Does ketosis accelerate AGEing?

[Hanna]

One of the strongest indictments of ketosis, in relation to methylglyoxal, is made in a fairly well referenced book by De Grey (2007)...:
… one established effect of very low-carbohydrate diets of the Atkins type is to bring down both triglyceride levels and the body’s total exposure to carbohydrates, so some advocates have hypothesized that these diets world reduce a person’s AGE burden. Unfortunately, it turns out that the metabolic state that these diets induce (the notorious “ketosis”) has the unfortunate side effect of causing a jump in the production of the oxoaldehyde methylglyoxal, a major precursor of AGEs that is also, ironically, produced within cells of diabetic patients when they are forced to take in more glucose than they can immediately process … methylglyoxal is far more chemically reactive than blood sugar (up to 40,000 times more reactive, in fact), and is known to cause wide-ranging damage in the body, of which AGE cross-links are but one example. This potentially makes the Atkins diet a recipe for accelerated AGEing…

http://healthcorrelator.blogspot.com/2010/03/ketosis-methylglyoxal-and-accelerated.html

Interestingly, the increase in methylglyoxal took 2 to 3 weeks to reach a peak (mentioned in the interesting comments by Tim Lundeen: http://www.proteinpower.com/drmike/lipid-hypothesis/the-low-fat-diet-cascade/)
So does "deep" ketosis accelerate AGEing? Here is the abstract of the original study:

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 ?-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.

http://onlinelibrary.wiley.com/doi/10.1196/annals.1333.025/abstract

[TylerDurden]

Hmm, PP may remember the specifics, but I vaguely recall some studies indicating that people on ketogenic diets are less  susceptible to AGEs because they have lower blood-sugar levels, so have less opportunity for proteins to combine with sugars to form AGEs. So that might counter the effect you mention.

[PaleoPhil]

Notice that the research and writings on methylglyoxal use the word "potential." They are talking about potential theoretical problems, not problems that have been found in the real world yet. Maybe they are real problems, maybe not.

Dr. Eades countered the argument for potential problems with methylglyoxal from ketosis here:
http://www.proteinpower.com/drmike/lipid-hypothesis/the-low-fat-diet-cascade/

The most plausible potential problems I've seen with ketosis are doing it too chronically. A fractal approach in which you are sometimes not in ketosis, perhaps randomly especially, may be healthier in the long run than always being in ketosis. Plus, every human society that has access to plants eats at least some of them. I doubt that H. sapiens would have survived and thrived as long as we have if staying in ketosis all the time was necessary, though it appears to have therapeutic applications with some illnesses.

Anyone who thinks ketosis should be avoided because of methylglyoxal may want to consider that the antibacterial benefits of manuka honey have been attributed to methylglyoxal:

"A research team led by Professor Thomas Henle, head of the Institute of Food Chemistry at the Technical University of Dresden, discovered naturally-occurring Methylglyoxal (MG) is the dominant constituent in Manuka honey that is almost exclusively responsible for its reliable anti-bacterial properties." (Methyglyoxal - the science behind the healing properties of MGO™ Manuka Honey
http://www.mgomanuka.com/methylglyoxal.cfm)

So are the folks who avoid ketosis also going to avoid methylglyoxal-rich honeys and warn others to avoid them?

Is methylglyoxal a poison that should be avoided or a beneficial medicinal that can be safely eaten on a regular basis or somewhere in between? The science is not clear on it yet.

[Hanna]

Anyone who thinks ketosis should be avoided because of methylglyoxal may want to consider that the antibacterial benefits of manuka honey have been attributed to methylglyoxal

Interesting. However, something can be antibacterial and nevertheless be unhealthy. For example, mercury (amalgam) has strong antibacterial effects, formaldehyde has strong antibacterial effects...

[PaleoPhil]

Sure, as I said, the science is not clear on it yet, and if someone feels that ketosis should be avoided due to methylglyoxal, then presumably they would want to avoid methylglyoxal-rich honeys too. I'm not overly concerned about either myself, though I don't engage in long-term chronic ketosis, which I find plausibly risky, given its rarity and some plausible arguments for why it might be a problem in the long term. The question remains unanswered--is anyone who avoids even shorter-term ketosis due to concerns about methylglyoxal also going to avoid methylglyoxal-rich honeys?

[Löwenherz]

For me, ketosis always FEELS like the original state of my body. It FEELS good, healthy and comfortable. And I FEEL that my body doesn't want to leave this state, especially at winter times.

But that's really not scientific, sorry!

Löwenherz

[Hanna]

Phil, have you ever eaten Manuka honey? How is its taste compared with other honeys? I read in the net that is has a "medicinal", antiseptic" and/or "strong" taste. From an instincto point of view, the perception of such a taste component would be an instinctive stop.

[PaleoPhil]

So I take it that you are going to avoid manuka honey, along with ketosis? That is admirably consistent.

I find that manuka honey has a strong taste. Nowhere near my favorite tasting honey, but not entirely unpleasant. If I were a HG living in the wild and manuka honey was the local wild honey, I would eat it. I've never seen anyone claim that it is seriously unhealthy. Quite the opposite. The makers of manuka honeys have even added a  methylglyoxal (MGO) rating system, with higher MGO content being treated as a plus:

It turns out that the sweet stuff's antibacterial qualities come from a compound called methylglyoxal (MGO) so you need to make sure that the honey you buy contains enough of the right stuff. And now, to make things easier, Manuka Health MGO Manuka Honey has been given a rating so that you know exactly what you're buying. The range includes MGO 30 which is recommended for general health, MGO 100 which can be used to treat coughs and colds and MGO 550 - the super-strength variety - powerful enough to treat wounds. Naturally amazing.

http://apitherapy.blogspot.com/2009/02/medicinal-honey-should-contain-enough.html
(emphasis mine)

Maybe the methylglyoxal in it causes increased aging or maybe it's mainly beneficial. I don't know.

[Hanna]

For me, ketosis always FEELS like the original state of my body. It FEELS good, healthy and comfortable. And I FEEL that my body doesn't want to leave this state, especially at winter times.

But that's really not scientific, sorry!

Löwenherz

Aha!  Well, I got the impression that you don´t like fruit (fructose etc.) for scientific reasons. 

[Hanna]

Phil, you know that my diet is basically "instincto", although with some modifications. If I would love Manuka honey and feel fine afterwards, I would eat it.

If we were hunters and gatherers, we would eat cooked meat and cooked starches and therefore lots of AGEs anyway. Moreover, I read that Manuka honey is found exclusively in New Zealand coastal areas.

Perhaps Manuka honey is tasty for people who need antiseptic medicine.

[PaleoPhil]

Phil, you know that my diet is basically "instincto", although with some modifications. If I would love Manuka honey and feel fine afterwards, I would eat it.

In my case I liked Manuka honey rather than loved or hated it and I felt relatively OK afterwards, though both raw and heated Manuka honey had the same negative effects on me (chapped lips, dry skin, dental crud, some nausea with excess and so forth) that other honeys had on me, though less than conventional heated honeys (and gradually less overall the longer I've been eating fermented raw honey, which seems to be improving my ability to tolerate carby foods). The only honey I've seemed to fare well on has been fermented raw honey, yet I wouldn't assume based on that that it's the only honey that's good for anyone and I would probably allow myself an occasional small amount of unfermented raw honey if fermented were not available. I also leave open the possibility that I might find some time in the future that beyond a certain amount of fermented raw honey is a net negative despite finding it very tasty and not getting a stop.

If we were hunters and gatherers, we would eat cooked meat and cooked starches and therefore lots of AGEs anyway.

Not necessarily. Remember, pre-cooking Stone Agers were hunter gatherers too and there are varying amounts of cooking and types of cooking within even recent HG populations, with the Eskimos and Nenets being famous for eating lots of raw animal foods and with at least some if not most or all HGs using mainly lower-AGE methods of cooking than moderners (for example, I've never seen traditional HGs use deep-fat-frying, though I've no doubt that some modernized former HGs do and likely are suffering negative consequences as a result of adopting this modern cooking technique). Plus, even most so-called "rawists" don't eat 100% raw ("high raw" is considered effectively raw and the definition of high raw ranges as low as 70% of foods). Given that I prefer largely raw, I would continue to eat mostly raw if I were a HG.

Moreover, I read that Manuka honey is found exclusively in New Zealand coastal areas.

If it were found that your favorite honey contained significant amounts of methylglyoxal, would you stop eating it?

Perhaps Manuka honey is tasty for people who need antiseptic medicine.

I don't know. I don't have any infection that I'm aware of and I'm not big on making assumptions just to prop up my hypotheses. I prefer to leave it at "I don't know" when I don't have decent evidence.

Mind you, I'm not trying to imply that methylglyoxal is definitely safe. Just maintaining some skepticism re: drawing firm conclusions from scientific reports that indicate in their own words only "potential" risks.

[Hanna]

Notice that the research and writings on methylglyoxal use the word "potential." They are talking about potential theoretical problems, not problems that have been found in the real world yet. Maybe they are real problems, maybe not.

There are real problems:

Since methylglyoxal is highly cytotoxic, the body developed several detoxification mechanisms.
... several articles indicate it is involved in the formation of advanced glycation endproducts (AGEs). In fact, methylglyoxal is proven to be the most important glycation agent (forming AGEs).[4] (...)
Due to increased blood glucose levels, methylglyoxal has higher concentrations in diabetics, and has been linked to arterial atherogenesis. Damage by methylglyoxal to low-density lipoprotein though glycation causes a fourfold increase of atherogenesis in diabetics.[6]

http://en.wikipedia.org/wiki/Methylglyoxal

[Hanna]

In my case I liked Manuka honey rather than loved or hated it

Well, you wrote:

I find that manuka honey has a strong taste. Nowhere near my favorite tasting honey, but not entirely unpleasant.

For me, the perception that something has a strong taste is clearly a so called instinctive stop.
In earnest, if i would eat sugary foods (fruit) as often and as long as I find them "not entirely unpleasant", I would eat much too much fruit and probably become seriously ill with time.

I haven´t eaten any significant amount of honey for many years. However, I would like to try raw fermented honey, thank you very much for this tip!  Your description of this honey ("best honey I have ever tasted" etc.) sounds like this honey could be the ideal "instincto therapy" food. 

[PaleoPhil]

Simplified executive summary: raw meat and raw honey good, yum, but do they kill me cuz of methyglyoxal? science not clear yet 

There are real problems: http://en.wikipedia.org/wiki/Methylglyoxal

You're getting a wee bit ahead of the science. The Wikipedia #6 source does use somewhat more confident language than the other sources, but it still says "possible" and it was a lab rat study:

Glycation of LDL by Methylglyoxal Increases Arterial Atherogenicity
A Possible Contributor to Increased Risk of Cardiovascular Disease in Diabetes
http://diabetes.diabetesjournals.org/content/60/7/1973

Lab studies on rats are useful, but they don't always correlate perfectly with real world human experience eating whole raw foods. It is worth bearing in mind, though, and I've been keeping my eye open for any signs of longer term symptoms from raw honey or raw meat due to methylglyoxal or any other factor.

My guess is that all honey contains some methylglyoxal and that medicinal honeys like Manuka honey just contain substantially more than most, and these sources support that:

"Q. Does heating honey above 160 degrees affect its healthful benefits?
A. Possibly.  Heating honey may increase the amount of methylglyoxal (MGO) found in honey."
FAQ about Honey
http://www.worldclassemprise.com/custom.aspx?id=6

This month a group from the Netherlands  published a study that compares the bactericidal (bacterial killing) properties of two major medicinal honeys– RevamilH (RS) honey and medical-grade manuka honey (Kwakman et al, 2011). RS honey is a controlled environment greenhouse honey produced in the Netherlands. Manuka honey is produced from bees that feed on the manuka bush from New Zealand and Australia.
Not All Medicinal Honey is Alike
http://contagions.wordpress.com/2011/03/

For the first time, researchers from the Netherlands have identified the ingredient in honey that kills bacteria. Defensin-1, a protein that bees add to honey, possesses powerful antibacterial properties. ....

Even after they had neutralized known factors such as hydrogen peroxide and methylglyoxal, honey retained potent antibacterial activity, Dr. Kwakman said. The researchers fractionated the honey to identify additional antibacterial factors, which led to the discovery of defensin-1, a small antimicrobial peptide that is part of the honeybee immune system.

“We neutralized bee defensin-1 using specific antibodies and showed that this protein was responsible for most of the remaining antibacterial activity of honey,” Dr. Kwakman said.

As a final step, the researchers increased the pH of honey from pH 3.2 to pH 7 and found that all remaining activity was negated. “Thus, we concluded that the high sugar content, hydrogen peroxide, methylglyoxal, bee defensin-1, and the low pH were responsible for the bactericidal activity of medical-grade honey.”

New Buzz About Honey: Protein bees add to honey has antibacterial properties

This is from the study:
Honey accumulated up to 5.62 ± 0.54 mM H2O2 and contained 0.25 ± 0.01 mM methylglyoxal (MGO).
How honey kills bacteria
http://www.fasebj.org/content/24/7/2576.abstract

Granted, I love the taste of raw meat and raw honey (and raw fruits), so I'm biased in their favor. Most folks here seem to have their favorite foods that they give the benefit of the doubt to. I try to be aware of that bias, which is why I didn't just dismiss the methylglyoxal issue when I read about it re: both medicinal honeys and meat. If it is a real issue, I suspect it's mainly a problem for people with chronically high blood sugar, especially those who eat mostly high-heated foods, such as diabetics who eat lots of fried meats or heated honey, though I could be wrong.

In my case I liked Manuka honey rather than loved or hated it

Well, you wrote:

I find that manuka honey has a strong taste. Nowhere near my favorite tasting honey, but not entirely unpleasant.

Yes, I did and the second statement was meant to support and re-emphasize the first.

For me, the perception that something has a strong taste is clearly a so called instinctive stop.

Not necessarily so for me. I sometimes love strong tastes. For example, I love the taste of horseradish and wasabi. Given the strong taste of the Manuka, I was surprised that I didn't like it more, actually, and some people apparently do like it quite a bit. A former member here raved about Manuka honey and it wasn't even a raw version.

In earnest, if i would eat sugary foods (fruit) as often and as long as I find them "not entirely unpleasant", I would eat much too much fruit and probably become seriously ill with time.

Same here. That's why I don't follow the Instincto law of the alliesthetic mechanism 100%, though I do employ it as a quite useful tool. I suspect that part of the problem is that I'm still largely carb intolerant, so that I only handle certain carbs relatively OK, such as the fermented honey--and my guess is that the biota it provides help me digest the sugars.

I haven´t eaten any significant amount of honey for many years. However, I would like to try raw fermented honey, thank you very much for this tip!  Your description of this honey ("best honey I have ever tasted" etc.) sounds like this honey could be the ideal "instincto therapy" food. 

Fair warning that my BG spiked quite a bit after eating it while I was eating a very low carb diet. Here are the numbers:

Fasting BG before consuming raw fermented honey: 87 mg/dl
Ate 2 tbsps of the honey
1 hour postprandial BG: 234 mg/dl
2 hour pp BG: 121 mg/dl

I plan on testing again in the near future now that I've been eating more carbs for a while, though I suspect that occasional acute BG spikes are not nearly as much of a problem as chronically high BG. I've been eating it often enough now because of the scalp/skin benefits and easy digestability that BG spikes could be an issue for me.

Also, the honey didn't clear up the scalp of a friend of mine at all, despite greatly reducing the dandruff in my scalp, so your mileage may vary.

The fermented honey was not my favorite on first taste. I think it was on the second bite that it seemed super good and seemed to get gradually better after that. Now the taste is pretty consistent to me. It's also one of the few foods that gives me a noticeable feeling of well being, along with raw suet, raw liver and raw red meats. I place more emphasis on how a food makes me feel and what effects it has on my symptoms than on the taste--the taste is a bonus.

[Hanna]

raw meat and raw honey good, yum, but do they kill me cuz of methyglyoxal?

"All things are poison, and nothing is without poison; only the dose permits something not to be poisonous." Paracelsus knew this already almost 500 years ago.

Q. Does heating honey above 160 degrees affect its healthful benefits?
A. Possibly.  Heating honey may increase the amount of methylglyoxal (MGO) found in honey."
FAQ about Honey
http://www.worldclassemprise.com/custom.aspx?id=6

Yes, of course, but you skipped the more interesting part of the answer:

MGO is known to be dangerous to individuals who have glucose intolerance or diabetes.  MGO may even affect insulin signaling which may be a cause of diabetes.  Honey that contains MGO should not be ingested.  It is however safe for topical use as an antibiotic.

Methylglyoxal in honey is formed during storage (http://www.manukahoneyus.com/news/origin_methylglyoxal.pdf).

Quote
In earnest, if i would eat sugary foods (fruit) as often and as long as I find them "not entirely unpleasant", I would eat much too much fruit and probably become seriously ill with time.

Same here. That's why I don't follow the Instincto law of the alliesthetic mechanism 100%

AFAIK even gcb does not claim that a food should be eaten until its taste is completely unpleasant. On the contrary, when I heard him speaking he even recommended to ideally eat each food only if (and as long as) it tastes heavenly provided that one has practised instincto already for some time.

Fair warning that my BG spiked quite a bit after eating it while I was eating a very low carb diet.

Do you notice such blood sugar spikes in any way when you don´t measure them? I never measured BG myself.

[PaleoPhil]

Yes, of course, but you skipped the more interesting part of the answer: Methylglyoxal in honey is formed during storage (http://www.manukahoneyus.com/news/origin_methylglyoxal.pdf).

Actually, according to that, methylglyoxal (MG or MGO) content is increased during storage, not created from a zero MG level. Fresh manuka honey and other medicinal honeys already contain methylglyoxal before they are stored, and I suspect there's some in all honeys, just less than the medicinal ones. I'm not overly concerned about it myself, though it will be interesting to see what further research produces.

Quote
In earnest, if i would eat sugary foods (fruit) as often and as long as I find them "not entirely unpleasant", I would eat much too much fruit and probably become seriously ill with time.

Quote
Same here. That's why I don't follow the Instincto law of the alliesthetic mechanism 100%

AFAIK even gcb does not claim that a food should be eaten until its taste is completely unpleasant. On the contrary, when I heard him speaking he even recommended to ideally eat each food only if (and as long as) it tastes heavenly provided that one has practised instincto already for some time.

I didn't mean to imply otherwise. I meant nothing more than what you wrote--that if I relied solely on the alliesthetic mechanim, "I would eat much too much fruit" (for me) and suffer negative health effects as a result.

Do you notice such blood sugar spikes in any way when you don´t measure them? I never measured BG myself.

No, though if I consume too much of any kind of starch or sugar I do later on get chapped lips, dental crud and possibly other issues, though with fermented raw honey it takes much more to produce this effect and the symptoms are much milder and resolve quickly. Also, if it's a refined sugar product, such as soda pop, I'll tend to get a sugar buzz and possibly mild mental fog.

I'm not hugely concerned about individual blood sugar spikes. I'm more concerned about chronic hyperglycemia as I consume more honey, though it's difficult to know at what if any point chronic hyperglycemia from unheated honey consumption becomes a problem when there aren't any physical symptoms beyond the little bit of chapped lips and dental crud when consumed in quantity, and even these symptoms are gradually decreasing with time. Not everyone gets these symptoms, so their absence wouldn't necessarily mean that your BG wasn't spiking. The only way to find out is to check the blood.

There are free BG meters offered in the USA, for those who live here, though the sticker device for mine just broke. It's made of fragile plastic. I haven't heard of such offers outside of the USA, unfortunately, and I'm wondering now if I would have been better off buying a more durable kit anyway.

My current approach is to try to limit myself to eating honey once per day, so as to minimize the amount of time I'm in a hyperglycemic state.

The increase in serum MG levels produced by honey apparently comes not only from the MG itself, but also from the sugar. According to studies, the concentration of MGO increases when there are sugars in the bloodstream. Thus it appears the scientists are saying that honey hits us with a methylglyoxal double-whammy. Is it a real problem outside of the laboratory for even raw fermented honey? Who knows? Being a raw fermented honey lover, I hope not. Here's some more info on that from the Eades link I provided earlier and some other sources:

"A reduction in blood sugar (even if accompanied by an increase in methylglycoxal) brings about a reduction of AGE formation that is orders of magnitude greater than the increase engendered by even a doubling of methylglycoxal levels (which is about what most papers report). In addition, most other papers demonstrate that methylglycoxal levels track WITH blood sugar levels and not in the opposite direction. ....

Virtually every other study shows that ongoing glycolysis is the source of most of the methyglyoxal found in the circulation. People with higher blood sugar levels tend to have the most methylgloxal while fasting (which generates ketones) appears to decrease the levels, which makes sense because glycolysis isn’t taking place during fasting."
-Michael Eades, MD, http://www.proteinpower.com/drmike/lipid-hypothesis/the-low-fat-diet-cascade

http://en.wikipedia.org/wiki/Methylglyoxal
"Due to increased blood glucose levels, methylglyoxal has higher concentrations in diabetics, and has been linked to arterial atherogenesis."

Methylglyoxal and high glucose co-treatment induces apoptosis or necrosis in human umbilical vein endothelial cells
Wen-Hsiung Chan1,2,*, Hsin-Jung Wu1
Article first published online: 23 AUG 2007
http://onlinelibrary.wiley.com/doi/10.1002/jcb.21489/abstract
"Here, we show that co-treatment with concentrations of MG and glucose comparable to those seen in the blood circulation of DM patients (5 µM and 15–30 mM, respectively) could cause cell apoptosis or necrosis in human umbilical vein endothelial cells (HUVECs) in vitro."

So if methylglyoxal is a problem, the evidence suggests it would be even more of an issue when consuming medicinal honey than when in ketosis.

[Löwenherz]

In earnest, if i would eat sugary foods (fruit) as often and as long as I find them "not entirely unpleasant", I would eat much too much fruit and probably become seriously ill with time.

That happened to all people I have seen at Montramé.. including myself. Instinctive eating is a nice idea but in real life complete nonsense, at least if you eat grotesque overbred high sugar fruits. As I mentioned, even the "instincto" children got cavities etc..

Löwenherz

[Ioanna]

Interesting timing because I just tried Manuka honey recently.  My first thought was that it was gross, tasted like medicine.  Now I know why   I didn't like it, didn't eat anymore.  I won't buy it again.  I was wondering what all the hype was about.

I do like the raw fermented honey though.  Seems like something subtly positive in a small amount, but IDK for sure. 

PP, I expected your BG to spike, but the company advertises on their website that their honey is safe for diabetics.  I don't like this marketing!

[PaleoPhil]

Interesting timing because I just tried Manuka honey recently.  My first thought was that it was gross, tasted like medicine.  Now I know why   I didn't like it, didn't eat anymore.  I won't buy it again.  I was wondering what all the hype was about.

The main hype is that it's supposed to kill bad microbes and thus fight internal and external pathological infections and the like. People with chronic infections that prescription antibiotics didn't help are one category of folks that try it.

I do like the raw fermented honey though.  Seems like something subtly positive in a small amount, but IDK for sure.

Yeah, it's hard to tell with so little scientific research. Seth Roberts discusses at his blog how an individual can do one's own scientific research, though his methods tend to be more thorough than I would think most folks would care to try. I do some similar things, though with less detail and accuracy.

PP, I expected your BG to spike, but the company advertises on their website that their honey is safe for diabetics.  I don't like this marketing!

That does seem to be quite a leap of faith. Which weblink is that at?

[Hanna]

A reduction in blood sugar (even if accompanied by an increase in methylglycoxal) brings about a reduction of AGE formation that is orders of magnitude greater than the increase engendered by even a doubling of methylglycoxal levels

This unreferenced claim is illogical since hyperglycemia and methylglyoxal levels are not independent from each other. On the contrary:

Indeed, the concentration of methylglyoxal in the plasma of diabetic patients is increased proportionally with the degree of hyperglycemia (13). Further, in cultured endothelial cells, under hyperglycemic conditions, it has been demonstrated that methylglyoxal accumulates rapidly and constitutes the most important precursor in the nonenzymatic glycation of proteins to yield irreversible AGEs (14).
http://diabetes.diabetesjournals.org/content/55/5/1289.long

Here we see that most AGEs in plasma are derived from methylglyoxal and 3-deoxyglucosone (13), and that it is methylglyoxal-derived AGEs that increase the most in diabetes: ....
The data we reviewed above ... suggest that methylglyoxal accounts for the majority of the increased AGEs seen in diabetes...

... A study published last year (26) showed that citrate reduced the formation of a methylglyoxal-derived AGE in the lens protein of diabetic rats.  Although it obliterated the massive increase in ketone levels seen in diabetes, it had no effect on hyperglycemia.
http://blog.cholesterol-and-health.com/2011/10/where-do-most-ages-come-from-o.html

BTW, this is an interesting thought:

...does high blood sugar cause AGEs?  I think we all agree that AGEs are increased in diabetes, but blaming all of the complications of diabetes on "high blood sugar" is like blaming all of the complications of familial hypercholesterolemia on "high cholesterol."
Diabetes involves a lot more than high blood sugar.  Most likely, increased concentrations of glucose and ketones, defective energy metabolism, defective insulin signaling, and oxidative stress lead to the increased production of and decreased detoxification of dicarbonyls.  These dicarbonyls then form AGEs, defective degradation of AGE-modified proteins elevates their concentration further, and if the diabetes damages the kidneys, even the free AGEs released from degraded proteins will not be efficiently excreted.  High blood sugar is a part of this, but only a part.

http://blog.cholesterol-and-health.com/2011/10/where-do-most-ages-come-from-o.html

Actually, according to that, methylglyoxal (MG or MGO) content is increased during storage, not created from a zero MG level.

We don´t know when the initial methylglyoxal was formed. At least, "nectar washed from manuka flowers contained ... no detectable methylglyoxal" (http://www.manukahoneyus.com/news/origin_methylglyoxal.pdf)

[PaleoPhil]

I was questioned about methylglyoxal by someone who was concerned because she heard that high fat, low carb (ketogenic) diets could produce a lot of it and thus theoretically causing harm (apparently the De Grey stuff gets passed around in vegetarian, vegan and anti-Atkins circles and filters out to other places on the Internet and by word of mouth, etc.) and I checked out this thread for a refresher on it and noticed that Ned Kock's article that Hannah referenced in the first thread was followed up by a second one in which he basically put the fears to rest. Robb Wolf also chimed in along the same lines in one of his podcasts and both of them jibe nicely with Tyler's response early in this thread. I'm embarrassed that I apparently didn't note Ned's followup blog post in this thread, so here's a summary of his points and Robb Wolf's that I shared with my friend:

Ketosis, methylglyoxal, and accelerated aging: Fact or fiction?
Thursday, March 11, 2010
Ned Kock
http://healthcorrelator.blogspot.com/2010/03/ketosis-methylglyoxal-and-accelerated.html
"Since glycation refers to “sugar” molecules sticking to protein and fats, its use in the context of methylglyoxal is arguably incorrect. Methylglyoxal is not a sugar, but an aldehyde."

Ketosis, methylglyoxal, and accelerated aging: Probably more fiction than fact
Sunday, March 14, 2010
Ned Kock
http://healthcorrelator.blogspot.com/2010/03/ketosis-methylglyoxal-and-accelerated_14.html
> 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.

> {It may be 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.

... 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.

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

Question 3 Methylglyoxal
Paleo Solution – Episode 132
Robb Wolf
http://robbwolf.com/wp/wp-content/uploads/2012/05/Paleo-Solution-Episode-132.pdf
"when you start eating a ketogenic diet, you get a spike and then a drop in methylglyoxal production and you get an increase in the enzymes that undo methylglyoxal association with proteins.
 
The state that you see rampant methylglyoxal production and a very low level of the enzymes that undo the methylglyoxal reactivity is actually during glycolysis and when we start seeing a lot of glycolysis is when people are insulin resistant, they're not able to access carbohydrate in a normal fashion for fuel and we actually see people heading in this more kind of acidotic glycolytic kind of direction.
 
So the state where you see a ton of methylglyoxal problem is in that diabetic or peri-diabetic state that is basically glucose field."

Chris Masterjohn also pointed out that glutathione (which is found in high amounts in foods like organs and egg yolks) cleans up AGEs and thus further offsets risks from consuming ketogenic or high-carb/sugar foods like honey:

Where Do Most AGEs Come From? O Glycation, How Thy Name Hast Deceived Me!
FRIDAY, OCTOBER 7, 2011
Chris Masterjohn
http://blog.cholesterol-and-health.com/2011/10/where-do-most-ages-come-from-o.html

Regardless of how important these different pathways {of producing methylglyoxal} are, it would be quite silly to blame AGEs on "carbohydrate," or "protein," or "fat," because these dicarbonyls cause nary a whiff of harm unless they slip past our good friend glutathione.

So, to summarize, methylglyoxal is apparently only a concern if you're in a chronic hyperglycemic state, especially with ketoacidosis (which may be what people are confusing ketogenic diets with), and especially with insufficient glutathione to handle the AGEs.

[Löwenherz]

Methylglyoxal production during ketosis is a very interesting topic!

Thanks for the links, PP.

Please let us know when you find further interesting infos.

Here is another discussion about methylglyoxal in the context of diabetes:

http://www.diabetesforum.com/diabetes/10198-methylglyoxal-revisited.html

As always, the scientific complexity of the details may overstrain our intellectual capabilities.

I would say: Saturated fat FEELS better than sugar. Raw FEELS better than cooked. The remaining question could be: Is Raw Low Carb better than Raw Zero Carb? I have seen some amazing healing processes in deep ketosis which are inhibited by even small amounts of carbs. Nevertheless I'm still not sure if ZC is also better in the long-run, due to thyroid health, fertility, longevity etc.

Löwenherz

[PaleoPhil]

Methylglyoxal production during ketosis is a very interesting topic!

Thanks for the links, PP.

You're welcome Lowenherz.

Here is another discussion about methylglyoxal in the context of diabetes:

http://www.diabetesforum.com/diabetes/10198-methylglyoxal-revisited.html

"...an article appeared EVERYWHERE about how the Atkins Diet (they actually mentioned it by name) causes increased methylglyoxal. What they obfuscated is that LC/HF causes an increase in SERUM MG (a good thing, overall) where the original findings of causing diabetes onset, its progression and its complications were about INTRACELLULAR MG. "

Indeed, sensationalistic articles damning Atkins and fatty meat in general were put out by irresponsible news sources (in other words, the majority of the popular press) and latched onto by propagandizing vegans/vegetarians and fearful folks. It pisses me off because friends, relatives and acquaintances see this stuff and tell me I'm going to die or decide to give up doing their own strict Paleo, or modify it for the worse, despite amazing success, because of scaremongering like this. Modern society is largely driven by fear and anxiety. Most people have become like skittish prey (aka sheeple).

As always, the scientific complexity of the details may overstrain our intellectual capabilities.

Quite right, the simplistic headlines and soundbites rarely grasp the (literally) infinite complexity of nature.

I would say: Saturated fat FEELS better than sugar. Raw FEELS better than cooked.

I like your gist about going by what foods produce good feelings and benefits, rather than just what tastes good, regardless of how thoroughly cooked and processed. How food makes us feel, minutes, hours, days, and years after we eat it is far more important than the initial taste sensation (though taste is an important tool within the realm of raw, wild foods, with which nature has provided us). And raw fruits and honey (especially wild and fermented) also feel better than refined and high-heated processed sugars. Table sugar doesn't even taste all that good on its own--that should be a hint. I've never seen anyone who regularly consumes table sugar straight, with nothing added (though I've no doubt there are some oddball exceptions out there). It's unpleasant for most, whereas most folks adore fruits. Is nature telling us something there?

The remaining question could be: Is Raw Low Carb better than Raw Zero Carb?

No society in all of human (or other mammal) history has been literally zero carb, so that should be a clue. Zero carb is a recent invention of humans, and even the diets of most of the supposed adherents aren't truly zero carb.

I have seen some amazing healing processes in deep ketosis which are inhibited by even small amounts of carbs. Nevertheless I'm still not sure if ZC is also better in the long-run, due to thyroid health, fertility, longevity etc.

Löwenherz

Muscle meat and fat alone never made sense to me, because I've never seen a wild carnivore forego organs because of the carb content, and I've never heard of a wild animal or hunter gatherer counting carbs. On the contrary, all the wild carnivores I've read about love organs, and many of them (such as wolves, coyotes, bears, etc.) eat berries and fruit drops. Tarsiers are an interesting case. I haven't seen any reports of them eating any fruits or honey yet. You'll never see a vegan or vegetarian mention tarsiers. They are the unmentionable, verboten, taboo primate which must remain unspoken (not to mention lorids).

[cobalamin]

Methylglyoxal seems like a clean up agent. I highly doubt Methylglyoxal is produced when eating only fruit, no high fat foods and the vains aren't subjected to hyperlipidemia.

Anyways, all these trials are invalid because they have been done on "sick people" with broken down organs that have been subjected to garbage foods that no mammal would eat out in nature. You know.. mixing meat(zero carb) with carbs on the same plate. Carbs inhibit fat metabolism and the excess fatty acids accumulate in the vains.

When in doubt, always take into account the human habits first.

No society in all of human (or other mammal) history has been literally zero carb, so that should be a clue. Zero carb is a recent invention of humans, and even the diets of most of the supposed adherents aren't truly zero carb.

Zero carb is survival metabolism, aka ketosis, not a recent invention, but the drive of human evolution from my experience of having an abundance amount of energy on the days after only eating meat. While according to "this" interesting article, carnivores only go into ketosis while starving.

The question I am interested in is.. how often should we be in ketosis? which would benefit our evolution? 1,2,3,4... days a week?

[PaleoPhil]

Zero carb is survival metabolism, aka ketosis, not a recent invention, but the drive of human evolution from my experience of having an abundance amount of energy on the days after only eating meat.

Please provide a single example of a society that was truly zero carb, else it's so much hot air. Hint: the Inuit "Eskimos" are not one such society (see "Eskimo potato"). Even Vilhjalmur Stefansson said some nice things about potatoes that one won't often find at Zeroing in on Health. And let's not forget the favorite food of every hunter-gatherer society that has access to decent variants of it: wild honey. Is honey zero carb?

ZC and VLC can be a beneficial therapy for some (including me in the past), but for millions and millions of years, humans and their forebears have been eating wild honey, wild fruits, wild livers and wild eggs. If all carbs were the Devil, it would be an uber miracle that H. sapiens managed to survive.

And I say this as someone who tolerates carbs less well than 99% of humanity. YMMV, and to each their own.

Slainte!