Harrison P. Nguyen, BA and Rajani Katta, MD

Department of Dermatology, Baylor College of Medicine, Houston, TX, USA

Conflict of interest:
None Reported.

ABSTRACT
First described in the context of diabetes, advanced glycation end products (AGEs) are formed through a type of non-enzymatic reaction called glycation. Increased accumulation of AGEs in human tissue has now been associated with end stage renal disease, chronic obstructive pulmonary disease, and, recently, skin aging. Characteristic findings of aging skin, including decreased resistance to mechanical stress, impaired wound healing, and distorted dermal vasculature, can be in part attributable to glycation. Multiple factors mediate cutaneous senescence, and these factors are generally characterized as endogenous (e.g., telomere shortening) or exogenous (e.g., ultraviolet radiation exposure). Interestingly, AGEs exert their pathophysiological effects from both endogenous and exogenous routes. The former entails the consumption of sugar in the diet, which then covalently binds an electron from a donor molecule to form an AGE. The latter process mostly refers to the formation of AGEs through cooking. Recent studies have revealed that certain methods of food preparation (i.e., grilling, frying, and roasting) produce much higher levels of AGEs than water-based cooking methods such as boiling and steaming. Moreover, several dietary compounds have emerged as promising candidates for the inhibition of glycation-mediated aging. In this review, we summarize the evidence supporting the critical role of glycation in skin aging and highlight preliminary studies on dietary strategies that may be able to combat this process.

Key Words:
AGEs, advanced glycation end products, collagen, dietary sucrose, fibroblasts, nutrition, skin aging

Background: Glycation and Aging Skin

Societal obsession with the process of aging dates back to ancient history, and myths related to the conservation of youth—ranging from a bathing fountain that confers eternal youth to a philosopher’s stone that could be used to create an elixir of life—populate both past and contemporary folklore. However, it is only within recent years that aging has been investigated from an empirical approach, as it continues to garner increasing attention from the scientific community. While several hypotheses have been proposed to explain the pathophysiology responsible for senescence, no single theory accounts for the diverse phenomena observed. Rather, aging appears to be a multifactorial process that results from a complex interplay of several factors and mechanisms.

Nevertheless, stratification of factors and mechanisms contributing to senescence is critical for the development of initial strategies in combating the aging process. The skin is an excellent paradigm for studying aging, in large part due to its easy accessibility. Moreover, in addition to its vulnerability to internal aging processes because of its diverse role in cellular processes, such as metabolism and immunity, the skin is subject to a variety of external stressors as the chief barrier between the body and the environment.

Aging factors can generally be classified as exogenous or endogenous. As ultraviolet (UV) radiation exposure is so strongly associated with a host of age-related skin diseases, endogenous and exogenous factors can theoretically be studied somewhat independently in the skin by differentiating between UVprotected and UV-exposed sites.1 Endogenously aged skin displays characteristic morphological features with resultant alterations in functionality. These include epidermal, dermal, and extracellular matrix atrophy leading to increased fragility, diminished collagen and elastin resulting in fine wrinkle formation, and marked vascular changes disrupting thermoregulation and nutrient supply. Endogenously aged skin also displays decreased mitotic activity, resulting in delayed wound healing, as well as decreased glandular function, resulting in disturbed re-epithelialization of
deep cutaneous wounds. Also seen is a reduction of melanocytes and Langerhans cells manifesting as hair graying and higher rates of infection, respectively.2-10 Exogenously aged skin, in which environmental factors such as UV radiation act in concert with endogenous processes, shares many of the characteristics of endogenously aged skin. In addition, exogenously aged skin displays a thickened epidermis and aggregation of abnormal elastic fibers in the dermis (i.e., solar elastosis).1

Among the many mechanisms thought to underlie aging, glycation has emerged in recent years as one of the most widely studied processes. Testament to the rapidly growing attention from the scientific community, a cursory literature search will yield thousands of articles related to glycation, the majority of them published in the last decade. Glycation refers to the nonenzymatic process of proteins, lipids, or nucleic acids covalently bonding to sugar molecules, usually glucose or fructose. The lack of enzyme mediation is the key differentiator between glycation and glycosylation. Glycosylation occurs at defined sites on the target molecule and is usually critical to the target molecule’s function. In contrast, glycation appears to occur at random molecular sites and generally results in the inhibition of the target molecule’s ability to function.The products of glycation are called advanced glycation end products (AGEs).

Increased accumulation of AGEs was first directly correlated to the development of diabetic complications. Since then, AGEs have been implicated in a host of other pathologies, including atherosclerosis, end stage renal disease, and chronic obstructive pulmonary disease.11 (It should be noted that AGE levels have been shown to vary by race and gender, and until larger studies are done to create ethnic- and gender-specific reference values, increased accumulation of AGEs should be defined as levels that are elevated for all demographic groups.12) Not coincidentally, many of the pathologies associated with AGEs, including diabetic sequelae, are closely related to senescence.

This extends to aging skin, as methods of AGE detection, such as immunostaining, have demonstrated the prevalence of glycation in aged skin. Glycation results in characteristic structural, morphological, and functional changes in the skin, a process colloquially known as “sugar sag.” With glucose and fructose playing such a prominent role in the mechanism, it is not surprising that diet plays a critical role in glycation and thus aging skin.

Perhaps more surprising, studies have shown that consumption of AGEs is not only tied to the sugar content of food, but is also affected by the method of cooking. Furthermore, as the
connection between diet and aging is more clearly characterized, a host of dietary compounds have surfaced as potential therapeutic candidates in the inhibition of AGE-mediated changes. In this review, we explore glycation as it pertains to skin aging and highlight evidence that demonstrates the quintessential role of diet in modifying the degree to which AGE-related processes are able to alter the largest organ of the human body.

Biochemical Processes in AGE Formation

First described over a century ago, glycation entails a series of simple and complex non-enzymatic reactions. In the key step, known as the Maillard reaction, electrophilic carbonyl groups of the sugar molecule react with free amino groups of proteins, lipids, or nucleic acids, leading to the formation of a Schiff base. This non-stable Schiff base contains a carbon-nitrogen double bond, with the nitrogen atom connected to an aryl or alkyl group. The Schiff base rapidly undergoes re-arrangement to form a more stable ketoamine, termed the Amadori product. At this juncture, the Amadori product can: (1) undergo the reverse reaction; (2) react irreversibly with lysine or arginine functional groups to produce stable AGEs in the form of protein adducts or protein cross-links; or (3) undergo further breakdown reactions, such as oxidation, dehydration, and polymerization, to give rise to numerous other AGEs.13 AGE formation is accelerated by an increased rate of protein turnover, hyperglycemia, temperatures above 120° C (248° F), and the presence of oxygen, reactive oxygen species, or active transition metals.14

AGEs comprise a highly heterogenous group of molecules. The first, and perhaps most well-known, physiological AGE to be described was glycated hemoglobin (hemoglobin A1C), now widely used to measure glycemic control in diabetes. However, the most prevalent AGE in the human body, including the skin, is carboxymethyl-lysine (CML), which is formed by oxidative degeneration of Amadori products or by direct addition of glyoxal to lysine. In the skin, CML is found in the normal epidermis, aged and diabetic dermis, and photoaging-actinic elastosis.15-17 Other AGEs detected in skin include pentosidine, glyoxal, methylglyoxal, glucosepane, fructoselysine, carboxyethyl-lysine, glyoxal-lysine dimer, and methylglyoxal-lysine dimer.18

AGEs and the Skin

AGEs accumulate in various tissues as a function, as well as
a marker, of chronological age.19 Proteins with slow turnover rates, such as collagen, are especially susceptible to modification by glycation. Collagen in the skin, in fact, has a half-life of approximately 15 years and thus can undergo up to a 50% increase in glycation over an individual’s lifetime.20

Collagen is critical not only to the mechanical framework of the skin but also to several cellular processes, and is impaired by glycation in multiple ways. First, intermolecular cross-linking modifies collagen’s biomechanical properties, resulting in increased stiffness and vulnerability to mechanical stimuli.21 Second, the formation of AGEs on collagen side chains alters the protein’s charge and interferes with its active sites, thereby distorting the protein’s ability to interact properly with surrounding cells and matrix proteins.22 Third, the ability to convert L-arginine to nitric oxide, a critical cofactor in the crosslinking of collagen fibers, is impaired.23 Finally, glycated collagen is highly resistant to degradation by matrix metalloproteinases (MMPs). This further retards the process of collagen turnover and replacement with functional proteins.24

Other cutaneous extracellular matrix proteins are functionally affected by glycation, including elastin and fibronectin. This further compounds dermal dysfunction,18,25 as glycation crosslinked collagen, elastin, and fibronectin cannot be repaired like their normal counterparts.

Interestingly, CML-modified elastin is mostly found in sites of solar elastosis and is nearly absent in sun-protected skin. This suggests that UV-radiation can mediate AGE formation in some capacity or, at the least, render cells more sensitive to external stimuli.26 It is hypothesized that UV-radiation accomplishes this through the formation of superoxide anion radicals, hydrogen peroxide, and hydroxyl radicals. This induces oxidative stress and accelerates the production of AGEs.27 AGEs themselves are very reactive molecules and can act as electron donors in the formation of free radicals. Occurring in conjunction with the decline of the enzymatic system that eliminates free radicals during the aging process, these properties lead to a “vicious cycle” of AGE formation in the setting of UV exposure.

Formed both intracellularly and extracellularly, AGEs can also have an effect on intracellular molecular function. In the skin, the intermediate filaments of fibroblasts (vimentin) and keratinocytes (cytokeratin 10) have been shown to be susceptible to glycation modification.28 Analogous to the diverse role of collagen in the skin, intermediate filaments are essential to both the maintenance of cytoskeletal stability and the coordination of numerous cellular functions. Fibroblasts with glycated vimentin demonstrate a reduced contractile capacity, and these modified fibroblasts are found to accumulate in skin biopsies of aged donors.28

In fact, general cellular function may be compromised in the presence of high concentrations of AGEs. In vitro, human dermal fibroblasts display higher rates of premature senescence and apoptosis, which likely explains the decreased collagen and extracellular matrix protein synthesis observed in both cell culture and aged skin biopsies.29,30 Similarly, keratinocytes exposed to AGEs express increased levels of pro-inflammatory mediators, suffer from decreased mobility, and also undergo premature senescence in the presence of AGEs.31

In addition to intermediate filaments, proteasomal machinery and DNA can undergo glycation. Proteasomal machinery, which functions to remove altered intracellular proteins, decline
functionally in vitro when treated with glyoxal.32 Similar in vitro findings were observed when human epidermal keratinocytes and fibroblasts were treated with glyoxal, leading to accumulation of CML in histones, cleavage of DNA, and, ultimately, arrest of cellular growth.33

Beyond the modification of host molecular physicochemistry, AGEs also exert detrimental effects through the binding to specialized cellular surface receptors, called the Receptor for
AGEs (RAGE). RAGE is a multiligand protein that, when activated, can trigger several cellular signaling pathways, including the mitogen-activated protein kinases (MAPKs), extracellular signalregulated kinases (ERK), phosphatidyl-inositol-3-kinase (PI3K), and nuclear factor kappa-beta (NFκ-β) pathways.34 These pathways are known to mediate various pathogenic mechanisms through the alteration of cell cycle regulators, gene expression, inflammation, and extracellular protein synthesis.34 Not surprisingly, RAGE is found to be highly expressed in the skin and is present at even higher levels in both UV-exposed anatomical sites and aged skin.35

Combating AGE with Diet

Nearly 70 years ago, Urbach and Lentz reported that the level of sugar both in the blood and in the skin is decreased with a diet low in sugar.36 Although its significance was not appreciated at the time, this finding demonstrated a quintessential connection between diet and skin health. We now understand that food is a source of both monosaccharides that, in high amounts, catalyze the production of AGEs in the body, and preformed AGEs.37

Preformed AGEs are absorbed by the gut with approximately 30% efficiency. They can then enter the circulation, where they may induce protein cross-linking, inflammation, and intracellular oxidative stress. The end result is the amplification of a similar “vicious cycle,” which may be as detrimental as the consumption of excess dietary sugar 38 Interestingly, preformed AGEs largely result from exogenous synthesis mediated by the food cooking process. Grilling, frying, deep fat frying, and roasting methods are all known to produce higher levels of AGEs in food. In contrast, methods of preparation that are water-based, such as boiling and steaming, produce a logarithmically lower amount of AGEs.39

A diet low in AGEs correlated with a reduction in inflammatory biomarkers (i.e., tumor necrosis factor-alpha, interleukin-6, and C-reactive protein) in diabetic human patients, as well as an improvement in wound healing and other diabetes-associated sequelae in mice.40,41 Other authors have cited the relatively youthful appearance that is often associated with the elderly Asian population as evidence of the long-term impact of employing water-based cooking practices, which are characteristic of Asian cooking.37

Tight glycemic control over a 4-month period can result in a reduction of glycated collagen formation by 25%.37,38 Consumption of a low-sugar diet prepared through waterbased cooking methods would limit both the consumption of preformed exogenous AGES and endogenous production through physiological glycation. Avoiding foods that result in higher levels of AGEs, such as donuts, barbecued meats, and dark-colored soft drinks, can be an effective strategy for slowing “sugar sag.”39

A diet low in AGEs correlated with a reduction in inflammatory biomarkers (i.e., tumor necrosis factor-alpha, interleukin-6, and C-reactive protein) in diabetic human patients, as well as an improvement in wound healing and other diabetes-associated sequelae in mice.40,41 Other authors have cited the relatively youthful appearance that is often associated with the elderly Asian population as evidence of the long-term impact of employing water-based cooking practices, which are characteristic of Asian cooking.37

Tight glycemic control over a 4-month period can result in a reduction of glycated collagen formation by 25%.37,38 Consumption of a low-sugar diet prepared through waterbased cooking methods would limit both the consumption of preformed exogenous AGES and endogenous production through physiological glycation. Avoiding foods that result in higher levels of AGEs, such as donuts, barbecued meats, and dark-colored soft drinks, can be an effective strategy for slowing “sugar sag.”39

Of interest, several culinary herbs and spices are believed to be capable of inhibiting the endogenous production of AGEs (specifically fructose-induced glycation). These include
cinnamon, cloves, oregano, and allspice.42 Other dietary compounds that have been linked to inhibition of AGE formation based on in vitro data and preliminary animal models include ginger, garlic, α-lipoic acid, carnitine, taurine, carnosine, flavonoids (e.g., green tea catechins), benfotiamine, α-tocopherol,niacinamide, pyridoxal, sodium selenite, selenium yeast, riboflavin, zinc, and manganese.42-44 The cosmeceutical industry has taken notice of this data, and several have recently released topical products containing carnosine and α-lipoic acid, with claims related to anti-AGE formation.38 However, data is lacking as to whether topical administration of these compounds is as effective as dietary delivery in slowing the aging process.

Since glycation is accelerated in the presence of reactive oxygen species, antioxidants should theoretically be effective in limiting the production of new AGEs. They may also impact AGE-induced tissue damage. One intriguing study looked at the effects of the antioxidant resveratrol. Popularly known for its abundance in red wine, resveratrol is a natural phenol produced by several plants in response to injury and is found in the skin of grapes, blueberries, raspberries, and mulberries. In one study, resveratrol inhibited AGE-induced proliferation and collagen synthesis activity in vascular smooth muscle cells belonging to strokeprone rats.45 Another study found that it decreased the frequency of DNA breaks in methylglyoxal treated mouse oocytes. Although resveratrol does not appear to reverse the glycation process itself, these studies suggest that it can reduce AGE-induced tissue damage.46 While these findings are promising, to our knowledge these laboratory results have not yet been demonstrated in human studies.

In one of the few human studies successfully conducted on antiAGE therapeutics, L-carnitine supplementation for 6 months in hemodialysis patients significantly decreased levels of AGEs in the skin.47 L-carnitine, which is naturally abundant in meat, poultry, fish, and dairy products, is an antioxidant. Furthermore, it may function synergistically to neutralize oxidative stress when given with α-lipoic acid.48

It warrants mentioning that dietary caloric restriction, the most effective strategy for slowing the general aging process known to date, may function to some degree by preventing accumulation of AGEs in the human body. Caloric restriction is capable of decreasing the levels of AGEs detected in rat and mice skin collagen and has resulted in an increased lifespan in mice models.49,50

Conclusion: Obstacles and Future Directions

There is clearly an abundance of in vitro data and a handful of in vivo animal findings that support various options for dietary therapy directed against “sugar sag.” However, studies in humans are limited by logistical, ethical, and inherent study design issues. In a stimulating commentary as part of a review article on controversies in aging and nutrition, Draelos writes about the frustrating obstacles that she encountered when she attempted to study the impact of vitamin C supplementation on skin health.38 Examples of problems she faced included: identifying a facility that offered affordable measurements of vitamin C levels not only in the serum but also in the skin; designing an ethical study that would include a control arm requiring subjects to adhere to a diet poor in vitamin C without any supplementation; and ensuring participant compliance to the diet and supplementation protocol while also minimizing confounding factors.Most of these challenges also exist in the human studies needed to identify and/or to verify evidence-based dietary strategies in combating glycation-mediated skin aging.

Nevertheless, the role of diet in skin aging is undeniable. As our understanding of how accumulation of AGEs affects a rapidly growing number of pathologies, it is inevitable that our research methods will evolve to better address the challenges that currently seem so discouraging. For instance, a research group reported in early 2014 that they were able to successfully create a model of reconstructed skin modified by glycated collagen to identify biological modifications of both epidermal and dermal markers.51 Perhaps the creation of an in vitro model that comprehensively and accurately represents aged human skin will serve as the next stepping stone in translating therapeutic findings from bench to bedside.

In the meantime, awareness of the critical impact of AGEformation in both diabetics and non-diabetics must be extended to all patients, regardless of their current health status. That task begins with clinicians. Dietary counseling should be incorporated into our regular interactions with patients, alongside essential discussions about UV-protection and avoidance of tobacco. After all, these are the three most important known exogenous aging factors. Their common grouping is reflective of their interconnected nature and their action in concert to disturb homeostasis.

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