Sunday, March 14, 2010

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

This is a follow up on this post. 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.

(Ketones also provide an energy source that is distinct from lipoprotein-bound fatty acids and albumin-bound free fat acids. Those fatty acids appear to be preferred vehicles for the use of dietary or body fat as a source of energy. Yet it seems that small amounts of ketones are almost always present in the blood, even if they do not show up in the urine.)

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.

8 comments:

Miki said...

Saw De Grey on TED. He looks miserable on caloric restriction. Believe a low carb + IF diet could do him a lot of good.

Ned Kock said...

I agree. By the way, De Grey has a minor co-author in his book, Ending Aging. That co-author is an active member of the calorie restriction society. The book has many references to calorie restriction. It usually refers to it as the ONLY proven method to delay aging. Oh well …

ET said...

Found this doing a search on methylglyoxal. Ketoacidosis does increase it, not ketosis.

The 2-oxoaldehyde methylglyoxal (MeG) is the precursor to a number of the known advanced glycation endproducts (AGE) implicated in the development of diabetic complications. Other 2-oxoaldehydes that are important in AGE formation, such as glyoxal, glucosone, deoxyglucosone, xylosone and deoxyxylosone, are produced by nonenzymatic reactions. By contrast, MeG is produced by both enzymatic and nonenzymatic processes, most of which appear to be enhanced in diabetes. MeG may be a major precursor to formation of AGE, and rates of production of MeG depend upon physiological conditions such as hyperglycemia and ketoacidosis. MeG is also unique compared to the other 2-oxoaldehydes in its complex metabolism. At least four pathways contribute to detoxification of MeG: (1) aldose reductase, a member of the aldo–keto reductase superfamily, catalyzes the NADPH-dependent reduction of a wide range of aldehydes. MeG is the best of the known physiological aldehyde substrates of aldose reductase. The distribution of aldose reductase in human tissue is restricted; there is little expression in liver; (2) the ubiquitous and highly active glyoxalase system converts MeG into -lactate. However, this system depends upon the availability of glutathione; activity is severely limited by conditions of oxidative stress that impact levels of glutathione; (3) betaine aldehyde dehydrogenase, also known as ALDH9, is able to catalyze the oxidation of MeG to pyruvate, although less efficiently than with its substrate betaine aldehyde; (4) the long-known but not widely studied 2-oxoaldehyde dehydrogenases (2-ODHs) catalyze the oxidation of MeG to pyruvate, primarily in liver. There are two NADP-dependent 2-ODHs in human liver. Both of these require an activating amine. The physiological activator is unknown.

Ned Kock said...

Thanks ET. Yes, and ketoacidosis is also strongly associated with very high glucose levels. Impaired glucose metabolism is the main contributor to the formation of AGEs. This makes it difficult to differentiate the negative effects of ketoacidosis from those caused by elevated glucose levels.

rick said...

It seems you MG is in hyperglycemia as well: "Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite formed during glucose, protein and fatty acid metabolism. MG levels are elevated in hyperglycemia and other conditions. An excess of MG formation can increase ROS production and cause oxidative stress. MG reacts with proteins, DNA and other biomolecules, and is a major precursor of advanced glycation end products (AGEs). AGEs are also associated with the aging process and age-related diseases such as cardiovascular complications of diabetes, neurodegenerative diseases and connective tissue disorders. AGEs also increase oxidative stress."
Abstract
http://is.gd/dNbu2
Fulltext
http://is.gd/dNbDE

Can a normal person go hyperglycemic on a ketogenic, high protein diet?

viagra online said...

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.

rick said...

From DrGreger’s PDFs re: AGEs and microflora:

“Sugars
may oxidise to dicarbonyls, e.g. glyoxal and methylglyoxal
which are particularly reactive towards arginine residues in
protein to form hydroimidazolones. When a reducing sugar
reacts with the epsilon amino group of lysine, a reaction
intermediate, known as an Amadori rearrangement product
(ARP) is formed. ARPs are pre-AGEs and when the initial
reducing sugar is glucose, the ARP is known as fructoselysine
(FL). ARPs are unstable reaction intermediates that
degrade to AGEs, including those reported to be the most
abundant representatives in food, i.e. Ne-(carboxymethyl)-
lysine (CML) and pyrraline [2]. AGEs comprise a diverse
group of compounds and the structures of l20 have been
elucidated to date. So far, most research on AGEs have
been directed to their effects in vivo, where they are associated
with the complications of diabetes, especially renal,
retinal and cardiovascular disease [3].”

“This is partly because the
efficiency of absorption is generally much less than 100%.
Up to 80% of dietary ARPs are not absorbed but are
degraded by the gut microflora. The majority of the AGE
compliment of foods that is absorbed is rapidly excreted by
the kidneys.”
from http://is.gd/TSngGS ‘AGE con.pdf’

-
http://perfecthealthdiet.com/?p=4720#comment-36161

rick said...

From DrGreger’s PDFs re: AGEs and microflora:

“Sugars
may oxidise to dicarbonyls, e.g. glyoxal and methylglyoxal
which are particularly reactive towards arginine residues in
protein to form hydroimidazolones. When a reducing sugar
reacts with the epsilon amino group of lysine, a reaction
intermediate, known as an Amadori rearrangement product
(ARP) is formed. ARPs are pre-AGEs and when the initial
reducing sugar is glucose, the ARP is known as fructoselysine
(FL). ARPs are unstable reaction intermediates that
degrade to AGEs, including those reported to be the most
abundant representatives in food, i.e. Ne-(carboxymethyl)-
lysine (CML) and pyrraline [2]. AGEs comprise a diverse
group of compounds and the structures of l20 have been
elucidated to date. So far, most research on AGEs have
been directed to their effects in vivo, where they are associated
with the complications of diabetes, especially renal,
retinal and cardiovascular disease [3].”

“efficiency of absorption is generally much less than 100%.
Up to 80% of dietary ARPs are not absorbed but are
degraded by the gut microflora. The majority of the AGE
compliment of foods that is absorbed is rapidly excreted by
the kidneys.”
from http://is.gd/TSngGS ‘AGE con.pdf’

-
http://perfecthealthdiet.com/?p=4720#comment-36161