Dr Beth Briden summarises the effects of glycation on the skin, and how antioxidants such as gluconolactone, lactobionic acid and maltobionic acid can help fight the negative effects of advanced glycation end products
In addition to the effect on our waistlines, research has shown how sugar affects multiple organs in our body and our skin. Glycation has become the new buzzword in anti-ageing technology. A normal enzyme-related reaction in the body, where sugars are combined with protein, is known as glycosylation. More commonly, reducing sugars, such as glucose, react and bind with the amino group of available proteins, causing an abnormal, non-enzmatic reaction called glycation which can be damaging to the proteins in our skin and other organs.
In our skin, the protein molecule that sugar bind to is collagen; more specifically, it is the lysine molecule in the collagen molecule which causes damaging and permanent cross-links called advanced glycation end products (AGEs).
Glycation was first discovered in 1910 but it wasn’t until the 1980s that it really became widely known. At that time, the food industry started using glycation to enhance the flavour and colour of foods, revealing its significance. It was discovered that the browning reaction when you bake a pie or cookies turning them brown and crispy, is due to protein alteration from glycation. When we grill meats, the crusty char is also caused by glycation.
The process is also significant in the skin. When we apply a self-tanner, the active ingredient, dihydroxyacetone—a sugar molecule—undergoes a glycation reaction with the stratum corneum and causes damage to the proteins and, therefore, the brown colouring. Although, usually confined to the stratum corneum, some of the dihydroxyacetone can penetrate into the skin causing further damage to the dermis.
The glycation process
To simplify the process of glycation, a protein binds to a sugar. Normally, under hot conditions or in the presence of triglycerides, the sugar will open up its structure and grab on to the amino group of these proteins, forming unstable intermediates called Schiff bases.
Schiff bases then react, either by breaking apart and dissolving, or they will go on to form an intermediate product called an Amadori product. Over a period of a few weeks, the Amadori produscts will form additional cross-links forming irreversible bonds resulting in advanced glycation end products.
AGEs are damaging; they can form and accumulate in the skin’s dermis, from normally occurring sugars and proteins and from exogenous ingestion of foods containing AGEs such as burnt steak as well as from excess reducing sugars in the bloodstream. Around 30% of the AGEs and sugars we eat ends up in the skin as AGE products. Smoking and ultraviolet damage can also add to glycation.
Studies on diabetics have shown the concentration of AGE products in the skin are more than double the concentration of non-diabetics. Studies have also shown that glycation end products accumulate in normal skin with ageing and that there is a five fold increase in AGE concentration in the skin between the ages of 20–85.
Glycation mainly effects the long-lasting collagen, such as type I and type IV.
Glycation accounts for around 10–20% of ageing changes. We used to think the oxidative stress from ultraviolent light accounted for around 90% of ageing, but currently UV is thought to contribute between 70–80% of ageing changes in the skin. The remaining 20–30% of ageing changes are due to glycation and the gradual slowdown of cellular reactions and the telomere and thymidine dysfunction.
Impact on the skin
The sallow complexion that can occur with ageing is due to the deposition of AGE products in the upper dermis, causing a yellowing of the skin. Some AGE products, such as pentosidine, actually fluoresce under a special light so that you can see the accumulation in the skin.
AGE products also damage the collagen and the elastic fibres, causing wrinkling and sagging of the skin. They also disrupt the cellular communication that occurs in the dermis and the skin. AGE product accumulation can also cause inflammation and trigger the release of a cascade of cytokines and inflammatory proteins such as matrix metalloproteinase (MMP) proteins, causing further degradation of the collagen and the elastic tissues.
The damaged glycated proteins are very stiff, break easily and are actually hard to degrade, so they hang around in the skin for a very long time. The glycation of skin proteins could be compared to the tanning of leather with its stiff nature, There are several ways to inhibit this glycation process, thanks to research in diabetics.
One way to reduce unwanted gylcation is to provide sugar competitors, which can bind up the sugar so it can’t attach to the proteins, such as aspirin or acetylsalicylic acid. The competitors will bind to the lysine and the protein molecule and inhibit the sugar from attaching.
We can provide other protein competitors such as additional amino acids to bind with the sugars like arginine. There is a cream currently on the market that loads amino acids into the skin, so that the sugar will bind to the exogenous amino acids, rather than to the lysine in the proteins of the skin.
There is also a category of compounds that interfere with the Amadori products; the intermediary in AGE formation. Aminoguanidine is the gold standard of inhibiting Amadori product formation. Unfortunately, aminoguanadine caused too many side effects to be helpful in preventing glycation is diabetic patients.
Another way to prevent glycation is with antioxidants that interfere with oxidation—it’s the oxidation reaction that causes the Amadori products to form into AGEs. Vitamins B6 and B12 have been helpful with this. Antioxidants appear to stop the reaction by inhibiting the glyco-oxidation.
Alpha hydroxy acids
The second and third generation alpha hydroxy acids called polyhydroxy acids and bionic acids have potent antioxidant properties, as well as inhibiting metal chelation, and lipid peroxidation. They also have many other beneficial effects on the skin. The second generation AHA is the polyhydroxy acid, gluconolactone. This is the lactone derivative of gluconic acid. It has four hydroxyl groups, so it can bind four molecules of water and is therefore more hydrating. It’s still a small molecule, so it can penetrate the skin, but does so more slowly so it doesn’t sting like the typical AHAs.
Gluconolactone, a natural component of the body, is formed in the Krebs cycle, and is a potent antioxidant, and has been shown to inhibit MMP (collagenase) and the breakdown of elastic fibres by inhibiting elastase. It’s also a heavy metal chelator and can inhibit the chelation of heavy metals such as iron in the dermis.
Gluconolactone also inhibits lipid peroxidation, which is very important in protecting the mitochondria in the cell membrane. It’s been shown to inhibit malonaldehyde production in the model of lipid peroxidation inhibition and also improves the barrier function. It also has the anti-ageing effects of stimulating collagen, elastic tissue, epidermal repair and the dermal matrix, the glycosaminoglycans, including hyaluronic acid.
The third generation AHA is a complex polyhydroxyacid called lactobionic acid. Lactobionic acid is composed of galactose, “brain sugar”, and gluconolactone. This results in two lactone rings, with eight molecules to absorb water, so it’s more hygroscopic and moisturising. It forms a gel matrix on the skin that attracts water and improves the barrier function. It’s also a powerful antioxidant. This is the main ingredient in the organ perfusion baths to bathe livers and kidneys when they’re being transported, because it’s non-irritating and is a natural component of the body—a strong antioxidant and strong humectant. It also inhibits MMPs, lipid peroxidation and heavy metal chelation and has stimulatory effects on renewing skin components, such as the epidermis, dermis and collagen elastic tissue.
Malotbionic acid is another bionic acid and is derived from corn sugar. It has the same beneficial effects as lactobionic acid, but in addition it has been shown to inhibits ultraviolet-induced pigmentation. In clinical studies, when B-16 melanocytes are stimulated with MSH (melanocyte stimulating hormone) simulating sunlight induced pigment formation—altobionic acid has been shown to inhibit the production of melanin in a dose-dependent fashion.
The polyhydroxy and bionic acids, gluconolactone, lactobionic acid and Malotbionic acid, has pronounced effects in preserving vital skin structures by preventing heavy metal chelation, lipid peroxidation, MMPs including collagenase and glycation. They help prevent the degradation of collagen and elastic fibres in the dermis and prevent damage to these proteins by inhibiting glycation-induced AGEs. They are also effective in improving the barrier function of the skin in addition to providing a stimulatory effect by increasing production of the ground substance (hyaluronic acid) in the dermis, and by stimulating collagen and elastic tissue production, they plump and firm the skin.
They also help even out pigmentation in the skin through exfoliation and dispersing pigmentation and by inhibiting UV induced melanin formation. They also decrease a sallow appearance by inhibiting the formation of AGE products in the skin.
In one study, a patient with moderate photodamage who had a thickened stratum corneum, a thin atrophic epidermis, without the ridges and some solar elastosis in the dermis was treated with lactobionic acid cream. After an 8% lactobionic (Bionic lotion) was applied to the skin twice daily for 12 weeks, the stratum corneum became thinner, more basket-weave and compact, with a thicker epidermis and a plumping effect with more glycosaminoglycan deposition in the dermal matrix.
This is another study showing the effect of MBA (malatobionic acid) in inhibiting MMP formation, In this study, maltobionic acid, at a very low concentration of 0.1%, effectively inhibited MMP formation as effectively as the standad phentrolamine. NeoStrata uses a much higher concerntration, 8%, in their creams.
Another study at the American Academy of Dermatology meeting in Denver 2014 showed the anti-glycation effects of matobionic acid, lactobionic acid and gluconolactone. In this study, the authors took three different concentrations of these products and combined them with the protein albumin in Petri wells. In half of those, they added glucose for the sugar substrate and water as the negative control. The AGE product can take a while to develop so after 24 days, they looked at the different concentrations. Aminoguanidine was their standard for the negative control of preventing glycation at a 0.5% concentration. Gluconolactone, even at 0.1%, actually exceeded aminoguanidine, the industry standard. The maltobionic acid and the lactobionic acid were also both effective in inhibiting glycation.
Following on from this, they performed a clinical study measuring the skin with a colorimeter to look at the different colours. They found that all three of those antioxidants decreased the yellowness or sallowness of the skin over 12 weeks.
So in summary, lactobionic acid and the multibionic acid in the second generation gluconolactone significantly reduced non-enzymatic glycation, comparably to the protein inhibitor aminoguanidine.
These products can help preserve the skin’s natural structures and reduce the effects of glycation and ageing on the skin over time.
They can be applied topically or taken internally—but if you’re going to apply to the skin, you have to make sure it will penetrate down to the dermis where these reactions occur.
Glycation and its damaging AGE products can be inhibited with topically applied polyhydrox acid and bionic acid creams, but, it is better controlled by watching our intake of glycated foods and sugars.
Dr Beth Briden is a dermatologist based in Minnesota. She is an adjunct professor of dermatology at the University of Minnesota and a dermatological consultant for NeoStrata