Methylglyoxal and the Ketogenic Diet – The Miraculous Compound that got Bad-Mouthed by Ignorance

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A ketogenic diet – a diet based on animal fats – is arguably the diet that made us thrive during our ancestral evolution.

I came across this information by reading an argument against a ketogenic diet. I decided to do some further research and what I found was astonishing to say the least. Those who are doing some ketogenic badmouthing through this argument are clearly shooting themselves in the foot since it is among the most jaw dropping information on the anti-cancer and anti-viral potential of a ketogenic diet that I have come across. As it happens it has been very well documented in the literature too. So let me introduce you to the subject via some of the critics:

Ann N Y Acad Sci. 2005 Jun;1043:201-10.

Ketosis leads to increased methylglyoxal production on the Atkins diet.

Beisswenger BG, Delucia EM, Lapoint N, Sanford RJ, Beisswenger PJ.

Dartmouth Medical School, Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA.

Abstract

In the popular and widely used Atkins diet, the body burns fat as its main fuel. This process produces ketosis and hence increased levels of beta-hydroxybutyrate (BOB) acetoacetate (AcAc) and its by-products acetone and acetol. These products are potential precursors of the glycotoxin methylglyoxal. Since methylglyoxal and its byproducts are recognized as a significant cause of blood vessel and tissue damage, we measured methylglyoxal, acetone, and acetol in subjects on the Atkins diet. We found that by 14-28 days, methylghyoxal levels rose 1.67-fold (P = 0.039) and acetol and acetone levels increased 2.7- and 6.12-fold, respectively (P = 0.012 and 0.028). Samples from subjects with ketosis showed even greater increases in methylglyoxal (2.12-fold), as well as acetol and acetone, which increased 4.19- and 7.9-fold, respectively; while no changes were seen in samples from noncompliant, nonketotic subjects. The increase in methylglyoxal implies that potential tissue and vascular damage can occur on the Atkins diet and should be considered when choosing a weight-loss program.

Here is a counter-argument and a fresh perspective on the subject:

Sunday, March 14, 2010

Ketosis, methylglyoxal, and accelerated aging: Probably more fiction than fact

by Ned Kock

Just to recap, an interesting hypothesis has been around for quite some time about a possible negative effect of ketosis. This hypothesis argues that ketosis leads to the production of an organic compound called methylglyoxal, which is believed to be a powerful agent in the formation of advanced glycation endproducts (AGEs).

In vitro research, and research with animals (e.g., mice and cows), indeed suggests negative short-term effects of increased ketosis-induced methylglyoxal production. These studies typically deal with what appears to be severe ketosis, not the mild type induced in healthy people by very low carbohydrate diets.

However, the bulk of methylglyoxal is produced via glycolysis, a multi-step metabolic process that uses sugar to produce the body’s main energy currency – adenosine triphosphate (ATP). Ketosis is a state whereby ketones are used as a source of energy instead of glucose.[…]

Thus it follows that ketosis is associated with reduced glycolysis and, consequently, reduced methylglyoxal production, since the bulk of this substance (i.e., methylglyoxal) is produced through glycolysis.

So, how can one argue that ketosis is “a recipe for accelerated AGEing”?

One guess is that ketosis is being confused with ketoacidosis, a pathological condition in which the level of circulating ketones can be as much as 40 to 80 times that found in ketosis. De Grey (2007) refers to “diabetic patients” when he talks about this possibility (i.e., the connection with accelerated AGEing), and ketoacidosis is an unfortunately common condition among those with uncontrolled diabetes.

A gentle body massage is relaxing, and thus health-promoting. Add 40 times to the pressure, and the massage will become a form of physical torture; certainly unhealthy. That does not mean that a gentle body massage is unhealthy.

Interestingly, ketoacidosis often happens together with hyperglycemia, so at least part of the damage associated with ketoacidosis is likely to be caused by high blood sugar levels. Ketosis, on the other hand, is not associated with hyperglycemia.

Finally, if ketosis led to accelerated AGEing to the same extent as, or worse than, chronic hyperglycemia does, where is the long-term evidence?

Since the late 1800s people have been experimenting with ketosis-inducing diets, and documenting the results. The Inuit and other groups have adopted ketosis-inducing diets for much longer, although evolution via selection might have played a role in these cases.

No one seems to have lived to be 150 years of age, but where are the reports of conditions akin to those caused by chronic hyperglycemia among the many that went “banting” in a more strict way since the late 1800s?

The arctic explorer Vilhjalmur Stefansson, who is reported to have lived much of his adult life in ketosis, died in 1962, in his early 80s. After reading about his life, few would disagree that he lived a rough life, with long periods without access to medical care. I doubt that Stefansson would have lived that long if he had suffered from untreated diabetes.

Severe ketosis, to the point of large amounts of ketones being present in the urine, may not be a natural state in which our Paleolithic ancestors lived most of the time. In modern humans, even a 24 h water fast, during an already low carbohydrate diet, may not induce ketosis of this type. Milder ketosis states, with slightly elevated concentrations of ketones showing up in blood tests, can be achieved much more easily.

In conclusion, the notion that ketosis causes accelerated aging to the same extent as chronic hyperglycemia seems more like fiction than fact.

Reference:

De Grey, A. (2007). Ending aging: The rejuvenation breakthroughs that could reverse human aging in our lifetime. New York: NY: St. Martin’s Press.

Sounds reasonable and I think the fear of this natural compound is completely unfounded. What I found interesting is that the first study which I quoted shows that those on an Atkins ketogenic diet have high levels of this compound. What if methylglyoxal is actually a good thing? I found the following article to be very interesting, especially from the anti-viral point of view!! As it happens I have written about the anti-viral properties of a ketogenic diet (see On Viral “Junk” DNA, a DNA Enhancing Ketogenic Diet, and Cometary Kicks), but this goes beyond my expectations! :

Biochemistry (Mosc). 2009 Oct;74(10):1059-69.

Critical evaluation of toxic versus beneficial effects of methylglyoxal

Talukdar D, Chaudhuri BS, Ray M, Ray S.

Department of Biological Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata, 700032, India.

Abstract

In various organisms, an array of enzymes is involved in the synthesis and breakdown of methylglyoxal. Through these enzymes, it is intimately linked to several other physiologically important metabolites, suggesting that methylglyoxal has some important role to play in the host organism. Several in vitro and in vivo studies showed that methylglyoxal acts specifically against different types of malignant cells. These studies culminated in a recent investigation to evaluate a methylglyoxal-based formulation in treating a small group of cancer patients, and the results were promising. Methylglyoxal acts against a number of pathogenic microorganisms. However, recent literature abounds with the toxic effects of methylglyoxal, which are supposed to be mediated through methylglyoxal-derived advanced glycation end products (AGE). Many diseases such as diabetes, cataract formation, hypertension, and uremia are proposed to be intimately linked with methylglyoxal-derived AGE. However methylglyoxal-derived AGE formation and subsequent pathogenesis might be a very minor event because AGE are nonspecific reaction products that are derived through the reactions of carbonyl groups of reducing sugars with amino groups present in the side chains of lysine and arginine and in terminal amino groups of proteins. Moreover, the results of some in vitro experiments with methylglyoxal under non-physiological conditions were extrapolated to the in vivo situation. Some experiments even showed contradictory results and were differently interpreted. For this reason conclusions about the potential beneficial effects of methylglyoxal have often been neglected, thus hindering the advancement of medical science and causing some confusion in fundamental understanding. Overall, the potential beneficial effects of methylglyoxal far outweigh its possible toxic role in vivo, and it should be utilized for the benefit of suffering humanity.

It seems to me that ignorance of sugar’s detrimental role in our bodies through advanced glycation end products- AGE (to mention just one) is among the obscuring elements those criticizing a ketogenic diet are using to portray methylglyoxal as harmful.

Needless to say, the above paper really caught my attention, so I downloaded it. Here is what seems to be only the tip of the iceberg:

SzentGyorgyi championed the idea that methylglyoxal is a natural growth regulator and can act as a strong anticancer agent [5]. Methylglyoxal has been found to possess strong activity against a number of pathogenic viruses [6]. In fact, the anticancer effect of methylglyoxal stemmed from the study of its antiviral effect [7]. Recently, it has been observed that methylglyoxal acts against a number of other pathogenic microorganisms. [810]. SzentGyorgyi and other investigators with remark able experimental evidences showed methylglyoxal could arrest growth and/or destroy malignant cells without any apparent toxic effect to the host [11, 12]. At the same time, Apple and Greenberg showed significant curative effect of methylglyoxal on animals harboring a wide variety of malignant cells [13]. Despite these promising results, until recently neither academic researchers nor clinicians have made any attempt to translate this research potential to the benefit of humankind. On the other hand, recent literature abounds with the toxic effects of methylglyoxal.[…]

Antimalarial activity of methylglyoxal. Recently anti malarial activity of methylglyoxal has been reported [8].
Proliferation of the malaria parasite, Plasmodium falciparum, was inhibited by methylglyoxal with IC50 of only 0.2 mM.[…]

Activity of methylglyoxal against Staphylococcus aureus. In a very recent publication, Mavric et al. have
shown that the active principle of the wellknown antibacterial property of New Zealand manuka (Leptospermum scoparium) honey is methylglyoxal [10]. The minimally inhibitory concentration against St. aureus was 1.1 mM.[…]

Antiviral effect of methylglyoxal. The antiviral activity of methylglyoxal has been briefly mentioned in the
introductory section. To elaborate, in 1957 de Bock et al. screened the growth inhibitory effect of a number of compounds towards a strain of influenza virus. In experiments with chicken embryo, they showed that a number of αketoaldehydes were active, and methylglyoxal almost topped the list [6]. The antiviral activity of methylglyoxal has also been found against NewCastle disease and influenza [59], foot and mouth disease [60], and other viruses by other investigators [61]. Surprisingly, no study on the antiviral effect of methylglyoxal was pursued thereafter.

ANTICANCER EFFECT OF METHYLGLYOXAL

The anticancer effect of methylglyoxal has been briefly mentioned in the introductory section. It appears
that the most remarkable positive effect of methylglyoxal arose from the studies of anticancer effect of methylglyoxal. As early as 1958, the anticancer effect of methylglyoxal was first studied and effective response was obtained [7]. These studies stemmed from the study of antiviral effect of methylglyoxal. Because virus is one of the causative agents of cancer, it was thought that methylglyoxal might have some anticancer effect. SzentGyorgyi and his collaborators in their pioneering work on the biological role of methylglyoxal put forward strong evidence for the anticancer and growth inhibitory effect of methylglyoxal [5]. Egyud and SzentGyorgyi showed that when methylglyoxal was injected into mice along with sarcoma 180 cells, no tumor developed and the mice remained completely healthy [11]. They even produced healthy offspring. However, the duration of the treatment was short, and methylglyoxal treatment began just after tumor inoculation. They also found that in tissue cultures methylglyoxal was more sensitive to malignant cells than to normal cells.

Apple and Greenberg showed that methylglyoxal significantly inhibited tumor growth and in some cases produced indefinite survivors among mice bearing leukemia, lymphosarcoma, adenocarcinoma, sarcoma 180, and other varieties of tumor at daily dose level of approximately 80 mg/kg of body weight. A single dose of about 225 mg/kg of body weight significantly inhibited advanced leukemia and produced indefinite survivors among mice bearing either lymphosarcoma or carcinoma [13]. The in vivo anticancer effect of methylglyoxal was augmented in the presence of glyceraldehyde [62].

Similar therapeutic activity of methylglyoxal towards cancerbearing animals has also been obtained by other
investigators [12, 56]. Numerous studies have shown that methylglyoxal acts against a wide variety of tumors. For the sake of brevity, we mention here only some of these studies.

Methylglyoxal is toxic to human neuroblastoma cells in a dosedependent manner above concentration of 0.15mM with a LD50 of approximately 1.25 mM. At the concentration of 5 mM methylglyoxal, the viable cells were only 6% [63]. When exogenous methylglyoxal was added to human leukemia HL60 cells in culture, inhibition of growth and toxicity was induced; the LD50 was 0.24 mM. Methylglyoxal, however, did not induce any toxicity in differentiated cells, i.e. neutrophils under similar culture conditions [64]. Methylglyoxal produced an apoptotic response of human MCF7 breast and RKO colon cancer lines. However, overexpression of glyoxalase II inhibited the methylglyoxalinduced apoptotic response of the cells. Glyoxalase II acts in tandem with glyoxalase I for the breakdown of methylglyoxal to Dlactate. Likewise, cells deficient in glyoxalase II were hypersensitive to methylglyoxalinduced apoptosis [65]. Methylglyoxal was also able to induce severe (>99%) cell death in 24 h in human prostate cancer cells [66]. The activities of glyoxalase I and/or glyoxalase II were found to be higher in several cancer cell lines [6769]. However, there are contradictory reports too [70].

[…]

As mentioned above, Apple and Greenberg showed remarkable curative effect of methylglyoxal on mice bear
ing a wide variety of cancers [13, 62]. From these results, it was logical to immediately investigate the efficacy of methylglyoxal in treating cancer patients. However, the first paper that reported the testing of methylglyoxal in treating cancer patients was as late as 2001 [80]. The study was extended to a larger number of cancer patients, giving promising results [81, 82]. It was found that methylglyoxal is quite effective in treating cancer patients who were suffering from a wide variety of cancers. Moreover, methylglyoxal is apparently devoid of any toxic effect, in contrast to other anticancer drugs that are now widely used. However, these studies need validation with greater numbers of cancer patients in different centers.

That methylglyoxal is effective against so many different types of malignant cells lends support to the view that different types of malignant cells have common and specific altered site(s).

CONCLUDING REMARKS

This review has critically evaluated both the reported toxic and beneficial effects of methylglyoxal and suggests
that the potential beneficial effects of methylglyoxal far outweigh its possible toxic effects. It has not been proved
that methylglyoxal significantly contributes to the suggested deleterious effects on the host. Compared to the
voluminous in vitro work, the in vivo studies are very limited. Moreover, many related carbonyl compounds,
which are vital for cellular metabolism and nutrition, might also be linked with similar effects in the organism.
Can we dispense with these nutrients? Any compound or even a metabolite has some potential adverse effect on the host however small this effect may be. The effect of a particular compound must be judged by balancing the benefit and adversity. The reported activity of methylglyoxal against a number of pathogenic  microorganisms and its anticancer properties raise the question whether methylglyoxal is a natural defense of the host especially for mammals. However, due to the mindset of a large of number of researchers the potential beneficial effects of methylglyoxal are not being translated resulting in a serious deterrent to the advancement of medical science. The primary effects of methylglyoxal, which can be translated to the benefit of suffering humankind, are its activities
against a number of pathogenic microorganisms and its anticancer effects.
We appeal to academics, clinicians, research administrators, and pharmaceutical companies to translate this research potential to the benefit of humankind.

The documented anticancer effect of this compound along with its antiviral and other anti-microorganism effects are among the most astonishing that I have read so far. And it increases with the ketogenic diet! It is really ironic that I stumbled upon it thanks to ketogenic diet critics.

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Comments

  1. Steve Boshkov  March 3, 2013

    This reminded me of some reading I had done some years ago. Another take on the de Grey argument is from Michael Eades, who followed closely upon Atlkins in promoting a VLC diet. Here’s his take on methylglyoxal:

    http://www.proteinpower.com/drmike/low-carb-library/low-carb-diets-reduce-oxidative-stress/

    So because a VLC diet actually increases anti-oxidant status/reduces oxidative stress, IF there is some additional methylglyoxal production, it would be more than neutered, assuming it had some negative potential effect. Eades cites this study demonstrating the effect noted:

    http://online.liebertpub.com/doi/abs/10.1089/rej.2007.0540

    On the issue of methylglyoxal and cancer, see also here for a non-technical discussion:

    http://www.cancerevolution.info/index.php?/cancer-therapy/Cell-energy-limitation-therapy/methylglyoxal-in-cancer-cell-energy-limitation-therapy.html

    In terms of CR being the only modality which has been demonstrated to increase human life span beyond the mean, Dr. Rosedale (and he is not alone) argues that the ketogenic diet creates the SAME conditions as CR in the body and because a person does not need to watch calories on a ketogenic diet (the body takes care of that itself when the leptin and insulin signalling are functioning properly and, more importantly, ketosis mimics the effects of CR), the benefits of CR will be achieved through a ketogenic diet. Many informative papers written by Rosedale are here (link at the top of the web page):

    http://drrosedale.com/#axzz2MQJCOGcj

    There is also an excellent debate reproduced at his site (in the Blog link) with Paul Jaminet about what the amount of “safe carbs” there might be. Jaminet has appeared on the scene with that argument, well argued. Rosedale is having none of it, but the exchange is educational. The debate is not settled, though I know where I stand unless the Jaminet argument changes my mind (which I don’t foresee). That said, Jaminet’s diet is an LC diet, so we’re in the realm of higher fat in any case.

    reply
    • Gabriela Segura, MD  March 3, 2013

      Thank you for the contribution! I just became aware of this methylglyoxal thing just recently. I find it fascinating. That something so beneficial as methylgyoxal got so buried down goes beyond crimes against humanity.

      Malaria, to name just one infectious disease, is a number one killer in some regions. According to WHO:

      Quote

      About 3.3 billion people – half of the world’s population – are at risk of malaria. In 2010, there were about 216 million malaria cases (with an uncertainty range of 149 million to 274 million) and an estimated 655 000 malaria deaths (with an uncertainty range of 537 000 to 907 000)[…]

      People living in the poorest countries are the most vulnerable to malaria. In 2010, 90% of all malaria deaths occurred in the WHO African Region, mostly among children under five years of age.

      Yet, with the research uncovered on this paper, malaria would have a hard time existing if people were in natural ketosis. So much for tropical fruit and its “healthy” effects!

      I have had the opportunity to read Rosedale research and cited papers. I’m also aware of Jaminet of “perfect diet or something” blog. I think he is very through in his research, so he sounds very convincing. That doesn’t necessarily means it is very insightful.

      Another great source is Primal Body Primal Mind by Nora Gedgaudas, she does a good job in synthesizing all the information and she bases her recommendations on Rosedale’s research as well. It is a great source for those who are starting up. Would certainly make a great recommendation to family or friends.

      Best!

      reply

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