Advanced Glycation End Product Crosslinking Part 3

April 30, 2019 7 min read

Hydrogen Water and AGEs

Part 3 of 3 

Since the seminal article published in Nature Med in 2007i, molecular hydrogen has spurned over 1200 unique articles discussing potential benefits with demonstrated results in over 170 models across every organ in the mammalian body. While predominantly studied in animals, over 60 human studies are currently published with dozens more registered and underway. Despite the volume of literature, exact mechanisms of action for the majority of the results are poorly understood. Current research on the pharmacodynamics of hydrogen revolves around gene expression, and while evidence is growing on this subject, exact mechanisms in which the affected genes’ regulation result in the positive outcomes remain unclear. The most recent hypothesis posits H2 has a hormetic like effect, and evidence suggests it works as an exercise mimetic- meaning that it mimics many of the benefits of exercise. An overlooked mode of action I believe is a leading benefit of Hydrogen-rich Water (HRW) is the inhibition of AGE formations.

As we know, AGEs form when sugars create irreversible glycation links between our proteins, lipids, and carbohydrates either through heat or reaction with free radicals. The more sugars and free radicals in our system, the more links form. AGEs increase inflammation, which leads to excess oxidative stress and free radicals, driving more and more crosslinks in a runaway train effect. In studies using hydrogen water on diabetes and metabolic syndrome we have seen a dose dependent response, with higher concentrations leading to greater benefits, where lower do not. Higher dose hydrogen therapy has shown to improve fasting glucose levels in humans in advanced disease models.ii iii That said, lower dosages have shown no statistically meaningful results for this outcome in a trial of patients with much more preliminary pathologiesiv, indicating that a higher dose at a higher damage shows a more prominent result. These studies have also shown hydrogen to have positive impacts on healthy cholesterol levels in serum, with others showing decreases in systolic blood pressurev. I propose that long term results of HRW in advanced pathologies including reduced blood glucose, cholesterol, and blood pressure are at least partially a result of hydrogen water inhibiting advanced glycation end product crosslinking formation through decreasing oxygen radicals necessary for AGE formation during the amadori rearrangement.

Speculative Evidence

Let’s start out with the single article showing a hydrogen-rich medium does inhibit AGE induced apoptosis while simultaneously dealing with the free radicals needed to form them.vi Of course, a single study in scientific terms is typically meaningless. That said, H2 has amassed enough evidence to demonstrate that inhibiting AGEs is not just simply plausible, but likely and by default almost guaranteed in some capacity.

In addition to direct study on insulin resistance and blood glucose demonstrating positive benefits with hydrogen, hydrogen has shown to modulate activities of NF-kB p65vii and significantly reduce the levels of TNF-alpha and other pro-inflammatory cytokines in an animal model of acute pancreatitis. Hydrogen therapy has also shown to upregulate SIRT1 in several studies, including in particular models explaining attenuation of amyloid-beta induced cytotoxicity, renal injury, and an in vitro model evaluating various biomarkersviiiixx Hydrogen has already been demonstrated as a possible solution in ameliorating glucose or mannitol induced oxidative stress in human skin fibroblasts, with the results showing increased levels of superoxide dismutase(SOD) and glutathionexi

Amadori product generation favours low concentrations of glutathione combined with high concentrations of glucosexii. SOD, which hydrogen water can also increase, has been shown to inhibit amadori products both in vitroxiii and in vivo in a compromised endothelial cell modelxiv . The results of SOD may be attributed to prevention of superoxide formation during the amadori rearrangement necessary for final reactivity to irreversible AGEs. Homeostatic function of our endogenous SOD and glutathione result in further reduction of AGEs due to AGE formation reliance on antioxidant inactivation.xv Hydrogen’s promotion of homeostatic function of our endogenous antioxidant/oxidative species via the Nrf2 pathwayxvixviixviii could lead to a maintenance of homeostatic levels of glutathione-glucose as well as increased SOD production necessary to attenuate superoxide formation.

The Takeaway
Of course, all of the above needs to be shown in a well-structured study, and then repeated and further studied. I’ve been playing around with this idea (hydrogen water and AGEs) for almost two years now, with sentences, references and snippets from this 3-part series being removed from an abandoned paper I had written. While writing this original paper, I reached out to various researchers focused on diabetes and heart health. While the feedback has been positive, with many of the Professors I am well acquainted with trying to introduce me to glycation experts for further correspondence, the motivation to request funding to study an esoteric and embryonic therapy’s benefit on a poorly understood pathology is low.

Science moves very slow, and that is necessary. That said, I personally cannot move slow. In fact, the relatively low amount of study on AGEs with their potentially critical role in aging itself being astronomical is the sole reason I delved deep into this. This philosophy and drive is why I have done what I have done, creating the open cup H2 tablets, designing the Elite Biohacking line and creating a researcher outreach program to donate product and funds for testing to public researchers under no contract stipulations of publication requirements (other than I strongly push for open access, indexed on pubmed). My only recourse is to completely privately fund this study, which I have been opposed to doing for potential conflict of interest, whether conscious or subconscious. There is a reason privately funded research is far more likely to find a result than research from public teams.xix 

While we need more evidence on literally every part of this 3 part series, from the degree of harm AGEs contribute, to the benefits of my mentioned stack and the role of hydrogen water, what we can acknowledge is this is the best evidence we have 
right now and the described methods to combat AGEs are safe and well tolerated. I cannot say for certain if they will have a meaningful impact, but I am willing to gamble they will have at least a slight and detectable benefit. Perhaps just enough to offset certain vices I’m not willing to give up, and likely most of you are not willing to either. Of course, diet plays a massive role. Watch out for our future blog series on healthy eating. There will be no ‘fad miracle diet’ endorsements, just prudent advice to protect your health and longevity, while accounting for enjoying your life.

i Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007, 13 (6): 688-694. 10.1038/nm1577.

ii Sizuo Kajiyama, Goji Hasegawa, Mai Asano, Hiroko Hosoda, Michiaki Fukui, Naoto Nakamura, Jo Kitawaki, Saeko Imai, Koji Nakano, Mitsuhiro Ohta, Tetsuo Adachi, Hiroshi Obayashi, Toshikazu Yoshikawa, Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance, In Nutrition Research, Volume 28, Issue 3, 2008, Pages 137-143, ISSN 0271-5317, https://doi.org/10.1016/j.nutres.2008.01.008.

(http://www.sciencedirect.com/science/article/pii/S0271531708000237)

Keywords: Hydrogen-rich water; Insulin resistance; Type 2 diabetes mellitus; Oxidative stress; Modified LDL; Oxidized LDL; Human; BMI; EC-SOD; ELISA; emLDL; ERW; FBS; HbA1c; HDL-C; hsCRP; IGT; IRI; LDL-C; OGTT; oxLDL; RLP-C; ROS; sdLDL; T2DM; u-IsoP

iii Ito M, Ibi T, Sahashi K, Ichihara M, Ito M, Ohno K. Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies. Medical Gas Research. 2011;1:24. doi:10.1186/2045-9912-1-24.

iv Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N. Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome—An Open Label Pilot Study. Journal of Clinical Biochemistry and Nutrition. 2010;46(2):140-149. doi:10.3164/jcbn.09-100.

v Masaaki Nakayama, Hirofumi Nakano, Hiromi Hamada, Noritomo Itami, Ryoichi Nakazawa, Sadayoshi Ito; A novel bioactive haemodialysis system using dissolved dihydrogen (H2) produced by water electrolysis: a clinical trial, Nephrology Dialysis Transplantation, Volume 25, Issue 9, 1 September 2010, Pages 3026–3033, https://doi.org/10.1093/ndt/gfq196

vi Jiang H, Yu P, Qian DH, et al (2013): Hydrogen-rich medium suppresses the generation of reactive oxygen species, elevates the Bcl- 2/Bax ratio and inhibits advanced glycation end product-induced apoptosis. Int J Mol Med, 31: 1381-1387.

vii Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K. Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles -. Medical Gas Research. 2015;5:12. doi:10.1186/s13618-015-0035-1.

viii Chih-Li Lin, Wen-Nung Huang, Hsin-Hua Li, Chien-Ning Huang, Sam Hsieh, Copper Lai, Fung-Jou Lu, Hydrogen-rich water attenuates amyloid β-induced cytotoxicity through upregulation of Sirt1-FoxO3a by stimulation of AMP-activated protein kinase in SK-N-MC cells, In Chemico-Biological Interactions, Volume 240, 2015, Pages 12-21, ISSN 0009-2797, https://doi.org/10.1016/j.cbi.2015.07.013.

(http://www.sciencedirect.com/science/article/pii/S0009279715300272)

Keywords: Amyloid β; Hydrogen-rich water; AMP-activated protein kinase; Sirtuin 1; Forkhead box protein O3a

ix Zhaoyu Xing, Wanma Pan, Jing Zhang, Xianlin Xu, Xuemei Zhang, Xiaozhou He, Min Fan, Hydrogen Rich Water Attenuates Renal Injury and Fibrosis by Regulation Transforming Growth Factor-β Induced Sirt1, Biological and Pharmaceutical Bulletin, Released May 01, 2017, Online ISSN 1347-5215, Print ISSN 0918-6158, https://doi.org/10.1248/bpb.b16-00832, https://www.jstage.jst.go.jp/article/bpb/40/5/40_b16-00832/_article/-char/en

x Robert Settineri1,Jin Ji2Chunlan Luo2Rita R. Ellithorpe3Gonzalo Ferreira de Mattos4Steven Rosenblatt5James LaValle6Antonio Jinenez7Shigeo Ohta8Garth L. Nicolson9 Effects of Hydrogenized Water on Intracellular Biomarkers for Antioxidants, Glucose Uptake, Insulin Signaling and SIRT 1 and Telomerase Activity American Journal of Food and Nutrition Vol. 4, No. 6, 2016, pp 161-168. doi: 10.12691/ajfn-4-6-4 |

xi Pan Yu, Zhenxiang Wang, Xuejun Sun, Xiaohua Chen, Suyun Zeng, Liang Chen, Shirong Li, Hydrogen-rich medium protects human skin fibroblasts from high glucose or mannitol induced oxidative damage, In Biochemical and Biophysical Research Communications, Volume 409, Issue 2, 2011, Pages 350-355, ISSN 0006-291X, https://doi.org/10.1016/j.bbrc.2011.05.024.

(http://www.sciencedirect.com/science/article/pii/S0006291X11007777)

Keywords: Hydrogen; Skin lesions; Human skin fibroblast; Reactive oxygen species; Superoxide anion; Mitochondrial membrane potential

xii Mikhail D. Linetsky, Ekaterina V. Shipova, Roy D. Legrand, Ognyan O. Argirov, Glucose-derived Amadori compounds of glutathione, In Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1724, Issues 1–2, 2005, Pages 181-193, ISSN 0304-4165, https://doi.org/10.1016/j.bbagen.2005.04.003.

(http://www.sciencedirect.com/science/article/pii/S0304416505001017)

Keywords: Non-enzymatic glycation; Glutathione; Glucose; Amadori compounds

xiii Azevedo M1Falcão JRaposo JManso CSuperoxide radical generation by Amadori compounds. Free Radic Res Commun. 1988;4(5):331-5.

xiv Rodríguez-Mañas, L., Angulo, J., Vallejo, S. et al. Diabetologia (2003) 46: 556. https://doi.org/10.1007/s00125-003-1056-1

xv Cell Glycobiology and Development; Health and Disease in Glycomedicine

M. Takahashi, ... N. Taniguchi, in Comprehensive Glycoscience, 2007

4.28.4.2

Elevation of Oxidative Stress and Carbonyl Stress by Glycation

xvi Tamaki N, Orihuela-Campos RC, Fukui M, Ito H-O. Hydrogen-Rich Water Intake Accelerates Oral Palatal Wound Healing via Activation of the Nrf2/Antioxidant Defense Pathways in a Rat Model. Oxidative Medicine and Cellular Longevity. 2016;2016:5679040. doi:10.1155/2016/5679040.

xvii Kawamura T, Wakabayashi N, Shigemura N, et al. Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013;304(10):L646-L656. doi:10.1152/ajplung.00164.2012.

xviii Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2014 Sep;26(9):629-33. doi: 10.3760/cma.j.issn.2095-4352.2014.09.005.

[Role of Nrf2 in the protective effects of hydrogen against cerebral dysfunction in septic mice].

[Article in Chinese]

Liu L1Xie KChen HDong XWang GYu Y.

xix https://blogs.scientificamerican.com/guest-blog/can-the-source-of-funding-for-medical-research-affect-the-results/


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