased SOD levels. HRW appeared to have greater redox regulatory effects in smokers vs. non-smokers. In a RDBPC study involving 60 subjects, HRW significantly increased SOD and GST levels and decreased MDA and XOD levels in chronic hepatitis B patients. However, when HRW decreases levels of oxidative stress, it only does so in subjects who are at the high end of oxidative markers.

In total, over 18 human clinical studies, which collectively monitored over 18 indices of either oxidative stress or antioxidant status indicate that HRW reduces markers of oxidation, but only in conditions of oxidative stress. That is HRW does not induce reductive stress and may even promote a mild hormetic protective effect by transiently elevating ROS levels.

A systemic review and meta-analysis reported that molecular hydrogen administration significantly decreased serum malondialdehyde levels (pooled standardized mean difference = -0.97 \[95% confidence interval \[CI\], from -1.65 to -0.19; P = 0.01\]), with results indicating a large effect of dihydrogen intervention.

In addition to these clinical studies, many animal studies also demonstrate that HRW can attenuate oxidative stress and regulate redox homeostasis. For example, a study investigated the effects of HRW in streptozotocin-induced diabetic mice. The results showed that HRW prevented the decrease in SOD levels and total antioxidant status, as well as the increase in MDA, mitochondrial ROS production, and NOX4 activity, maintaining similar values to non-diabetic control mice. Importantly, however, the administration of HRW to non-diabetic control mice did not result in any statistical changes in these markers. This suggests that HRW can help maintain redox homeostasis without causing unnecessary reductive reactions.

Mechanistically, studies have demonstrated that H2 selectively reacts with the most oxidative free radicals, such as hydroxyl radicals, while leaving important signaling reactive oxygen species, such as NO, H2O2, O2-, untouched. Bioactivation of H2 to reduce highly oxidative free radicals is facilitated by Fe-porphyrin, which is present in large amounts in red blood cells and mitochondria. Furthermore, H2 exerts its antioxidative effects by upregulating the Keap1/Nrf2 pathway, which is a transcription factor that regulates the expression of endogenous antioxidants like glutathione, superoxide dismutase, catalase, and others.

In conclusion, the evidence indicates that the claim that HRW supports the maintenance of healthy redox homeostasis is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

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Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “supports a healthy inflammatory response” is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies. Many of these studies used tablets of this formulation. At least 10 clinical studies have investigated the effects of hydrogen-rich water (HRW) on more than 10 different markers of inflammation. In a 24-week DBPC study in sixty subjects with metabolic syndrome, HRW decreased TNF-α by 18.75%, IL-6 by 15.8%, and induced a light decrease in CRP. In a 2-week RDPC pilot study in COVID-19 patients, HRW tended to affect TNF-α and decreased IL-6 by 5.8%, while IL-6 increased by 16.2% in the placebo group. HRW for 4-weeks significantly decreased transcriptional profiles of IL-1B, IL-8, IL-6R and TLR-NF‐κB signaling in the HRW group compared to placebo. Another clinical study showed that HRW tended to reduce levels of NF-κB, heat-shock protein 70, and matrix metalloproteinase-9, which slightly increased in the placebo group. However, in contrast to these studies in largely unhealthy subjects, HRW seems to not decrease markers of inflammation such as CRP and/or IL-1β in healthy populations.

In addition to the clinical studies, HRW has also shown to decrease or favorably regulate the inflammatory response in many animal studies. However, HRW does not decrease inflammatory mediators when they are not elevated.

In conclusion, the evidence indicates that the claim that HRW supports a healthy inflammatory response is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “supports gut health” is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies. A randomized, double-blinded, placebo-controlled study (n=20) was conducted to evaluate the effects of two-weeks of HRW (0.15 mg/day) ingestion on changes in the gut microbiota composition. Compared to placebo, HRW induced an increase in Bifidobacterium longum and Bifidobacterium adolescentis. This was indicated by another clinical study (n=38) that likewise demonstrated that 8 weeks ingestion of HRW restored lower baseline levels of Bacteroides. The study also found that HRW enhanced gut flora abundance and diversity of the gut flora.

Similar favorable effects of HRW (1.4 mg/day) were observed in a clinical trial (n=73) in subjects with impaired glucose tolerance for eight weeks. The participants' metabolic parameters and fecal gut microbiota were evaluated at the beginning of the study (week 0) and after eight weeks. HRW led to a significant reduction in fasting blood glucose levels and a higher number of subjects with initial abnormal pre-experimental fatty liver achieved remission in the HRW group compared to the pure water group. The analysis of the gut microbiota using 16S RNA revealed that HRW had a positive impact on the dysbiosis of gut microbiota in the fecal samples of IFG patients. Furthermore, a correlation analysis identified a strong association between the specific gut microbiota and nine metabolites. In conclusion, the study suggests that HRW improved metabolic abnormalities and gut microbiota dysbiosis in patients with impaired fasting glucose.

HRW may also support gut health improving gut barrier integrity. A human clinical study reported that 12-week HRW intake could modulate microbiota derived products. Specifically, a strong positive trend was reported toward hydrogen-rich water being superior to placebo in augmenting total serum short-chain fatty acid levels while the mean fecal calprotectin levels were significantly reduced after hydrogen-rich water intervention.

In addition to these clinical studies, many animal studies also indicate that H2 favorably impacts the gut microbiome. For example, administration of hydrogen-rich saline altered the abundance of key bacterial taxa - such as Bacteroides, Bifidobacteria, and Lactobacillus - in the feces of high-fat diet mice, which may have contributed to improvements in lipid metabolism disorders. Similarly, H2 administration to the gut via hydrogen nanocapsules increased levels of the beneficial bacterium Akkermansia muciniphila while attenuating metabolic dysfunction-associated fatty liver disease. Six months of HRW administration in rats induced significant changes in the composition of the gut microbiota. There was a significant increase in the abundance of Lactobacillus, Ruminococcus, Clostridium XI, Elusimicrobium, Barnesiella, and Aquabacterium, and decrease in Bacteroides, Anaerotruncus, Desulfovibrio, Mucispirillum, and Bifidobacterium. In NAFLD-rats H2 inhalation significantly reduced microflora dysbiosis by improving the relative abundance of Bacteroidetes-to-Firmicutes. Many other animal and disease model studies also indicate that H2 can support a healthy microbiome. HRW was also demonstrated to have comparable effects as the drug sulfasalazine for the treatment DSS-induced ulcerative colitis in mice, supporting gut health. Additionally, the therapeutic potential of HRW in small intestinal inflammatory diseases is supported by its ability to alleviate NSAID-induced enteropathy in mice.

In conclusion, the evidence indicates that the claim that HRW supports gut health is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “Promotes healthy aging” is supported by a randomized, double-blinded, placebo-controlled (RDBPC), human clinical study as well as in vitro studies.

Telomeres, the protective caps at the ends of chromosomes, play a significant role in aging and disease. As cells divide, telomeres naturally shorten, acting as a biological clock. When telomeres become critically short, cells can no longer divide and become senescent or die. This process is associated with aging and age-related diseases, as shortened telomeres are linked to increased susceptibility to cellular dysfunction, genomic instability, and various health conditions. Understanding telomere dynamics holds promise for uncovering strategies to promote healthy aging and potentially mitigate the risk of age-related diseases. Activation of the telomerase enzyme can prevent telomere shortening and reverse age-related conditions. It has been demonstrated in an in vitro study that HRW increased telomerase activity by 148.4%, which may explain the positive effects noted in the previously mentioned clinical study.

Importantly, increased telomere length was also reported in a clinical study. In a RDBPC parallel study in 40 elderly (\> 70 years) subjects, 24 weeks HRW (\>7.5 mg/day) administration was shown to increase telomere length by 4.1% compared to baseline, which length decreased (11.1%) in the placebo group.

SIRT1 is a crucial protein linked to longevity and age-related disease prevention. Research indicates that as mammals age, SIRT1 expression declines. However, activating and inducing SIRT1 has shown to be associated with increased lifespan. HRW has been shown to increase SIRT1 expression dose-dependently in human umbilical cells. Another study also observed that HRW induced SIRT1 expression.

Another line of evidence to support the claim of healthy aging comes from a study using human umbilical vein endothelial cells (HUVECs). The HUVECs were incubated with a common organic pollutant (2,3,7,8-Tetrachlorodibenzo-p-dioxin; TCDD) resulted in age-related pathological changes. TCDD exposure resulted in increased 8-OHdG, acetyl-p53 expression, decreased NAD+/NAD ratio, impaired Sirt1 activity, and increased senescence-associated β-galactosidase. However, HUVEC cells incubated with molecular hydrogen and TCDD did not exhibit these pathological changes, which was mediated by H2-induced Nrf2 activation. It was also observed that mtUPR pathways were activated by H2, as evidenced by the induction of mtUPR-related proteins through histone modification. In humans, the induction of mtUPR by H2 may lead to the activation of various anti-stress responses, potentially extending healthy life expectancy.

Animal studies also support this claim. For example, HRW was given to transgenic DAL101 mice, which have shorter life span than normal wild type mice, at 1 month old. Although HRW did not expand the maximal lifespan of DAL101 mice, HRW did significantly extend the mean lifespan. Additionally, HRW was reported to extend the lifespan of C. elegans (nematodes) by up to 30% compared to control, likely via attenuating oxidative stress. Similar results of increased lifespan were also reported in Drosophila.

Finally, the evidence reviewed herein regarding the favorable effects of hydrogen in supporting a healthy redox and inflammatory homeostasis as well as the benefits to the cardiovascular system, collectively add credence to the claim that HRW can promote healthy aging.

In conclusion, the evidence indicates that the claim that HRW Promotes healthy aging is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “promotes liver health” is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies. For example, HRW decreased AST and mildly increased GGT, but values were within normal range. In a 28-day RDBPC crossover study in patients with NAFLD, HRW intervention significantly reduced liver fat accumulation, baseline liver fat, and reduced serum levels of aspartate aminotransaminase by 10%. Similarly, other clinical studies have demonstrated that HRW can reduce levels of enzyme markers alanine amino transferase (ALT), and aspartate amino transferase (AST). In a study in patients with chronic hepatitis B, ingestion of HRW for 6 weeks significantly improved liver function. Moreover, a clinical trial in 144 cancer patients found that ingestion of HRW prevented mFOLFOX6 chemotherapy-induced liver damage. This was evidenced by the levels of ALT, AST, and bilirubin, which was only elevated in the placebo group.

A systemic review and meta-analysis reported that molecular hydrogen administration was associated with a strong trend for a reduction in various liver enzymes (i.e., AST and ALT). The authors conclude that molecular hydrogen can favorably affect the hepatic function panel.

In animals, HRW decreased intracellular lipid accumulation induced by palmitate overload and reduced CD36 protein. Moreover, molecular hydrogen has been shown to protect the liver against various toxins including acetaminophen, ethanol, pneumoperitoneum, hepatectomy, lipopolysaccharide, obstructive jaundice, ischemia/reperfusion injury, carbon tetrachloride, diethylnitrosamine, thioacetamide, doxorubicin, and diabetes. Many articles illustrate the hepatoprotective effects of HRW, resulting in H2 being proposed as a regulator of liver homeostasis.

In conclusion, the evidence indicates that the claim that HRW promotes liver health is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “Supports sperm health” is supported by a randomized, double-blinded, placebo-controlled (RDBPC) study as well as various animal and in vitro studies.

For example, in a double-blinded placebo-controlled study of 12 healthy young men (6 with oligospermia), drinking HRW for 8 weeks affected sperm viability. Following 8-week hydrogen-rich water supplementation, sperm concentration and morphology tended to increase by 12.4 million per milliliter (95% CI; –31.8 to 56.6), and live cells increased by 3.8% (95% CI; –12.5 to 20.1), respectively (P ≤ 0.30). A significant difference between HRW and control water was found in sperm vitality (P = 0.03), with hydrogen-rich water being superior to the placebo in terms of an increase in the number of live sperm cells.

In another study it was also reported that the application of H2 had a significant positive effect on the rate of forward motility in human sperm, whereas treatment with nitrogen gas showed no such improvement. It was observed that even a 30-minute treatment with H2 was effective in enhancing motility, although it did not impact the speed of sperm swimming. Furthermore, after a 24-hour period, a subsequent H2 retreatment further increased the motility. In addition to the motility enhancement, H2 treatment resulted in an increase in mitochondrial membrane potential. When low motile frozen-thawed sperm from patients were exposed to a cleavage medium containing H2, there was a significant improvement in forward motility. These results are also supported by a study in which sperm motility and ATP levels were measured in frozen-thawed sperm treated with H2 and from 172 normospermatic patients. Treatment with H2 enhanced toxin-induced decrease in sperm motility and enhanced sperm ATP levels.

Male fertility relies on the concentration of intra-testicular testosterone, which is produced by Leydig cells. Excessive levels of ROS can disrupt testosterone production and impair sperm function, leading to male infertility. Molecular hydrogen has the potential to regulate cellular signals and counteract the effects of ROS, thereby improving testosterone production and potentially serving as a remedy for male infertility. This hypothesis suggests that molecular hydrogen may enhance male fertility by restoring redox balance and supporting testosterone hormone production. Indeed, higher levels of testosterone were observed in smoke-induced reproductive damage in rats drinking HRW. Similar results were reported in a previous study. The study observed that vitamin C and vitamin E had a limited impact on reducing oxidative levels in the testes of mice exposed to chronic nicotine treatment. Additionally, these vitamins did not effectively improve the reproductive damage and apoptosis caused by nicotine. In contrast, hydrogen-rich saline exhibited unique antioxidant properties by reducing oxidative stress in the testes and providing protection against nicotine-induced male reproductive damage. It was also reported that HRW in combination with Ginseng enhances antioxidation, stimulates spermatogenesis, and promotes sex hormone production, leading to increased sperm production and motility. These effects were particularly notable in aged mice. These rats also exhibited larger amount of sperm count and a smaller sperm deformation rate.

In conclusion, the evidence indicates that the claim that HRW supports sperm health is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “Helps maintain brain metabolism after acute sleep deprivation” is supported by a randomized, double-blinded, placebo-controlled (RDBPC), human clinical study.

This study aimed to assess the acute effects of hydrogen-rich water (HRW) compared to caffeine, HRW plus caffeine, and control water on alertness, brain metabolism, oxygen saturation, and adverse events in sleep-deprived, habitual coffee-drinking individuals. Sixteen healthy adults received a single dose of HRW, caffeine, HRW plus caffeine, or control drink. Results showed that both HRW and HRW plus caffeine led to improved performance in cognitive tests compared to the control drink. Additionally, HRW and caffeine increased the choline-to-creatine ratio in certain brain regions, while HRW and the combination intervention affected brain metabolism. These findings suggest that HRW could be a safe and novel intervention for enhancing attention in stressful conditions, and improving brain metabolism following sleep deprivation. Similar findings were reported earlier showing that HRW had comparable effects to caffeine in maintaining mental alertness.

In conclusion, the evidence indicates that the claim that HRW Helps maintain brain metabolism after acute sleep deprivation is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW “Reduces mental fatigue” is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies.

For example, a study found that a single-dose HRW positively improved the neuropsychological performance in young sleep-deprived adults. Specifically, significantly less time was needed to complete trail-making test after both HRW and HRW plus caffeine compared with the control drink (p \< .05). The number of errors in the symbol digit modalities test was significantly lower after drinking HRW or caffeine than control drink (p \< .05). Another study using the HRW tablets reported that in 24 COVID-19 patients HRW improved several blood biomarkers and alleviated disease-related fatigue.

This claim is also supported by the findings that HRW was comparable to caffeine at promoting brain alertness following sleep deprivation, with a single-dose hydrogen-rich water (HRW) increased VAS alertness for 1.7 points on average (P = 0.003) and reduced orientation stress for 2.4% (P = 0.05) in 23 young adults who were sleep-deprived for 24 hours. Finally, it was also reported in a systemic review and meta-analysis that HRW helps reduce exercise-induced psychometric fatigue.

In conclusion, the evidence indicates that the claim that HRW Reduces mental fatigue is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and animal studies.

Human studies: The expert panel reviewed human clinical studies examining brain metabolism and related parameters in elderly populations (full citations available in the Expert Opinion Report reference list). Animal and mechanistic studies were also considered for context.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW promotes healthy brain metabolism in elderly individuals is supported by human clinical studies examining brain health parameters and metabolic markers in relevant older populations. The expert panel reviewed the available human studies on brain metabolism, cognitive function, and related physiological outcomes in elderly individuals. The analysis included evaluation of how molecular hydrogen may influence brain energy metabolism and oxidative stress parameters that become particularly relevant with aging.

The panel considered both direct measurements of brain metabolism and supporting data on redox balance and inflammation in older adults. In addition to the primary human clinical data, related animal and mechanistic research was reviewed to provide context on potential pathways. The doses of molecular hydrogen used in the supporting studies are at or below the levels delivered by tablets of this formulation when used as directed.

In conclusion, the evidence indicates that the claim that HRW promotes healthy brain metabolism in elderly individuals is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical studies in elderly populations as well as supporting research.

Human studies: The expert panel reviewed several randomized, double-blinded, placebo-controlled human clinical studies evaluating effects on neuropsychological tests, alertness, and cognitive performance (full citations in the Expert Opinion Report reference list). Supporting mechanistic research on brain metabolism and oxidative stress was also reviewed.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW supports brain performance is supported by several randomized, double-blinded, placebo-controlled (RDBPC), human clinical studies. The expert panel reviewed human clinical studies evaluating effects on neuropsychological tests, alertness, attention, and other brain performance outcomes. The analysis included both acute and repeated-dose studies measuring cognitive performance parameters.

The panel examined data from studies that assessed brain performance under normal conditions as well as under conditions of stress or fatigue. Supporting mechanistic research on brain metabolism, oxidative stress, and cellular signaling was also considered to provide additional context. Several of the supporting human studies used doses of molecular hydrogen comparable to or lower than those produced by tablets of this formulation.

In conclusion, the evidence indicates that the claim that HRW supports brain performance is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical studies and related research.

Human studies: The expert panel reviewed several randomized, double-blinded, placebo-controlled human clinical studies on exercise performance, including measurements of time to exhaustion, power output, and endurance (full citations in the Expert Opinion Report reference list). Animal and mechanistic studies were also considered.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW supports exercise performance is supported by several randomized, double-blinded, placebo-controlled human clinical studies. The expert panel reviewed the relevant exercise performance trials, which included measurements of time to exhaustion, power output, endurance capacity, and other performance markers during various types of physical activity. Many of these studies used doses of molecular hydrogen comparable to or lower than those produced by tablets of this formulation.

The analysis examined both the direct performance outcomes and supporting physiological data, including effects on oxidative stress and inflammation during and after exercise. In addition to the human clinical evidence, animal and mechanistic studies were considered for context on potential pathways by which molecular hydrogen may influence exercise performance.

In conclusion, the evidence indicates that the claim that HRW supports exercise performance is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical studies and related research.

Human studies: The expert panel reviewed randomized, double-blinded, placebo-controlled human clinical studies measuring fatigue markers during and after exercise, along with meta-analytic data on exercise-induced psychometric fatigue (full citations in the Expert Opinion Report reference list).

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW lowers fatigue from exercise is supported by the same body of randomized, double-blinded, placebo-controlled human clinical studies reviewed for exercise performance, along with additional studies specifically measuring fatigue markers. The expert panel analyzed data on both objective fatigue indicators and subjective ratings of perceived exertion and fatigue during and after exercise.

Several studies demonstrated reductions in exercise-induced fatigue with HRW supplementation. The panel also considered meta-analytic data showing benefits on exercise-induced psychometric fatigue. Supporting research on how molecular hydrogen may influence oxidative stress, inflammation, and energy metabolism during physical activity was reviewed to provide mechanistic context.

In conclusion, the evidence indicates that the claim that HRW lowers fatigue from exercise is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical studies and related research.

Human studies: The expert panel reviewed human clinical trials conducted specifically in older adult populations measuring functional fitness outcomes such as mobility, strength, and endurance (full citations in the Expert Opinion Report reference list).

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW supports functional fitness performance in older adults is supported by human clinical trials conducted specifically in older adult populations. These studies measured outcomes relevant to functional fitness, including mobility, strength, endurance, balance, and daily activity performance markers. The expert panel reviewed these age-specific trials and performed a structured analysis of the evidence.

The panel noted that the doses used in the supporting studies are at or below the levels delivered by tablets of this formulation. Supporting data from related research on mitochondrial function, redox balance, and inflammation in aging populations was also considered.

In conclusion, the evidence indicates that the claim that HRW supports functional fitness performance in older adults is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than those used in the clinical trials supporting this claim. The evidence comes from human clinical studies in older adults and related research.

Human studies: The expert panel reviewed human studies examining mitochondrial markers and related physiological outcomes (full citations in the Expert Opinion Report reference list). Mechanistic research on mitochondrial processes and the Keap1/Nrf2 pathway was also reviewed.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW supports mitochondrial function is supported by human studies examining mitochondrial markers and related physiological outcomes. The expert panel reviewed the available clinical data on mitochondrial function, energy metabolism, and oxidative stress at the cellular level. Several studies measured parameters linked to mitochondrial health, efficiency, and resilience under various conditions.

In addition to the human evidence, the panel considered mechanistic research on how molecular hydrogen may interact with mitochondrial processes, including the selective reduction of highly reactive free radicals while leaving important signaling species relatively untouched.

In conclusion, the evidence indicates that the claim that HRW supports mitochondrial function is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical and mechanistic studies.

Human studies: The expert panel reviewed relevant human clinical evidence on joint comfort, mobility, and related parameters (full citations in the Expert Opinion Report reference list). Supporting research on inflammation and oxidative stress (factors known to affect joint health) was also considered.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW can help restore healthy joint function and structure is supported by relevant human clinical evidence examining joint comfort, mobility, range of motion, and related structural and functional parameters. The expert panel reviewed the available studies on joint health outcomes and performed a detailed analysis of the evidence.

The panel considered both direct measurements of joint function and supporting research on factors known to influence joint health, including inflammation and oxidative stress.

In conclusion, the evidence indicates that the claim that HRW can help restore healthy joint function and structure is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than those used in the clinical trials supporting this claim. The evidence comes from human clinical studies and related research.

Human studies: The expert panel reviewed human studies examining skin parameters including hydration, elasticity, and wrinkle-related outcomes (full citations in the Expert Opinion Report reference list). Supporting research on oxidative stress and collagen-related pathways was also reviewed.

Expert Determination: Overall, looking to the totality of the reviewed evidence, in our professional scientific and medical opinion, there is competent and reliable scientific evidence on HRW that substantiates this claim for tablets of this formulation.

The claim that HRW improves skin and wrinkles is supported by human studies examining skin parameters, including hydration, elasticity, wrinkle depth and appearance, and other dermatological outcomes. The expert panel reviewed the clinical data on skin health and performed a structured analysis of the evidence.

The panel considered both direct skin measurements and supporting research on oxidative stress and collagen-related pathways that influence skin appearance and structure. The doses used in the supporting studies are comparable to or lower than those delivered by tablets of this formulation.

In conclusion, the evidence indicates that the claim that HRW improves skin and wrinkles is substantiated. Importantly, the doses of molecular hydrogen provided by tablets of this formulation are as great as or more than the clinical trials used to support this claim. The evidence to support this claim comes from human clinical studies and related research.