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Physiology of the Skin: The Impact of Glycation on the Skin, Part 1

By Peter T. Pugliese, MD
Posted: March 3, 2008, from the March 2008 issue of Skin Inc. magazine.

Conventional wisdom says, “You are what you eat.” Science now appears to verify that statement, although if you said this in a scientific meeting 40 years ago, you would have been laughed out of the room. When considering what you really are—essentially electrons and protons in a staggeringly complex arrangement that needs an energy input to function—you must think about from whence this energy comes. Obviously, it is obtained from the food you intake, and the hows and whys of its conversion into energy do not seem to merit much consideration. Yet, it is important to know so very much about food and energy in order to understand the process of glycation. The vast amount of information about glycation and related diseases is not only impressive, but also overwhelming. What could be presented to the sharp and conscientious esthetician that could be understood without having to wade through a mountain of basic references? My thoughts centered on the principle of learning, “start with the basics and build,” and so it shall be in this article. Let’s climb this mountain starting from the bottom.

In the beginning
      There are many conflicting reports regarding what primitive man’s diet was like. Human beings, that is as you are now physically, date back to the time in archeology known as the Pleistocene period, which started about 1.8 million years ago. The first use of fire in history remains even more controversial, placed anywhere from as early as 1 million years ago to 500,000 years ago. A recently published article in Science magazine states that fire was used in what is now Israel in 750,000 BC.1 This is important because it relates to how long mankind has eaten foods cooked at high temperatures.
     Man is a predatory animal. He has canine teeth and forward-facing eyes. Prey, such as cattle, have no canine teeth and their eyes are on the sides of their heads in order to keep watch for predators. How long mankind was only eating meat is unknown—surely vegetables and fruits were also consumed because they were available. All of this information is needed to understand how glycation has so drastically altered the lifespan of man.
     Let’s consider for a moment that mankind ate only raw meat for hundreds of thousands of years. First, he would have to live where there was a plentiful supply of animals large enough to support his family or tribe. This assumes they were Homo erectus—upright man—that appeared about 1.8 million year ago and survived until 300,000 years ago.
     Meat is mostly protein and fat with a lot of water. For example, beef is 60% water, 18% protein and 22% fat. Chicken is 65% water, 30% protein and 5% fat. Consider that 100 grams of beef contains a total of  270 calories. Vegetables contain far fewer calories per unit weight. Celery contains about 7 calories per gram and broccoli has about 2.5 calories per gram. The point here is that you need a much larger intake of vegetables to meet your daily caloric requirement. About 10,000–15,000 years ago, when the last Ice Age ended, mankind started to plant vegetables and domesticate animals. The whole nature of life changed when abundant food and more free time become available. At this time, early building and pottery-making were practiced, more sophisticated tools were used, clothing was worn and there were abundant, but limited, types of food. Now mankind had leisure time, and the whole genesis of civilization was set in motion.
     Notice that these diets were almost glucose-free. This indicates that the human body evolved up to this point with no genes to control glucose intake. Along with civilization came a host of diseases the likes of which man had never seen, including infections, cancer, diabetes and a host of other conditions that were either disabling or resulted in death. Only recently, that is during the past 50 years, has there been a rise in research that has implicated glucose intake as a major cause of many modern diseases. This article will explore the role of glucose and other simple sugars in the pathogenesis of metabolic diseases and relate them particularly to changes seen in the aging of the skin. First, a little chemistry is needed in order to become familiar with the terms needed to explain glycation; then the process of how glycation interferes with normal physiology will be examined.

Basic and glycochemistry
     Physiological chemistry is related to organic chemistry, also called carbon chemistry. Fortunately, only a few elements in carbohydrate chemistry, or glycochemistry, need to be learned. Carbon, which is designated as C in chemical formulae, has the ability to attract and hold four other atoms. This process is called valence. Hydrogen is designated by H and has a valence of one. So a carbon atom could capture and hold four hydrogen atoms to make methane gas, which is written as CH4. Oxygen is designated as O and has a valence of two, so CO2 is carbon dioxide. This would be all the atoms you would need to know if only carbohydrates were studied, but glycation involves proteins, which contain nitrogen. Nitrogen is designated by N and it has a valence of three. So, there are the basic building blocks of glucose chemistry: carbon C, hydrogen H, oxygen O and nitrogen N. Next, they need to be put together in order to make molecules.a Chemists represent these molecules by putting the atoms together in certain ways. Glucose can be written as C6H12O6, or it can be written as seen in Figure 1.
     If you look carefully at the three formulae in Figure 1, you will see that they all have the same number of carbon, hydrogen and oxygen atoms, but they have different arrangements. These three compounds are known as structural isomers—they have the same molecular weights, but different structures. Because they have six carbons, they can be called hexoses, or monosaccharides, which are simple sugars. Humans eat disaccharides, such as sucrose, which are made up of two simple sugars: glucose and fructose. These are joined together by a glucosidic bond.
     Following are a few more terms to be aware of in order to understand carbohydrate chemistry. Polysaccharides are complex sugars made up of strings of simple sugars, such as glucose. Starch is an example of a complex polysaccharide composed of several hundred glucose molecules linked together by the glucosidic bond attaching at carbons 1 and 4 on the glucose molecule. See Figure 2 for details.
     Note that the linkage is between carbons 1 and 4. Cellulose is linked between carbons 1 and 4, and is not digestible by man or young calves. The difference is a beta linkage of 14, while starch is an alpha 14. One more term that may come up is glycogen, which is a large molecular form of polymerized glucose used for the storage of a quick energy source. The liver and muscles are the major sources of glycogen.

Glycation and glycosylation
      Frequently, these terms are confused and thought to be interchangeable. Although both mean the joining of a sugar with a second molecule—either a protein or a fat—there is a big difference between the two. Glycation is an abnormal process and is pathological; it is the nonenzymatic joining of a sugar, and a protein or fat. Glycosylation is a normal enzymatic, physiological process in which sugars are joined to proteins and fats. Glycosylation will not be discussed in this article. First, why glycation occurs and how it happens need to be examined.
      There is a pretty good relationship between a high level of glucose (hyperglycemia) and diabetic complications, but now an even more extensive implication of glucose in other diseases and the aging process has been suggested by many investigators. Studies of the contribution of glycation to disease have focused not only on diabetes and diabetes-related complications, but also on glucose-induced damage in nondiabetic subjects. Glycation is known to advance slowly and involves every fundamental process of cellular metabolism, which is staggering.
     Glycation affects physiological aging, neurodegenerative diseases such as Alzheimer’s disease and even amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease. In the process, glycation can change the biological function of proteins and even alter how they are degraded. The nasty thing about all this is the end result. When proteins are cross-linked, they form aggregates that are detergent-insoluble and highly resistant to proteases.b There is a paradox here because glycation reactions produce reactive oxygen species (ROS), and then glycation itself is promoted by oxidative stress. All of it seems to be initiated by a high level of glucose, which the body cannot dispose of in a nontoxic manner. Let’s take a look at the chemistry of glycation reactions and examine the steps needed to produce a cross-linking protein.

The chemistry of glycation
    A basic principle of chemistry is the law of mass action. This law states that the concentration of a particular substance will determine the direction of a reaction. What that means can be illustrated by the example of a fire.
     All you need to make a fire is fuel and air. For example, a forest fire: There is plenty of fuel (trees) and lots of air, even more if there is wind. Both of these compounds are needed to make a fire; without wood or air, there is no fire. When you eliminate the wood by making a firebreak, the fire will stop. So it is with any chemical reaction; reactants are on one side and products are on the other.
Ex: Carbohydrate (wood) x oxygen (air) = heat + CO2 + H2O + charcoal
     In the human body, if there is an excess of glucose, it will drive a reaction to the right side of the equation. The simple energy equation that runs every cell in the body: Glucose + oxygen + enzymes = CO2 + H2O + energy
     This reaction is one way. There is no way you can get the trees back after the fire except to grow them. In another reaction, two-way traffic, back and forth, can occur. This is called a reversible reaction, or an equilibrium reaction. Following is an example that relates to the topic of glycation: Glucose + protein » Schiff base (azomethine), which can also be written as Schiff base (azomethine) » glucose + protein.
     Why is this so important? Because you learn that if your glucose (sugar) intake is high, you will have more glycation products produced, and, therefore, will age faster and be more debilitated. Conversely, if you consume normal levels of glucose, the first and second stage of glycation can actually reverse themselves. Wow! That is spectacular: You can actually get younger by eating less sugar-containing foods, and it doesn’t mean a hoot if it is raw or refined sugar. OK, let’s leave this easy stuff and get into the real reaction so you can understand what is going on in the black box of the cell and the intercellular spaces.

The union of glucose and a protein
     Glucose is a reactive compound because it has an aldehyde group as part of its structure. This is just a carbon atom with a double-bond oxygen and one hydrogen molecule linked to the rest of the glucose molecule. See Figure 6 for an illustration of the aldehyde group.
     Note the aldehyde group at the top of the molecule. In this linear arrangement, glucose is most active, but most of the time it is a cyclic form and cannot react easily with proteins. An example of the cyclic form can be seen in Figure 7. Note that the aldehyde group is no longer available.
     Now examine the first step in glycation on the way to making advanced glycation end-products (AGEs).

     Shiff base. After you just eat a generous slice of pie, your glucose is sky high and is racing through your body. All of a sudden, it hits some protein and, in a matter of minutes, the glucose molecules will latch on to this protein and form a Schiff base.c See the reaction in Figure 8; it is the first step in forming AGEs.
     Look carefully at the molecule in Figure 9 and see that the double-bond nitrogen has no hydrogen molecules attached to it. It is different from the nitrogen in Figure 8 because the initial step is only temporary and the molecule flips over to form Figure 9, which is the real Schiff base. The more glucose you have circulating, the more of these compounds you will make. This reaction can take from a few minutes to several hours, but it is completely reversible if the blood sugar is reduced to normal levels.

     Amadori product. The next step in the process of glycation is forming an Amadori product. The transition from a Schiff base to an Amadori product occurs by forming a ketone from one of the hydroxyl groups on the sugar. This reaction is seen in Figure 10.
     This reaction takes several days to occur, but after a couple of weeks, it is in equilibrium with the glucose level. The backward, or reverse reaction is much slower. At this stage, however, the process is still reversible, but it can go on to form other reactions, either cross-linking or ending in Maillard reaction products.d

     The Maillard reaction. The Maillard reaction is a very famous reaction in food chemistry. It is responsible for the browning of foods, and for adding flavors to all kinds of foods and candies. To produce the Maillard reaction, you must go through the Schiff base stage and the Amadori stage. There are many Maillard products—not all of them are bad. Think of it this way: There are at least five critical steps to form AGEs. The first two are related to sugar content and are spontaneously reversible; the remaining reactions are permanent and have adverse pathological actions on the body. These reactions have been shown to be reversible, in part, by new chemical agents still in trial.

In part two of this article, learn about the physiological consequences of glycation, as well as ways you can work with clients to make changes to help reverse the effects of glycation.