Lorna Bowes examines the concept of glycation and reviews the evidence behind various topical ingredients shown to inhibit accumulation of Advanced Glycation Endpoints (AGEs)
As we, aesthetic practitioners, cosmetic dermatologists and cosmetic scientists, learn more about the ageing process, we uncover new and improved ways to target the many signs and symptoms of ageing skin. Sometimes, these new understandings pave the way for new ingredients, and at other times we discover that existing proven technologies have actions previously not described or fully understood.
There are many processes implicated in ageing, however one generating increased interest in both general and aesthetic medicine is glycation.
AGEs, or Advanced Glycation End products, is the name given to the irreversible damage caused to proteins by sugar molecules, i.e. glycation. This is a negative process that is not exclusive to the skin, but is found throughout the body where proteins are present. Glycation differs from glycosylation, as glycosylation is a normal process in which sugars are combined with protein in a site-specific, enzyme-mediated process that is essential for molecular function. Glycation, however, is an abnormal process; a non-enzymatic joining of a sugar with a protein that impairs molecular function and causes irreversible damage to proteins in the skin, as well as other organs. The more we understand AGEs, the more interest there is in finding the perfect AGE inhibitor. AGEs are not only relevant in aesthetics; exogenous AGEs are formed when sugars are cooked in combination with proteins and fats. This is seen by the food industry as a very positive reaction as they are able to use this to create a cooked effect. For example, by adding sugar to food before cooking, the glycation process creates the non-enzymatic browning reaction, which improves the appearance of the food and is important for flavour.1 The food industry terminology for this is ‘caramelisation’, first described by Louis-Camille Maillard, a French chemist in 1912, and hence known as the Maillard reaction, a non-enzymatic browning process.3 Glycation has been widely studied in relation to diabetes, with results from multiple medical studies1 showing that not only is there a link between obesity and the onset of diabetes, but that there is a correlation between the quantity of food cooked at high temperature and the development of type 2 diabetes and related cardiovascular disease. Researchers have looked for possible links between increased AGEs and a reduction in the body’s natural defense against insulin resistance. It is this research which led to new research being undertaken focusing on the skin ageing effects of glycation.
The Maillard reaction occurs irreversibly in the skin, causing protein crosslinking, which leads to yellow colouring and a sallow appearance.2 The production of AGEs in skin is a slow three-step chemical process; the longer the biological half-life of a protein, the stronger the effect of glycation on the protein. Collagen is a triple helical structure of protein, mostly glycine, proline and hydroxyproline, which is essential for the structure of the Extra Cellular Matrix (ECM) in the skin. Collagen has a significant half-life in the dermis and is thus highly susceptible to the damage potential of AGEs. In the presence of heat, the primary amino acid component of the collagen triple helix is ‘grabbed’ by a sugar (glucose) yielding glycation intermediates known as Schiff bases (step 1), which in turn are oxidised and either disseminate or form a further intermediate known as an Amadori product (step 2). Finally in step 3, lasting several weeks, irreversible oxidative crosslinks are formed by the Amadori products and AGEs are ultimately formed causing slow deterioration of structural tissue.3,4,5
The damaged collagen is less susceptible to normal catabolism and therefore AGEs accumulate in the skin, as described above in the Maillard reaction. Additionally, with around 30% of the sugars and AGEs that we eat ending up in the skin, accumulation of AGEs is compounded. In addition, UV exposure, pollution and smoking add to the production of AGEs. Likewise, increased accumulations of AGEs are seen in certain diseases such as diabetes.6,7
AGEs accumulate in the upper dermis and this causes the yellowing of skin known as sallowness. Due to the effect of the crosslinking of the collagen and damage to the elastin in the skin, the skin becomes brittle and inflexible, wrinkles develop and the loss of elasticity leads to stiffness of the skin. The dermal processes involve the mid dermis as well as the upper dermis, creating an immediate challenge to formulators as the processes that active ingredients are required to affect are protected by the skin barrier function.
To create an anti-glycating effect, scientists have studied a selection of inhibitors. For example, aspirin blocks glycation by acetylating lysine residues; there are protein competitors that work by inhibiting sugars, such as aldose and ketose, which prevent a Maillard reaction in the presence of proteins. This is in fact one of the key pharmaceutical approaches in diabetes, along with the use of aminoguanidine and pyridoxamine.8
Aminoguanidine was one of the first substances shown to have an effect on AGE formation. This is not routinely used in topical anti-ageing formulations, but as well as being used in diabetes, it is frequently cited as the positive control in studies of other AGE inhibiting ingredients. The effect of aminoguanidine is attributed to its trapping of early glycation products, although effects on later stages of glycation have not been shown and it has been associated with adverse effects when trialled in patients with diabetes.
The challenge for topical anti-glyactors is to discover their efficacy. In particular, whether they provide adequate dermal penetration and tolerability. Metal chelation and anti-oxidative effects could, theoretically, affect the oxidative steps in AGE formation. Zinc, manganese, ascorbic acid, alpha lipoic acid, green tea and Vitamins C & E have all been shown to have antioxidant and/or metal chelation benefits. These ingredients are increasingly being used in nutraceutical skin beverages and as topical antioxidants in cosmeceutical formulations.9,10Hydroxyacids have attracted much interest as antiglycation ingredients. Second generation hydroxyacid, gluconolactone, a so-called polyhydroxyacid, and third generation ‘bionic polyhydroxyacids’ lactobionic and maltobionic acid were studied and shown to reduce the visual measure sallowness. The key study to assess antiglycation effects used aminoguanidine 0.01% as the positive control, and compared gluconolactone at 0.05%, 0.10% and 0.50%, lactobionic acid at 0.05%, 0.10% and 0.50%, and maltobionic acid at 0.05%, 0.10% and 0.50% over a 24-day incubation period.
Glycation is a significant part of the process that causes the visual signs of photodamage such as sallowness and the typical criss-cross pattern of fine lines seen in severe photodamage. These are ageing concerns that the vast majority of patients coming in to our clinics demonstrate to some degree. We have a wide array of cosmetic ingredients available to us, in an even greater number of formulations. The choices of both single active ingredients with single or multiple potential actions, and the selection of specific combined active ingredients made by the formulators, can make a vast difference to the effect of topical products. Polyhydroxyacids and bionic polyhydroxyacids come from the dermatologist/dermatopharmacologist team who discovered the first alpha hydroxyacid, glycolic acid, to be used in either pharmaceutical preparations or cosmetic formulations.16 Alongside the other proven anti-ageing actions of increased exfoliation and keratinization (improved clarity and reduced acne lesion count, improved skin depth and density, reduced skin surface roughness, improved laxity, reduced pore size and improved skin barrier function), polyhydroxyacids and bionic polyhydroxyacids have been shown to effectively inhibit non-enzymatic glycation. Long-term use of these advanced hydroxyacid ingredients will therefore maintain healthy skin and reduce exposure to the damaging and cosmetically distressing effects of AGEs.1
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