Clinical, Cosmetic and Investigational Dermatology 2022:15 911–927
Glycation is a physiological, non-enzymatic reaction between free reducing sugars and proteins, DNA and lipids that can damage the tissue.1 The process is typically initiated by the reactive carbonyl groups of sugars, resulting in intermediate Amadori products that are modified further by oxidation, dehydration, polymerization and cross-linking leading to the formation and advanced glycation end products (AGEs). Glycation frequently involves the modification of the arginine residues of the protein with metabolic factors, such as Glyoxal, Methylglyoxal and 3-Deoxyglucosone.2 There is also a close biological association between the formation of AGEs-modified macromolecules and glycemic index-linked to tissue damage in early and advanced metabolic syndromes that were recorded in clinical trials.3,4 In addition, glycated macromolecules can be formed during oxidative stress due to hyperglycemia and plasma levels of circulating AGEs often correspond to glycemic index control.5
Accumulation of the glycated macromolecules, predominantly proteins, has been shown to impair organ function and is regarded as a plausible hallmark of tissue damage linked to aging and age-related diseases.6 There is also extensive experimental and theoretical evidence pointing at the accumulation of AGEs in the tissues of aged animal models, frequently linked to metabolism-mediated life span.7,8 The AGEs that have been extensively characterized in this context include pentosidine, N-(carboxyethyl)-lysine (CEL) and N-(Carboxymethyl)-lysine (CML), which accumulate in several aged tissues including the eye, heart and arteries.9,10
There are several theoretical explanations and empirically supported mechanisms for the glycation-induced damage specifically affecting aged tissues. The studies point at glycation as a cause of the damage affecting mitochondrial proteins involved in fatty acid b-oxidation and tricarboxylic acid (TCA) cycle leading to a decline in capacity for energy production.11 Post-translation modification of proteins by glycation could also interfere with the process of angiogenesis in aging and age-related disorders.12 Finally, the formation of AGEs and the macromolecular damage are facilitated by an increase in oxidative stress and controlled by feedback involving reactive oxygen and nitrogen species (ROS and NOS) and the antioxidant capacities of the cells.13
Events of glycation have also been extensively studied in the skin. As a large, stratified organ, the skin is composed of two main layers with defined structure and function: the epidermis, the outermost layer formed predominantly by keratinocytes and providing a protective barrier, and the dermis, formed predominantly by dermal fibroblasts, elastic fibers and collagen contributing to the mechanical strength and overall skin elasticity.14 Effects of glycation on the skin include impairment in the mechanical propensity, wound healing and angiogenesis, with the accumulation of AGEs directly linked to the diet.15 Critical effects of glycation on skin aging are indicated by the impact of AGEs on the physical and biological properties of the collagen and elastic fibers affecting the architecture of the dermis and extracellular matrix (ECM) remodeling.16 The major mechanisms contributing to the damage involve the accumulation of AGEs within the ECM and chemical reactions typically leading to a significant decrease in the connective tissue elasticity and increased stiffness. Such changes are frequently accompanied by activation of the inflammatory and oxidative stress pathways and are further exasperated by low expression or absence of the enzymes removing the glycated products. In aged tissues and the skin, the most prevalent AGEs modifications involve CML and pentosidine, which accumulate with time and can permanently alter the structure of collagen and elastic fibers.17 Glycation of collagen coincides with a decrease in its turnover, intermolecular cross-linking, impaired remodeling and interactions with the cell.18,19 AGEs modifications are also detected in the epidermis, where they could be potentially linked to changes in the epidermal structure and homeostasis.20
Several natural bioactive compounds have been recently identified as promising candidates with the ability to inhibit glycation and glycation-mediated skin aging. Compared with synthetic molecules, the small molecules from natural sources are generally considered safe for both consumption and topical applications.21 Such ingredients have also added protective beneficial effects stemming from their biological functions, such as antioxidants, which can potentiate the antiglycation activity in the cell. The effect of the compounds is evident in the inhibition of AGEs formation and trapping of reactive dicarbonyl species, which are frequently related to the precise modification and chemical structure of the compound.22–24 For some ingredients, the anti-glycation capacities appear similar or even stronger than for synthetic compounds such as aminoguanidine originally identified in the in vivo studies.25 Therefore, the naturally occurring small bioactive molecules can be evaluated further and incorporated into cosmetic formulations with skincare benefits.
In this study, we investigated the effect of glycation on dermal-epidermal compartments and cellular renewal in an invitro 3D skin model. We found that AGEs-related damage to the collagen and elastic fibers is closely associated with the alterations in the fibroblast-dense upper layer of the dermis, which interacts directly with the epidermis, leading to a decrease in the epidermal thickness and stratification. Treatment of cultured dermal fibroblasts with Methylglyoxal induces senescent phenotypes of the cells, such characteristics can be prevented by the presence of Resveratrol and its derivatives, OxyResveratrol, Piceatannol and Triacetyl Resveratrol in growth media. Subsequent topical applications of the aqueous solutions of the compounds in skin models ameliorate the effects of glycation, including inhibition of AGEs formation, increase in fibroblasts and collagen density, and improved epidermal stratification. These data provide further insight into the anti-aging propensity of Resveratrol and its derivatives and inform the potential novel applications for cosmetic formulations based on the anti-glycation activity.