Thursday, March 11, 2010

Ketosis, methylglyoxal, and accelerated aging: Fact or fiction?

Ketosis is a state typically associated with very low carbohydrate diets, such as the Atkins diet. In this state, the liver produces ketones based on fat (body fat or dietary fat). Unlike fats, ketones are water soluble and used by many tissues (including brain tissues) as a source of energy.

Unlike glucose and lipoprotein-bound fats (in VLDL, for example), unused ketones cannot be converted back to substances that can be stored by the body. Thus excess ketones are eliminated in the urine; leading to their detection by various tests, e.g., Ketostix tests.

This elimination of unused ketones in the urine is one of the reasons why very low carbohydrate diets are believed to lead to enhanced body fat loss.

From an evolutionary perspective, one could argue that a ketosis state that involves the elimination of ketones in the urine is an inefficient and unnatural emergency mechanism. For our Paleolithic ancestors, dying of starvation was a much bigger problem than dying of obesity complications.

An interesting hypothesis has been around for quite some time about a possible negative effect of ketosis. It goes more or less like this. Ketosis leads to the production of an organic compound called methylglyoxal, which is believed to be a powerful agent of glycation (a misnomer; see note below).

Glycation is a process whereby sugar molecules “stick” to protein or fat molecules, impairing their function. Glycation leads to the formation of advanced glycation endproducts (AGEs), which appear to be associated with a host of diseases, including diabetes, and to be implicated in accelerated aging (or “ageing”, with British spelling).

In short: ketosis leads to the production of methylglyoxal, which leads to the formation of AGEs, which in turn cause diseases and accelerated aging.

Note: 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.

One of the strongest indictments of ketosis, in relation to methylglyoxal, is made in a fairly well referenced book by De Grey (2007); the full reference to the book is at the end of this post. De Grey’s book is about aging, and how to stop or at least delay it. Overall, it is an excellent book. Here is some relevant text, from page 173 of the book:
… 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 …
Is this notion that ketosis, through methylglyoxal, can cause accelerated aging fact or fiction?

Sorry, but I need to consult with my guru before I post my answer.


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


Unknown said...

"One believed purpose of the methylglyoxal pathway is to help release the stress of elevated sugar phosphate concentration."
"High concentrations of DHAP encourage methylglyoxal synthase to produce methylglyoxal"

The worst is definitely fructose, not only sugar, but a ketone sugar. Then glycolytic pathway. Then glycerol from too much fat. I doubt that ketosis by itself is the main source of glycation agents.

Dr Eades addressed this before:
(search page using methylglyoxal).

Ned Kock said...

Thanks PaleoDoc. Yes, I had seen those exchanges on Dr. Eades's blog. Peter and Hyperlipid also posted on this.