compounds (eg, dihydroxyacetone [DHA], the active browning ingredient in sunless tanning lotions) capable of increasing levels of AGEs in the skin.7,8 While most AGEs appear to arise from Maillard reactions occurring at the stratum corneum of the skin, studies suggest that self-tanning components (from sunless/chemical tanners) such as DHA (~12%, according to a US Food and Drug Administration [FDA] investigator-led study) may also slightly penetrate the epidermis and dermis layers where they can then promote some glycation.9-11 However, the use of self-tanners is generally considered a safe alternative to UV-induced tanning.
Consequences of Skin Glycation
Due to their ability to negatively alter skin biology, the accumulation of AGEs is tied to several adverse effects in both the extracellular and intracellular compartments (Figure 1). One particularly problematic effect of AGEs is their ability to diminish protein function by altering their structure through cross-linking mechanisms.1-3 This impacts several protein factors that comprise the architectural framework of the extracellular matrix (ECM). For example, ECM proteins, such as collagen and elastin, can be captured and cross-linked by various AGEs, resulting in the loss of their native conformation (ie, normal structure). This compromises the integrity and biomechanical properties of the skin, ultimately causing reduced skin elasticity and increased stiffness.1-3 These processes are further exacerbated by the fact that, as humans age, skin fibroblasts exhibit a reduced capacity to secrete elastin and collagen fibers, further decreasing the quality of the ECM in the dermis.1,12 In addition to the deepening and lengthening of skin wrinkles, these molecular events contribute to several manifestations of skin aging, such as yellowing, pigmentation changes (browning), and autofluorescence.1,3
Due to their ability to negatively alter skin biology, the accumulation of AGEs is tied to several adverse effects in both the extracellular and intracellular compartments (Figure 1). One particularly problematic effect of AGEs is their ability to diminish protein function by altering their structure through cross-linking mechanisms.1-3 This impacts several protein factors that comprise the architectural framework of the extracellular matrix (ECM). For example, ECM proteins, such as collagen and elastin, can be captured and cross-linked by various AGEs, resulting in the loss of their native conformation (ie, normal structure). This compromises the integrity and biomechanical properties of the skin, ultimately causing reduced skin elasticity and increased stiffness.1-3 These processes are further exacerbated by the fact that, as humans age, skin fibroblasts exhibit a reduced capacity to secrete elastin and collagen fibers, further decreasing the quality of the ECM in the dermis.1,12 In addition to the deepening and lengthening of skin wrinkles, these molecular events contribute to several manifestations of skin aging, such as yellowing, pigmentation changes (browning), and autofluorescence.1,3
Another important biological effect of AGEs and their intermediates is their capacity to independently react with molecular oxygen and metals to generate reactive oxygen species (ROS), furthering their toxic potential.1-3 Additionally, AGEs can promote an inflammatory phenotype in cells by stimulating the production and release of pro-inflammatory cytokines and ROS.1-3 The ROS and cytokine-inducing phenotypes observed in cells with elevated levels of AGEs may also be partly mediated by the binding of AGEs to the receptor for advanced glycation end-products (RAGE), the activation of which results in oxidative stress and upregulation of pro-inflammatory cytokines.13,14 Lastly, AGEs can impair the signal transduction properties of cell growth and survival pathways, impinging upon important cellular cascades, including those required for normal proliferation, differentiation, motility, and cell death.2,3,15
Given the pleiotropic effects of AGEs in the cell, it is no surprise that their presence and persistence are linked to several disease pathologies (Figure 1).1-3,5 The role of AGEs in patients with chronic metabolic disorders, such as diabetes, has garnered much attention, being a condition marked by a hyperglycemic state where patients may eventually suffer from skin complications (eg, ulcers, wound healing issues).2,3,16,17 The high glucose levels in patients with diabetes can serve as a reservoir for accelerating AGE-related metabolism.2,3,18 Indeed, patients with diabetes display higher levels of AGEs in their skin than healthy individuals.19,20 Studies have also shown a correlation between high sugar levels and skin aging among patients with diabetes, and it has been revealed that patients with diabetes have impaired structural and mechanical properties in dermal collagen.2,3,21,22 These observations point to a possible role of AGEs in mediating some aspects of diabetic disease. However, the exact mechanisms are poorly understood and likely involve other biological factors.
The formation of AGEs and activation of AGE pathways are also implicated in other chronic illnesses and conditions marked by an underlying inflammatory element, such as cardiovascular disease, neurodegenerative processes, and kidney disorders (Figure 1).1-5,23 Whether AGEs are involved in initiating or driving the progression of such diseases remains unclear. Still, research scholars theorize that AGEs may help elicit cellular responses and pathways that involve pro-inflammatory signals and promote oxidative stress, leading to age-related disease and metabolic disorders (see Figure 1 for a summary of key biological effects and consequences of AGEs in humans).2
Recommendations for Preventing Skin Glycation and Reducing AGEs
Lifestyle Modification
Clinicians should emphasize to their patients that the most direct strategy to mitigate the accumulation of AGEs is to restrict the intake of exogenous sources of sugar and heat-treated foods (eg, fried and baked foods) (Figure 2). This aligns with the observation that patients with diabetes and renal failure who receive a diet low in AGEs have reduced circulating levels of AGEs and inflammatory biomarkers.15,24,25 Therefore, it is recommended that patients are educated on how to modify their lifestyle by regularly exercising and changing their diet to consume healthier foods. Consuming fruits and vegetables may be beneficial since they contain antioxidants, such as phytochemicals, phenolic acids, and polyphenols, that can contend with AGE-related free radical stress.1-5 Additional lifestyle modifications include limiting
Lifestyle Modification
Clinicians should emphasize to their patients that the most direct strategy to mitigate the accumulation of AGEs is to restrict the intake of exogenous sources of sugar and heat-treated foods (eg, fried and baked foods) (Figure 2). This aligns with the observation that patients with diabetes and renal failure who receive a diet low in AGEs have reduced circulating levels of AGEs and inflammatory biomarkers.15,24,25 Therefore, it is recommended that patients are educated on how to modify their lifestyle by regularly exercising and changing their diet to consume healthier foods. Consuming fruits and vegetables may be beneficial since they contain antioxidants, such as phytochemicals, phenolic acids, and polyphenols, that can contend with AGE-related free radical stress.1-5 Additional lifestyle modifications include limiting
