Picture: Advanced glycation endproduct pathway. Source: Nature.

As you age, not only does collagen production decrease, but collagen itself changes, becoming tough, stiffened, and inflexible. According to DeGrey, advanced glycation endproducts (appropriate acronym: AGE) play an important role in the aging of all of the cells of your body, including within the skin. AGEs come from the processing of blood sugar via the Maillard pathway (see below). The advanced glycation endproduct called glucosepane is believed to be responsible for the toughened, hardened, aged state of collagen.

What are Advanced Glycation Endproducts?

Advanced glycation products are formed as a result of the Maillard pathway (which has been simplified here):
1. A blood sugar glycates (attaches to) a protein molecule, forming a Schiff base.

2. The Schiff base either falls apart, or forms a more stable product called an Amadori product. Examples of Amadori products include the molecule used to measure blood sugar levels, glycated hemoglobin (Hb1ac), in red blood cells.

3. The Amadori product forms an advanced glycation product (AGE), either directly or thorugh the action of oxoaldehydes, such as methylglyoxyal.

4. The advanced glycation endproduct (AGE) undergoes glycoxidation, a process that is accelerated by the presence of free radicals. This is the super-dangerous part: through glycoxidation, AGEs cross-link into a second, neighboring protein. These cross links have proven to be responsible, at least in part, for the hardening of cardiovascular structures, improper filtering of the kidneys, and, when the AGE is glucosepane, the hardened, stiffened collagen within aged skin. Cross links of the AGE glucosepane alter the structure of the collagen within the skin and accumulate as you age, progressively making collagen harder and more inflexible.

Can antioxidants be used to treat AGEs?

No. Although antioxidants have been shown to have many anti-aging effects, they do not prevent AGE-induced cross-links. According to DeGrey, studies in which rats were treated with antioxidants via green tea extracts actually increased their number of AGE-induced cross-links. This does not seem to make intuitive sense, as free radicals accelerate the rate at which age-induced cross-links are formed (see 4 above); it seems that fighting free radicals with antioxidants should in turn decrease the rate. However, according to DeGrey, AGE cross-linking is a very resilient process. With or without free radicals, under certain conditions, AGEs will form dangerous cross links, simply by going down different biochemical pathways to achieve this aim. As DeGrey puts it, “The AGE cross-links don’t disappear…they have to go somewhere…[for example] in a congested highway, you end up with more cars down side streets, not less traffic.” The inefficacy of antioxidants in fighting AGE cross links, however, is not enough to refute the other numerous benefits of antioxidants, so it is not advisable to stop using antioxidants.

If AGEs come from blood sugar, does this mean that avoiding sugars will help my skin?

Based on current knowledge, the answer would be that sugars should be eaten in moderation to best help your skin. High levels of sugar have been proven to be detrimental to your health. For instance, studies from Port et al. and Khaw, amongst others, have shown that higher levels of blood glucose increase death rates. It seems that, under certain conditions within the body, some blood sugar molecules automatically travels down the Maillard pathway, forming dangerous AGE products and ultimately, AGE cross links. Based on basic principles of chemistry, the more blood sugar you have, the more sugar molecules you have forming AGEs.

However, sugar avoidance (i.e., Atkins diet) is not the solution. In a 2005 study by Beisswenger, patients were put on the Atkins diet, and it was found that the rate of AGE formation was actually doubled. (The patients were proven to be following the diet and appropriately “in ketosis” by the presence of ketones in their urine.) It seems that ketosis doubles the presence of methylglyoxal (see 3 above) in the body, which react with Amadori products, forming twice the AGE products that would normally be present. It is further notable that methylglyoxal is 40000 times more reactive than blood sugar itself, so it seems that avoiding sugar in hopes of decreasing AGE formation is incredibly counterproductive. It thereby seems to be the best advice to eat a well-balanced diet, with sugars in moderation, but certainly not restricted as in the Atkins diet.

Is there a drug to fight AGEs? Or a skincare treatment?

Currently, no. There are AGE inhibitors in the market, but these are not triggered for glucosepane, the AGE that is responsible for the aging of collagen. For instance, one AGE inhibitor drug, alagebrium, has been shown to reduce AGE cross links within the kidney, improving filtering of the kidney. This is because alagebrium breaks α-diketone cross links that are formed by an AGE called pentosidine. Unfortunately, according to DeGrey, the α-diketone cross links formed by pentosidine are much weaker than the cross-links formed by glucosepane, so attempting to treat collagen cross-links in the skin with alagebrium would be futile.

How important is the AGE glucosepane in collagen cross-linking?

Extremely. Glucosepane has been found by Sell et. al to cross link one in five molecules of collagen in older, healthy adults. This means that glucosepane is present in one hundred times higher concentration than any other known AGE. Thankfully, the structure of glucosepane has been identified (Biemel, 2002), so hopefully glucosepane- and glucosepane-cross-link-selective drugs and treatments will soon be developed.

Are some AGEs inevitable?

Some AGEs are in fact inevitable. Metabolism naturally produces some AGEs from the processing of blood sugars. Further, in regulated metabolism, according to DeGrey, macrophages produce myeloperoxidase in attempts to clear cholesterol from the arteries. Myeloperoxidase, in turn, produces hypochlorous acid, which combines with the amino acid serine and — you guessed it — forms AGE-induced cross-links. However, it is still widely accepted that reducing (not eliminating) your levels of blood sugar can still slow rates AGE-cross link formation, even if it cannot eliminate them.

So what should I do now to prevent AGEs?

Eat a balanced diet. Limit sugars, but based on the alarming evidence from a 2005 study by Beisswenger at Dartmouth, do not eliminate sugars completely from your diet. Further, stay on top of current research and skincare advancements; hopefully, a treatment for glucosepane will be developed soon. I will post as soon as I hear about one.