Part 7 Hormesis - Molecular Hydrogen
Hormesis (exposure to stress to create a benefit) is proving to be an incredibly effective tool in our health arsenal. From cold exposure to calorie restriction and much more in between, the field has lots of promise. The final part in our 7 part hormesis series, addresses, in my opinion, the most interesting form of hormesis, molecular hydrogen. This is the one that may lead to the most compounding benefits. It is easy, affordable, and can be used in conjunction with the rest without fear of overuse.
Read a complete introduction to Hormesis in the first part of our Hormesis series.
Molecular Hydrogen Research
Following the seminal research article on molecular hydrogen (H2) published in Nature Medicine (2007),ii research on molecular hydrogen as a therapeutic agent has exploded. In recent years, the number of peer-reviewed publications has doubled year on year, leading to over 1,200 unique articles (as of 2018) and 65 published human clinical trials (61 showing a benefit and 4 showing no significant benefit but with emerging trends) citing evidence of beneficial effects in over 170 disease models across every organ in the human body.
For years, the intricate pharmacodynamics and mechanisms of action of molecular hydrogen eluded research efforts. However, recent discoveries and publications have elucidated some of the diverse functions in which H2 is a key player. H2 has the potential to be a product with the ability to impact all demographics with unique marketing and formulations targeting specific sub-groups. From natural health and sports science to science-based anti-aging, H2 therapy can be impactful.
Impact on Anti-Aging Markers in Molecular Hydrogen Research
I’ve previously suggested that molecular hydrogen, specifically hydrogen water, is the most comprehensive longevity supporting supplement currently on the market. This claim does not come without evidence and the data on what hydrogen therapy can do is becoming quite remarkable. While it isn’t a “miracle” and will not reverse aging of the overall system, many important markers and functions are repaired and rejuvenated leading to preferential outcomes (for those who prefer to be healthy).
A recent article published in Scientific Reports suggests that hydrogen administration can prevent vascular aging of the aorta in LDL-deficient mice on a high-fat diet to simulate atherosclerosis,iv which may be part of the story we talk about later regarding metabolic syndrome. Certainly, vascular aging plays a role in age-related illnessv and mortality.vi
Sirtuins (SIRT), SIRT1 specifically, have been extensively linked to agingviiviiiix and SIRT1 activators have been linked to extending lifespanx which we will touch on regarding calorie restriction. Research has shown that hydrogen water is able to activate SIRT1.xi
Research by David Sinclair, now supported by many others, on elevating NAD+ to mitigate disease and even partially reverse aging, such as skeletalxii mitochondrial aging in mice,xiii has created an explosion in research and public interest.xiv
Many have quickly jumped on the bandwagon despite a dearth of human evidence, especially considering the evidence that has shown no tangible benefit on markers outside NAD+ itself,xvxvixviixviii even when administered in 10-15x the dosage marketed to consumers in a trial with significant conflict of interest present (one of the authors is tied to the patent-holding company of the method used to raise NAD+).xix
While other molecules certainly raise NAD+ but do seemingly little else, molecular hydrogen has shown to balance NAD+/NADH ratios, while alleviating cellular senescence in endothelial cells,xx on top of all of the other known benefits.
As discussed in part 3 of this series, fasting, we know that autophagy plays a critical role in aging. I wrote about the complexity of autophagy and suggested that it may be another function where tight regulation is needed as we know it plays a critical role in both cell survival and cell death, as well as suppressing and promoting cellular senescence.
Molecular hydrogen has shown to regulate autophagy rather than simply activating it. In three studies, hydrogen has shown to activate autophagy for a beneficial outcomexxixxiixxiii and in another, the beneficial effects were attributed to inhibiting autophagy.xxiv Furthermore, molecular hydrogen has been shown to inhibit cellular senescencexxvxxvi and apoptosis.xxviixxviiixxixxxxxxxixxxiixxxiiixxxivxxxvxxxvixxxviixxxviii
We know that the telomere crisis activates autophagy as a last line of defense,xxxix however, when we get to this state, our bodies are in trouble. Molecular hydrogen’s ability to regulate autophagy while protecting against senescence and apoptosis independent of telomere distress is important and potentially very beneficial towards longevity. In fact, hydrogen water has been shown to significantly increase telomerase activity in vitro, suggesting it may play a role in protecting against telomere shortening.xl
Many forms of hormesis play a role in inflammation and exercise raises inflammation dramatically. However, IL-6’s role as a myokine leads to a stronger anti-inflammatory response and mobilization of IL-10 as discussed in part 2 of this series here. We know that molecular hydrogen regulates the production of pro-inflammatory cytokines, such as TNF-a and IL-6,xlixliixliiixlivxlvxlvixlviixlviiixlixlliliiliiiliv and know that it does not always reduce inflammatory markers.lv In the only trial I am aware of where inflammatory markers were measured during H2 inhalation and exercise, H2 blunted excessive inflammatory cytokine production.lvi
This suggests that H2 may attenuate excessive inflammation due to exercise, while not completely blunting it. It has been shown that H2 protects against stresslvii and perhaps while exercising, H2 potentiates those benefits by modulating our redox balance and attenuating the excessive inflammatory responses via another mechanism. We know that H2 activates heat shock proteins,lviii similar to exercise and heat exposure, and heat shock proteins tend to regulate inflammatory responses towards homeostatic function.lix
H2’s role during the inflammatory response still needs further research and I personally would like to see more and better-controlled studies elucidating the mode of actions in which H2 regulates the inflammatory cytokine production. Does H2 elevate cytokines, such as IL-6 in its’ myokine role when another stressor isn’t present? This is one of the questions that still need answers.
Redox, Up and Down for ROS
Many believe antioxidants will help you live longer, a fallacious notion born out of the free radical theory of aging. In reality, it is the redox status in our cells that is important, with the homeostatic function being critical. Most antioxidants indiscriminately react with even the beneficial reactive oxidative species, and studies on high use antioxidants showed either no benefitlx or in some cases significant harm.lxilxii
Hydrogen water has shown to improve endogenous production of antioxidant activity in human trialslxiii and has been shown to regulate our redox status in a human trial of athletes exposed to several bouts of strenuous exerciselxiv and protect against free radical damage in another group of athletes.lxv
Animal and in vitro data have shown molecular hydrogen has the ability to activate the NRF2 pathway to promote homeostatic function (and not beyond), regulating our bodies endogenous antioxidant productions of glutathione, catalase, superoxide dismutase, etc. protecting against oxidative damages and promoting a homeostatic antioxidant/oxidative balance.lxvilxviilxviiilxixlxx
Radiation damage is a topic discussed less frequently in terms of aging, however very critical.lxxilxxiilxxiii Some have even suggested low dose radiation could extend lifespan by acting as a form of hormesis.lxxiv As is true for overexposure to other forms of hormesis, such as exercise and alcohol, molecular hydrogen has shown to protect against radiation-damaging effects.lxxvlxxvilxxvii For example, this was observed in rodent models with full-body damagelxxviiilxxixlxxxlxxxi and another study where it aided in healing post-radiation burns in rats,lxxxiilxxxiii as well as one model studying chickens to determine relevance for those exposed to radiation during Fukushima.lxxxiv
With two human studies using hydrogen water to mitigate side effects of radiation therapy in cancer patients,lxxxviilxxxviii research on hydrogen water and its protection against radiation is well underway with positive results, but more research needed. It is of note that the hydrogen water was used specifically to reduce side effects, and not to enact any beneficial response towards cancer itself.
Neuroprotection of H2
Like other forms of hormesis, molecular hydrogen has been implicated in protection against the development of diseases of the brain and the central nervous system. It has been studied extensively in rodents and humans with varying results. This topic deserves an entire article of its own, which will be released in the coming months.
Calorie Restriction Mimetics and the Links to Molecular Hydrogen
Acarbose is an anti-diabetic drug used to treat, and in some cases prevent diabetes mellitus type 2. Research has found that acarbose reduces body weight, body fat, and improves glucose metabolism regardless of caloric reduction occurs in both rodentslxxxix and humans.xcxcixcii Acarbose has been suggested by others to be a caloric restriction mimicking moleculexciiixcivxcvxcvi and has shown to significantly increase lifespans in male mice.xcvii
Acarbose has shown to positively impact ulcerative colitis via the production of H2 in the small intestine, a position put forth in hypothesis and followed up with a study.xcviiixcix While it follows that acarbose should increase intestinal H2 via slowing down digestion and increasing carbohydrate break down from bacteria,c more research is needed on the subject to understand H2’s role in relation to the benefits of acarbose.
I have discussed resveratrol in some detail in both our article on alcohol as a form of hormesis last week here and our article on advanced glycation. It has been suggested that resveratrol is a calorie restriction mimetic,ciciiciii explaining in part the mode of action of resveratrol in anti-aging.
A single paper published in an American Chemical Society journal has suggested resveratrol may work by creating molecular hydrogen inside the mitochondria. To quote the authors, “It is suggested that the activity of resveratrol in living cells is driven by dissociative attachment of electrons “leaked” from the respiratory chain to this polyphenolic molecule, followed by the formation of the H2 antioxidant species inside mitochondria and participation in mitochondrial energy biogenesis”.civ
In my talk with Tyler W. LeBaron, we briefly touch on this study and he mentions he isn’t sure if he believes it, but finds it interesting. The hypothesis is interesting and if it turns out to be true, it would be quite convenient in supporting the assertion that H2 is a calorie restriction mimetic, however, it requires more research.
I briefly discuss curcumin, the challenges in bioavailability, and the source we use to overcome the challenge in my previously linked article on advanced glycation end-product crosslinking. Regarding life extension, curcumin has been shown to significantly extend the lifespans of fruit flies.cv Perhaps this can be due to its ability to mimic calorie restriction, a hypothesis numerous teams have published.cvicviicviii
Another team reported that curcumin (in combination with piperine, found in black pepper) can improve the benefits of calorie restriction when added on top of the protocol in mice,cix however, a replicative study concluded there were no additive benefits of curcumin and/or piperine on top of caloric restriction.cx
Molecular hydrogen is connected to curcumin as well. As many readers may know, curcumin is the active component of turmeric. Turmeric consumption has been shown to increase H2 production in the small intestine by activation of gut flora,cxi resulting in a similar H2 creation process as discussed above regarding acarbose.
Similar to resveratrol and acarbose, the evidence is still lacking. While it is logical and accurate to state that curcumin will increase H2 production, such increases via lactulose were ineffective in one study but effective in others. Notably, methods such as the consumption of hydrogen water were effective in the study that showed no effect.cxii
Perhaps localized effects of such an increase in production are more prominent, only more research and data can elucidate molecular hydrogen's role in curcumin’s reported benefits.
Molecular Hydrogen as a Caloric Restriction Mimetic
It has been suggested that many of the benefits of caloric restriction stem from activation of PGC-1αcxiii and SIRT1,cxiv with PGC-1α being a key regulator in energy metabolism cxv and overexpression shown to mimic rejuvenation in mice.cxvi This is also true for calorie restriction mimicking molecules, such as metformin,cxviicxviiicxix which has been suggested as a tool to extend lifespancxxcxxi and is currently the first approved substance to be studied for this use.cxxii
Previously mentioned molecules such as curcumin,cxxiii resveratrolcxxivcxxvcxxvi have shown to activate PGC-1α and SIRT1 as modes of action and while research on acarbose’s role in the activation of SIRT1 and PGC-1α is lacking, acarbose has shown to regulate IGF-1 and FGF-21,cxxvii both of which are linked to caloric restriction,cxxviiicxxix although the significance and impact in humans is disputedcxxx and a matter of controversy/debate.cxxxi
Molecular hydrogen has been linked to activation of PGC1α,cxxxii increased expression and upregulation of SIRT1.cxxxiiicxxxivcxxxv Furthermore, it can improve obesity and diabetes in mice by increasing the expression of FGF-21 and increasing energy metabolism.cxxxvi
While hydrogen water has not been directly studied in relation to IGF-1, a single hypothesis article talks about the potential benefits and cautions regarding the dangers of H2 stimulating IGF-1 mediated by ghrelin depending on the modelcxxxvii presumably based on this study identifying hydrogen water’s regulation of ghrelin excretion, particularly in the interest of Parkinson’s Disease.cxxxviii
The conclusion of the hypothesis, both describing potential benefits, and concerns, follows as if hydrogen water would impact this function in the same way for every model regardless of current function, which shows a complete lack of understanding of how molecular hydrogen works. It assumes that molecular hydrogen indiscriminately raises IGF-1 in a pharmacological method while disregarding the evidence suggesting it promotes homeostatic function across many systems.
Molecular Hydrogen and Diabetes, Body Composition and Metabolic Syndrome
As discussed in my write up regarding our recent publication on our hydrogen tablets and NAFLD, molecular hydrogen, specifically hydrogen water, is already being studied as a potential therapeutic aid in diabetes in humanscxxxix and rodents.cxlcxli Other studies show that hydrogen water positively impacts metabolic syndrome and body composition in humans and rodents,cxliicxliiicxliv which are both closely related to diabetes and metabolic syndrome, which encompasses some parameters referred to as “pre-diabetes”.cxlv
Importantly, the study on our own hydrogen tablets showed early promise in NAFLD,cxlvi an issue suggested to be bidirectionally causative with metabolic syndromecxlviicxlviii and perhaps even part of metabolic syndrome.cxlixcl
We are also sitting on some phenomenal metabolic syndrome data from a relatively long and significant scale study, however, I cannot expand on that further until it is finished being written and goes through peer review. Some of the altered markers revealed, providing they are accurate and no mistakes are caught in review, go a long way to strengthen this narrative.
Molecular Hydrogen as an Exercise Mimetic
While other forms of hormesis, such as fasting, permanent caloric restriction, and alcohol, are known to negatively affect exercise performance, in some instances of overuse or when done in conjunction with exercise,cliclii they have either no impact or positively in others, particularly when moderation is considered.cliiiclivclv
When it comes to molecular hydrogen, especially hydrogen water, we have not reached a threshold in which hydrogen has shown to be deleterious to exercise. In fact, hydrogen has shown to not just work along with exercise, but to potentiate it.
Molecular hydrogen has received a considerable amount of research regarding its benefits for athletes. Studies have focused on decreasing healing time by speeding up the healing of soft tissue injury, decreasing inflammation (or rather proteins in our blood which coincide with inflammation), and plasma viscosity.clvi Hydrogen water also helps by decreasing blood lactate levels leading to increased work completed before fatigue,clviiclviiiclix overall peak performanceclx as well as potentially decreasing recovery time.clxi
A study on our hydrogen tablets has shown to increase work capacity, time to exhaustion and VO2 max,clxii and another using our hydrogen tablets demonstrated that the H2 group significantly decreased their sub-maximal heart rate without affecting VO2 intake, meaning participants were under less stress to complete the same activity.clxiii
Another study has shown that hydrogen water decreases soreness post-exercise when administered topically,clxiv something our team has very interesting data on that should be published sometime in 2019. Other studies have shown that hydrogen is capable of regulating redox status in humans to eliminate exercise-induced oxidative stress without blunting gains,clxvclxvi while a well-controlled rodent study was able to show that molecular hydrogen increases reactive oxygen species during exercise and blunts it at completion, potentiating the benefits gained while mitigating the damage.clxvii
Molecular Hydrogen Toxic Threshold? When is too Much?
We know that molecular hydrogen can start creating narcotic-like effects at very high doses under high pressure through data from mixed sea diving.clxviii However, it has been shown only to happen at doses higher than even nitrogen,clxix which we know has a high safety threshold as it makes up 78% of our atmosphere.clxx Furthermore, molecular hydrogen has been shown to suppress some of the neurological symptoms of high-pressure nervous system symptoms, even when hydrogen narcosis is present, providing another benefit in deep-sea diving.clxxiclxxii
The dosage of hydrogen needed under pressure to exhibit signs of narcosis is significantly higher than any commercial method could potentially deliver to consumers. Thus, hydrogen narcosis (which exhibits no known long-term damages, toxicity, or side effects), is of relatively small concern.
In clinical research, we have yet to determine an upper limit in therapeutic dosages of molecular hydrogen, especially hydrogen water which is particularly difficult to create with new research emerging showing very promising results from methods, such as our hydrogen tablets, which deliver the highest dosages on the market.
While other hormetic stressors need to be monitored to prevent them from becoming harmful, the safety of molecular hydrogen is extremely high. We know that alcohol has a very sharp J-shaped curve, with benefits in a tight range, and harm and damage following very closely after.
Even exercise has a reverse J curve in terms of healthy gene expression that many people overdo. A rough curve may look something like this:
Note that “low”, “moderate”, “high”, and “extreme” levels would be based on individuals, intensity, and many other variables.
For H2, we have yet to establish a downtrend. As we have increased dosages, we have often found increased benefits. This is incredibly impactful as it shows that molecular hydrogen can be utilized safely alongside other hormetic agents and (likely) medications to improve outcomes in a wide range of models.
These benefits will likely be conferred with limited or no inherent risks. A graph of our study on hydrogen water and benefits may look something like this:
Hormesis - Molecular Hydrogen Conclusion
Molecular hydrogen has shown to have a very high level of safety and tolerance. On top of acting as a beneficial form of hormesis in many of the same ways as other known beneficial hormetic aids, molecular hydrogen can protect against the damages incurred by other hormetic aids, whether they are “dosed” appropriately or in excess and potentiate their benefits, even working synergistically via different pathways.
Hydrogen Water, and molecular hydrogen therapy in general, can be utilized by virtually everyone as an integral part of their overall health and wellness routine.