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20 April 2025

Synthetic and Natural Agents Targeting Advanced Glycation End-Products for Skin Anti-Aging: A Comprehensive Review of Experimental and Clinical Studies

,
,
and
1
Department of Biomedical Science, The Graduate School, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Republic of Korea
2
BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu 41944, Republic of Korea
3
Department of Dermatology, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
4
Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu 41944, Republic of Korea
Antioxidants2025, 14(4), 498;https://doi.org/10.3390/antiox14040498
This article belongs to the Special Issue Antioxidants for Skin Health
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Abstract

Advanced glycation end-products (AGEs) cause blood vessel damage and induce diabetic complications in various organs, such as the eyes, kidneys, nerves, and skin. As glycation stress causes aesthetic, physical, and functional changes in the skin, glycation-targeting skin anti-aging strategies are attracting attention in cosmetology and dermatology. The primary goal of this review is to understand the significance of glycation-induced skin aging and to examine the therapeutic potential of glycation-targeting strategies. This study covers experimental and clinical studies exploring various interventions to attenuate glycation-induced skin aging. Glycation stress decreases the viability of cells in culture media, the cell-mediated contraction of collagen lattices in reconstructed skin models, and the expression of fibrillin-1 at the dermo-epidermal junction in the skin explants. It also increases cross-links in tail tendon collagen in animals, prolonging its breakdown time. However, these changes are attenuated by several synthetic and natural agents. Animal and clinical studies have shown that dietary or topical administration of agents with antiglycation or antioxidant activity can attenuate changes in AGE levels (measured by skin autofluorescence) and skin aging parameters (e.g., skin color, wrinkles, elasticity, hydration, dermal density) induced by chronological aging, diabetes, high-carbohydrate diets, ultraviolet radiation, or oxidative stress. Therefore, the accumulating experimental and clinical evidence supports that dietary supplements or topical formulations containing one or more synthetic and natural antiglycation agents may help mitigate skin aging induced by AGEs.

1. Introduction

When we talk about the aging of the body, skin aging is often the first thing that comes to mind because it is easily visible to the naked eye [1,2]. Among the various changes that accompany skin aging, the aesthetic changes of skin appearance, such as wrinkles, sagging, color, and gloss, are of particular interest in cosmetology, and the physical and functional changes in skin barrier integrity, immune response, wound healing, and other physiological aspects are of significant importance in dermatology [3,4]. Skin aging is theoretically divided into intrinsic and extrinsic types based on the origin of the causal factors, but in reality, the boundaries are ambiguous due to many overlapping factors [5,6]. Innate genetic traits and chronological aging are included in intrinsic skin aging factors [5], while environmental factors, such as ultraviolet (UV) rays, air pollution, and dry climate, are included in extrinsic skin aging factors [7,8,9]. On the other hand, smoking, drinking alcohol, drug use, and dietary habits may be considered mixed skin aging factors because these behaviors introduce external substances into the body, which then undergo chemical changes due to internal metabolism or environmental influences [10,11]. Intrinsic, extrinsic, and mixed skin aging factors can all have negative effects on the appearance and function of the skin in general.
Dietary carbohydrates are digested in the body to produce monosaccharides, such as glucose, fructose, and galactose. These monosaccharides are metabolized into small molecules through the glycolytic pathway and the citric acid cycle, generating NADH and FADH2, which are oxidized in the electron transport chain of the mitochondria for ATP synthesis [12]. Thus, under normal physiological conditions, carbohydrates function as essential nutrients that provide metabolites and energy required for cell survival and function. However, under pathological conditions (e.g., persistent hyperglycemia due to diabetes), they participate in non-enzymatic condensation reactions with proteins, lipids, and nucleic acids, forming advanced glycation end-products (AGEs) [13,14]. Glycation reactions also increase according to chronological age, inactive lifestyle, the consumption of high-carbohydrate diets, and exposure to UV rays [15,16,17,18]. AGEs are considered to be one of the representative mixed skin aging factors that combine external sources, intrinsic pathological alterations, and environmental exposures [19,20].
Reducing sugars, such as aldoses (e.g., glucose) and ketoses (e.g., fructose), can form Schiff bases in which their carbonyl groups are linked to free amine groups of various substrates, such as proteins, lipids, and nucleic acids, via the Maillard pathway or the polyol pathway [21,22]. These adducts then form early glycation products, such as Amadori products (e.g., glucose-derived AGEs) and Heyns products (e.g., fructose-derived AGEs), through intramolecular rearrangements. These early glycation products undergo oxidative degradation, generating various forms of reactive aldehydes (e.g., glyceraldehyde, glycolaldehyde), dialdehydes (e.g., diacetyl, glyoxal, methylglyoxal), diketones (e.g., 1-deoxyglucosone, 3-deoxyglucosone), etc., which participate in the formation of various types of AGEs [23,24,25,26]. Glycation products include the early glycation products (not included in AGEs), such as fructosamine and furosine; the intermediate glycation products, such as Nε-(carboxymethyl)lysine (CML), Nω-(carboxymethyl)arginine (CMA), and Nε-(carboxyethyl)lysine (CEL); and the late glycation products, such as Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine [also called “methylglyoxal-derived hydroimidazolone 1 (MG-H1)”], argpyrimidine, pentosidine, and glucosepane. The receptor for advanced glycation end-products (RAGE) is highly expressed in the skin [27] and mediates several cell-signaling pathways involved in inflammation, fibrosis, melanin synthesis, etc. [28,29]. AGEs stimulate the production of reactive oxygen species (ROS) via NAD(P)H oxidase- or mitochondrion-dependent mechanisms, worsening diabetes and diabetic complications [14,30,31,32]. Glycation inhibitors, such as aminoguanidine (AGD), and antioxidants, such as N-acetylcysteine and glutathione, have been shown to attenuate the toxic effects of AGEs [33,34,35]. Different types of breakers of the preformed AGEs have been studied as a therapeutic approach [36,37,38,39].
There are previous review papers that provide an overview of the molecular mechanisms, pathogenesis, and inhibition strategies of glycation reactions [15] and a comprehensive discussion of the therapeutic potential of various natural compounds that inhibit the formation of AGEs [40]. There are also review papers that focus on the skin, examining the formation and effects of AGEs in the skin, methods for measuring skin AGE levels, and strategies to reduce skin glycation stress [19,41]. Despite the existence of such excellent review papers, there is a lack of a comprehensive review of the experimental and clinical evidence supporting or opposing the therapeutic potential of various interventions on glycation-induced skin aging.
The goal of this review is to understand the significance of glycation-induced skin aging and to explore treatment strategies for the mitigation of glycation-induced skin aging. We comprehensively examine the experimental and clinical studies on the relationship between glycation and skin aging and the various interventions with synthetic and natural agents. This review limits its scope to skin aging induced by glycation, excluding other specific skin diseases. It covers studies at various levels, namely, in vitro studies undertaken using proteins, cells, and reconstructed skin models; ex vivo studies using live skin explants; in vivo studies using animals; and clinical studies involving human subjects. We hope that this comprehensive review will help recognize the significance of skin aging induced by AGEs and develop treatment strategies against glycation-induced skin aging.

2. Methods

We searched the PubMed (https://pubmed.ncbi.nlm.nih.gov/, accessed on 1 March 2025), Web of Science (https://www.webofscience.com/, accessed on 1 March 2025), and Google Scholar (https://scholar.google.com/, accessed on 1 March 2025) databases for experimental and clinical studies on the topic of this narrative review using various keywords, such as ‘advanced glycation end-products’, ‘skin aging’, ‘antioxidants’, ‘aminoguanidine’, ‘in vitro’, ‘ex vivo’, ‘in vivo’, ‘animal’, ‘mice’, ‘rats’, ‘chicks’, ‘clinical’, ‘synthetic’, and ‘natural’, using Boolean search commands, such as ‘AND’ and ‘OR’. The selected articles were cited and discussed in the appropriate chapter(s) or section(s) according to the level of studies, such as in vitro, ex vivo, in vivo (animal), and clinical studies.

3. Significance of Glycation-Induced Skin Aging

3.1. Experimental Evidence

As summarized in Table 1, increases in AGE levels in blood, skin, and other tissues due to diabetes, aging, and high-carbohydrate diets have been observed in various animal models. In addition, changes in skin appearance and function have been observed as skin AGE levels increase.
Table 1. Animal studies on the detection of advanced glycation end-products (AGEs) in the skin and observation of glycation-induced skin aging.
In rats and mice with diabetes induced by the injection of streptozotocin, the levels of AGEs in various tissues, such as blood, skin, liver, and ears, and the glycation of proteins, such as collagen and histone, increased [42,44,46,48,52]. In diabetic animals, the skin permeability and microbial barrier were weakened [46], and inflammation around the wound was worsened [52]. Protein glycation and carbamylation were responsive to diabetes and chronic kidney diseases, respectively, and there was a mutual competition between these two different types of protein modifications [51].
In several animal models, AGE levels in various tissues, such as skin, brain, and aorta, and the glycation of proteins, such as collagen, tended to increase with age [24,25,47,50,53]. This trend differed between breeders and non-breeders in mole-rats: breeders had higher AGE levels but longer lifespans [47]. Between mouse strains, those with higher glycemic levels had higher AGE levels, higher transepidermal water loss (TEWL) rates, stronger inflammatory reactions, lower skin moisture content, and lower collagen content than the other strains, and these differences expanded with age [53]. In lamin B receptor-deficient icJ/icJ mice showing symptoms of premature aging (progeria), AGE levels in the heart and liver were higher than in the control animals, although the differences in skin tissue were not evident [49].
In animal models, high-sugar diets increased AGE levels in blood and skin, increased collagen glycation, decreased collagen solubility, and increased urinary lipid peroxidation product levels [43]. They also increased the expression levels of collagen type I, fibronectin 1, laminin-5, and tenascin C among extracellular matrix proteins and receptors, along with AGE levels in the skin and darkened skin color [54]. On the other hand, they increased sebum secretion and decreased TEWL associated with enhanced fatty acid synthesis [54]. Feeding a high-AGE diet increased the AGE levels in the skin and collagen in diabetic db/db(+/+) mice and delayed skin wound healing [44]. The subcutaneous injection of glycated collagen caused apoptosis of fibroblasts [45].

3.2. Clinical Evidence

As summarized in Table 2, several clinical studies have shown that AGE levels in the blood or skin of human subjects increase due to diabetes, aging, UV irradiation, smoking, etc., and are correlated with skin color and function and the incidence and severity of other diseases or complications.
Table 2. Clinical studies on the detection of AGEs in the skin and observation of glycation-mediated skin aging.
In clinical trials, HbA1c, one of the glycated forms of Hb, is usually analyzed in human blood samples, and the fingertip skin autofluorescence is often measured as an indicator of AGEs in the skin. In diabetic patients, both blood HbA1c levels and skin autofluorescence tended to increase [55,63] and showed a mutual correlation [59], but there were exceptions [48]. Considering the relatively short lifespan of erythrocytes, AGE levels in the skin may reflect a longer-term accumulation of glycation products than those of Hb [66,67]. In addition, the actual levels of AGEs measured in blood or skin were correlated with the incidence or severity of cognitive impairment, glaucoma, and other diseases, regardless of whether the patient was diagnosed with diabetes [48,62,64].
The skin AGE level increased with age, and it showed a correlation with changes in skin color and muscle strength [57,58]. Skin AGE levels increased due to exposure to UV rays, and oxidative damage to DNA and lipid peroxidation also occurred [60,65]. In diabetic patients, persistent hyperglycemia decreased skin moisture and sebum, but TEWL was reduced in the high HbA1c group, so the effects of AGEs on skin physiology and function may not be straightforward [56].
The AGE level increased while galectin-3 expression was reduced at the edge of the skin wound bed in both diabetic and non-diabetic patients, supporting that galectin-3 may function as a receptor for AGEs involved in AGE clearance, and its absence leads to the accumulation of AGEs [61,68].

4. Interventions for Glycation-Induced Skin Aging

4.1. In Vitro Cell-Free Studies

Table 3 summarizes the selected in vitro studies on the glycation of protein substrates and the effects of potential glycation inhibitors of synthetic and natural origins.
Table 3. In vitro studies on the glycation of protein substrates and their inhibition by various materials.
To induce glycation in vitro, a protein substrate and a glycating agent are reacted in an aqueous medium. Albumin, the major protein of blood, and collagen and elastin, the major proteins of the dermis, are frequently used as protein substrates, which provide useful experimental models for glycation reactions in blood and skin, respectively. Glycation agents used include reducing sugars, such as glucose, fructose, and ribose; aldehydes, such as glycolaldehyde and glyceraldehyde; dialdehydes, such as glyoxal and methylglyoxal; and diketones, such as dehydroascorbic acid. The pH of the medium is usually maintained at 7.4 and the temperature at 37 °C to match the biological conditions, but the pH and temperature may be adjusted to accelerate the reaction rate. The total reaction time is adjusted according to the reactivity of the reactants, from several days to several weeks. In the case of a relatively long reaction time, it is common to add a preservative such as NaN3 to prevent changes caused by microorganisms. To quantify AGEs produced through in vitro glycation reactions, fluorescence is usually measured (fluorimetry) [71], although absorbance is often measured (colorimetry) after the nitroblue tetrazolium (NBT) reaction or elastase digestion. In addition, enzyme-linked immunosorbent assays (ELISAs) or dot blots using antibodies immunoreactive to general AGEs or a specific type of AGEs (e.g., CML) are also performed. The increase in protein size resulting from the glycation reaction is confirmed by a decrease in protein mobility in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE).
In vitro, the glycation reaction is performed to produce protein-AGE adducts (52, 35) or to discover and evaluate inhibitors of the glycation reaction (Table 2). In studies for the latter purpose, AGD or alagebrium (ALT-711) is often used as a positive control. These studies reported that various materials, such as gold nanoparticles [73]; mycosporine-like amino acids [82,87]; N-acetylhydroxyproline [95]; carnosine [80]; phenolic compounds, such as silibinin [76], rosmarinic acid [80], quercetin [81], gallic acid [86], methyl gallate [89], apigenin, chlorogenic acid [90], vanillic acid [92], and flavolignans [83]; alkaloids [85]; polysaccharides [88]; and extracts derived from Manilkara and Argania [75], Silybum marianum flower [76], Akebia quinata fruit [77], Cecropia pachystachya [81], back cumin (Nigella sativa) seed [84], hazelnut (Corylus avellana) skin [86], Cirsium japonicum flower [90], cranberry [93], and chlorella (Parachlorella beijerinckii) [91] significantly inhibited protein glycation reactions. These materials are thought to function as glycation inhibitors that competitively participate in glycation reactions or as antioxidants that inhibit a series of oxidative reactions involved in the production of AGEs.

4.2. In Vitro Studies Using Cultured Cells and Reconstructed Skin Models

Cultured cell models are used to study the pathological responses induced by glycation stress (Table 4). Given their relevance to skin aging, dermal fibroblasts are mainly used, although epidermal keratinocytes and other cell types are also occasionally used [52,97]. Cells are grown into a monolayer on the bottom of a culture plate or a 3-dimensional structure in a collagen gel (for a reconstructed dermis or skin model). Cells are treated with AGES, protein-AGE adducts, or different glycation inducers, such as glyoxal, methylglyoxal, H2O2, etc. These treatments are sometimes combined with UV irradiation.
Table 4. Effects of glycation stress and various interventions on the pathological responses of cells in vitro. Upward (↑) and downward (↓) arrows indicate increases and decreases, respectively.
When cells were exposed to AGEs, protein-AGE adducts, or conditions that increase AGEs (e.g., several glycating agents, t-butylhydroperoxide, H2O2, or UV radiation), cell senescence or death (apoptosis) increased [50,77,109,111]. ROS production increased [77,79], and antioxidant enzymes decreased [111], leading to increased oxidative stress and endoplasmic reticulum stress [50]. RAGE expression increased [79,110], and various cell signaling pathways were activated, resulting in the increased expression of inflammatory cytokines [79,109,111]. Gene expression of matrix metalloproteinases (MMPs) increased, whereas collagen gene expression decreased, resulting in the lowered collagen level [79,90,105,109,111]. These changes were further amplified by the combination of glycating agents and ultraviolet irradiation [96].
The glycation-induced changes in human dermal fibroblasts (HDFs) were reversed by various interventions, including AGD [109]; N-acetylcysteine [50]; carnosine [103,107]; supramolecular carnosine [110]; polyphenolic compounds, such as plantamajoside [79], resveratrol, oxyresveratrol, piceatannol [107], plant extracts derived from Akebia quinata fruit [77], and unripe Carica papaya fruit [109]; hydrolyzed fish collagen [104]; and the K formulation containing hyaluronan and collagen peptide [111]. In HaCaT keratinocytes, sunflower sprout extract inhibited AGE formation induced by UVA irradiation [106], and plantamajoside attenuated ROS production and the inflammatory response induced by bovine serum albumin (BSA)-AGE adducts and UVB irradiation [79]. Pholiota nameko polysaccharides and Djulis (Chenopodium formosanum) extract attenuated ROS production and enhanced the viability of Hs68 cells treated with methylglyoxal or CML [88,105]. Vanillic acid enhanced the viability of RAW264.7 cells exposed to methylglyoxal [92]. Hazelnut (Corylus avellana) skin extract and carnosine improved the vitality and phagocytic function of macrophages derived from THP-1 cells in removing senescent cells [94,103].
The antiglycation effects of Jasminum sambac cell extract were observed in an experimental model in which cultured cells were fixed with formalin and then treated with glyoxal to explore the production of AGEs [108]. Chemical changes due to glycation can be studied using dead dermis, which is prepared by killing the cells of the separated skin and removing the epidermis. UV irradiation caused the production of ROS and an increase in AGEs in the dead dermis, and these changes were alleviated by AGD and Argania extract [75]. Glyoxal treatment of mouse skin explants without cultivation caused the yellowing of skin color and increased TEWL, suggesting that glycation causes aesthetic and functional changes in the skin [97].
In a reconstructed dermis model in which HDFs were embedded in a three-dimensional collagen gel, the collagen gel contracted as the cells grew, whereas the change was inhibited in the glyoxal-treated collagen gel [91]. Chlorella (Parachlorella beijerinckii) extract, AGD, and N-acetylhydroxyproline inhibited the production of AGEs and recovered the cell-mediated collagen contraction [91,95].
The effects of collagen glycation have been studied in a reconstructed skin model with a stratified structure in which dermal keratinocytes are grown on top of a dermal-like structure after HDFs are grown in a collagen matrix with or without glycation [74,78,98,112]. Ribose-induced glycation of collagen inhibited the contraction of the collagen lattice, increasing the epidermal thickness and decreasing the dermal thickness of a reconstructed skin model [85,112]. Ribose increased CML levels and extended the suprabasal integrin β1 expression, whereas most of these changes were attenuated by AGD or blueberry extract [71]. In the skin model (MimeskinTM, BASF BC, Lyon, France) reconstructed with ribose-treated collagen, the diameters of collagen fibers were reduced, and cell growth and layer formation were inhibited, but these changes were alleviated by AGD and Davilla extract with anti-glycation effects [75]. AGD or several alkaloids from Ocotea Paranapiacabensis inhibited the thinning of the dermal layer in skin models reconstructed using different glycated collagens [78,85].
In an endothelialized and innervated reconstructed skin model prepared from collagen-chitosan sponge seeded with HDFs, human umbilical vein endothelial cells (HUVECs), sensory neurons from the dorsal root ganglia of mouse embryos, and human epidermal keratinocytes, glyoxal increased CML and decreased the number of capillaries and the expression of angiogenesis markers, such as platelet endothelial cell adhesion molecule (PECAM) 1, loricrin, filaggrin, and Krüppel-like factor (KLF) 4, and these changes were attenuated by AGD but not alagebrium (ALT-711) [101].
In a full-thickness skin model (EpiDermFT, MatTek Life Sciences, Ashland, MA, USA), carnosine, resveratrol, oxyresveratrol, and piceatannol attenuated the cellular and structural changes induced by glycation stress [107].

4.3. Ex Vivo Studies

Human skin explants provide an ex vivo model that allows observation of the histological changes due to glycation stress imposed during the subsequent cultivation (Table 5).
Table 5. Effects of glycation and various interventions on the pathological responses of skin explants ex vivo. Upward (↑) and downward (↓) arrows indicate increases and decreases, respectively.
Methylglyoxal increased the expression of CML during culture period, while decreasing the expression of fibrillin-1 protein [76,77,108], a component of microfibrils present in oxytalan fibers at the dermo-epidermal junction [116]. These changes were alleviated by AGD, carnosine, methyl gallate, and extracts of Silybum marianum flowers, Akebia quinata fruits, Jasminum sambac cells, and Dunaliella salina [76,77,89,108,113,114]. In skin specimens, glucose or glycolaldehyde treatment increased autofluorescence, which was reduced by incubation with N-acetylhydroxyproline [95] or deglycating enzymes, such as fructosamine 3-kinase and fructosyl-amino acid oxidase [115]. Fructosamine 3-kinase further improved the elasticity of hypertrophic scar tissue ex vivo [115].

4.4. In Vivo Animal Studies

Table 6 summarizes selected in vivo studies that explored the effects of various interventions on AGE accumulation and pathological changes induced by aging, diabetes, high-dose sugar administration, UV irradiation, etc.
Table 6. Effects of glycation and various interventions on the pathological responses of the skin in experimental animals in vivo. Upward (↑) and downward (↓) arrows indicate increases and decreases, respectively.
In rats with streptozotocin-induced diabetes, AGD, rutin, and vanillic acid reduced the AGE levels in the skin [92,117]. Streptozotocin-induced diabetes in hairless mice increased skin AGE levels and wrinkles and decreased skin hydration and elasticity; these changes were attenuated by an AGE blocker containing goji berry, fig, and Korean mint extracts [135]. Red blood cell-immunoglobulin (Ig) G crosslinking and tail tendon collagen crosslinking increased in Lewis rats with streptozotocin-induced diabetes, whereas the oral administration of ALT-711, an AGE breaker, reduced these changes [36]. Topical lotion containing ALT-711 improved skin elasticity and hydration in Fischer 344 rats [36]. On the other hand, AGE-breakers, such as N-phenacylthiazolium and N-phenylacy-4,5-dimethylthiazolium halides, or pyridoxamine had no effects on the crosslinking of skin collagen and acid-solubility of tail collagen affected by streptozotocin-induced diabetes in rats [37].
In rats, mice, chicks, and monkeys, dietary restriction reduced the increase in the levels of AGEs, such as furosine, CML, and pentosidine, in the skin or skin collagen induced by chronological aging [26,119,120,122,128]. In Emory mice prone to age-related cataracts, dietary restriction reduced cataract grade and dermatological lesions and shortened the tail tendon breakdown time [118]. AGD, vitamins C and E, and green tea extracts had little or weak effects on skin AGE levels and tail tendon breakdown time in aging rats [126,127]. The increments in the AGE level due to aging and the effect of dietary restriction were smaller in the aorta and blood than in the skin [120]. The type of carbohydrates (cornstarch, sucrose, glucose, fructose, or a combination of glucose and fructose) in the diet had little effect on serum glycemic stress and AGE levels, whereas overall calorie restriction had significant effects in aging Fischer 344 rats [124].
In mice orally administered high-dose glucose, blood glucose levels were unchanged, but AGE levels in the subcutaneous tissue were elevated, microvessel diameters were reduced, and vascular lesions were increased; these changes were alleviated by drinking water containing AGD [121]. In mice administered high concentrations of galactose, blood AGE levels were elevated, and cognitive impairment was aggravated, which was alleviated by AGD [123]. In addition, the increase in skin AGE levels by galactose was accompanied by increased oxidative stress, decreased collagen expression and dermal thickness, and inhibition of microvascular development, and these skin aging-related changes were alleviated by adiposepderived stem cell injection [129,130]. Lactobacillus fermentum CQPC04-fermented soy milk and dapagliflozin (a medication used to treat type 2 diabetes) exhibited antioxidant, anti-inflammatory, and antiglycation effects in the skin and enhanced dermal collagen or hyaluronan in mice administered high galactose [132,136].
In UV-irradiated mice, the skin level of AGEs was reduced by Schizonepeta tenuifolia extract (containing rosmarinic acid) and idebenone-loaded nanoparticles [133,134]. In addition, Schizonepeta tenuifolia extract improved skin wrinkles, hydration, and the dermal levels of collagen and hyaluronan, and idebenone-loaded nanoparticles showed skin-whitening and antioxidant effects [133,134]. Mycosporine-like amino acid-containing emulsions enhanced the expression levels of antioxidant enzymes, such as SOD and CAT, in the ear skin irradiated with UV, although it had no significant effects on the skin AGE levels in DBA/2CrSlc mice [87].
In chicks, allopurinol injections reduced uric acid, which has antioxidant activity, causing oxidative stress, while hemin reduced uric acid, but both increased pentosidine in the skin and were relieved by dietary restriction [125].

4.5. Clinical Studies

Dietary and topical agents with antioxidant and antiglycation activities have been tested in clinical studies to address their effects on skin aging (Table 7).
Table 7. Clinical studies on the effects of various interventions on the glycation levels and skin aging parameters in human subjects.
The clinical effects of dietary supplements containing synthetic or natural substances with antioxidant and antiglycation activities on human skin aging parameters vary widely. In diabetic patients, dietary supplementation with vitamins E and C with antioxidant activity had no significant effect on skin AGE levels [137]. The oral intake of a capsule containing vitamins, amino acids, and carnosine with antiglycation activity improved skin surface parameters compared to the placebo control group [140]. An equol supplement containing S-equol and several other natural phenolic compounds did not improve skin aging parameters nor AGE levels, although it improved climactic symptoms in post-menopausal women [141]. Fish-derived collagen peptides reduced skin AGE levels and insulin resistance indices compared to the placebo control group [142]. Twelve weeks of intake of capsules containing rosemary extract reduced the levels of 4-hydroxynonenal-protein adducts and AGEs in the skin, supporting its antioxidant and antiglycation activity [144]. A green tea oral supplement had no significant effects on skin aging parameters even when its intake was combined with the topical application of a cream containing green tea extract enriched with (−)-epigallocatechin gallate and other phenolic compounds [138].
Several topical formulations have shown significant efficacy in improving human skin aging parameters. A topical formulation containing C-xylose and glycation-inhibitory blueberry extract mitigated skin aging symptoms, although the skin AGE level was not reduced significantly [139]. A cream containing glycation-inhibitory Argania plant extract, α-tocopheryl acetate, rutin, and ferulic acid lowered free radical production as measured by UVA-induced chemiluminescence [75]. An ampule containing hydrolyzed fish collagen (25% tripeptide) reduced skin AGE levels and improved periorbital and glabellar skin wrinkles, skin surface elasticity, and dermal density [104]. A gel cream containing Dunaliella salina extract rich in colorless carotenoids (phytoene and phytofluene) reduced skin AGE levels and inflammatory skin reactivity to histamine stimulation while improving skin aging parameters, including periocular wrinkles and red spots [114]. A lotion containing Cirsium japonicum flower extract also improved skin aging parameters [90].
A serum containing sunflower sprout extract exhibited antiglycation activity in cells and anti-inflammatory effects in an ex vivo model and improved facial skin conditions, such as radiance, smoothness, fine lines of crow’s feet, and overall eye appearance, in a human study [106]. An essence containing supramolecular carnosine with antiglycation activity reduced brown spots and the melanin index in the face and brightened the skin tone [110].

5. Discussion

5.1. Skin Anti-Aging Strategies Targeting Glycation

Glycation stress and oxidative stress are interconnected conditions with overlapping mechanisms of action, yet they also exhibit distinct effects. Oxidative stress due to an increase in prooxidants (e.g., ROS) and a decrease in antioxidants and antioxidant enzymes causes oxidative damage to proteins, lipids, and nucleic acids [145]. In contrast, glycation stress causes chemical modifications of proteins, lipids, and nucleic acids by sugars (glucose, fructose, and galactose), their metabolites, or their breakdown products [15]. On the protein side, protein carbonyls are formed via oxidation [24], and protein-AGE adducts are formed via glycation or glycoxidation [126], which are distinct from another type of protein modification, carbamylation [51]. Because of the mechanistic redundancy of glycation stress versus oxidative stress, in principle, many known antioxidants may be used in alleviating glycation stress and the associated skin aging [146,147,148]. Currently, targeting glycation with competitive glycation inhibitors or antioxidants is considered to be a practical and feasible skin anti-aging strategy [149,150].
It is necessary to recognize that glycation stress may be crucial, especially in patients with diabetes, older people, and people who mainly eat carbohydrate-based meals. These people are advised to reduce high-carbohydrate diets, high-AGE diets, and UV exposure or to increase physical activity in addition to medical management [151,152,153]. It is clear that eliminating the cause of glycation stress through disease management and lifestyle modification is the primary option for glycation-induced skin aging. A secondary option may be the appropriate use of dietary supplements or topical formulations containing anti-glycation agents or antioxidants. Multiple levels of evidence from in vitro, ex vivo, in vivo, and clinical studies over the past 30 years support that glycation-induced skin aging can be mitigated by certain synthetic and natural agents with antiglycation and/or antioxidant activity (Figure 1).
Figure 1. Causative factors for glycation stress-associated skin aging and interventions using synthetic and natural agents with antiglycation or antioxidant activity. Sharp arrows (↓) indicate stimulation. Plus and minus signs in parentheses indicate increases and decreases, respectively. Interventions are indicated with a blue background.
In vitro experiments showed that several synthetic compounds, natural products, and plant extracts had anti-glycation activity (Table 3). In experiments using cultured cells, glycation stress increased ROS production, the gene expression of inflammatory cytokines, and cell death or senescence, which were suppressed by several synthetic and natural agents (Table 4). In reconstructed skin models prepared using glycated collagen, cell-mediated collagen contraction was impaired, and dermal thickness was reduced, whereas these changes were partially restored to normal by several synthetic and natural agents (Table 4). In ex vivo experiments using human skin explants, several natural and synthetic agents restored the expression of fibrillin-1 at the dermo-epidermal junction, reduced by glycation stress (Table 5).
In animal models, glycation stress due to diabetes, aging, high-carbohydrate diets, UV radiation, and oxidative stress increased AGE levels in the blood or skin and oxidative damage to blood or skin, decreased dermal thickness and the dermal contents of collagen and hyaluronan, and prolonged the tail tendon breakdown time (Table 1 and Table 6). Dietary restriction, oral and topical administration of synthetic or natural agents, and other interventions reversed these changes and alleviated glycation-induced dermal lesions or skin aging symptoms (Table 6). In clinical trials, several dietary supplements or topical formulations containing vitamins, amino acids, peptides, plant extracts, or phytochemicals reduced skin autofluorescence (or the AGE level), which was increased by diabetes, aging, high-carbohydrate diets, or UV irradiation (Table 2 and Table 7). They also improved skin aging parameters, such as skin tone, wrinkles, elasticity, and hydration, in human subjects (Table 7).

5.2. Synthetic and Natural Agents Targeting Glycation

There are several synthetic compounds that inhibit the formation of AGEs or decompose preformed AGEs, with studies supporting or questioning their therapeutic potential and safety. AGD has been used as a positive control substance in many studies and exhibits various biological effects but is not clinically used due to concerns about insufficient safety/efficacy balance or off-target effects [126,154]. Alagebrium (ALT-711), the first AGE-breaker, and later version compounds, such as N-phenacylthiazolium and N-phenylacy-4,5-dimethylthiazolium halides, also had similar shortcomings, limiting their applications [37,155].
Various other synthetic compounds, such as amino acids or derivatives (e.g., histidine, methionine, N-acetylcysteine, N-acetylhydroxyproline), peptides (e.g., carnosine, supramolecular carnosine), vitamins or their derivatives [e.g., vitamin B5 (pantothenic acid), pantethine, vitamin B6 (pyridoxine, pyridoxamine), vitamin C (ascorbic acid), vitamin E (α-tocopherol), α-tocopheryl acetate], and drugs (e.g., dapagliflozin), have been studied for application to glycation-induced skin aging, but their efficacy has not yet been well proven [137].
Among natural agents, phenolic compounds distributed in plants (e.g., rutin, quercetin, apigenin, rosmarinic acid, gallic acid, methyl gallate, vanillic acid, chlorogenic acid, ferulic acid, S-equol, resveratrol, oxyresveratrol, piceatannol, silibinin, plantamajoside) have been studied extensively for their antiglycation and skin anti-aging effects. Mycosporine-like amino acids derived from algae (e.g., Agarophyton chilense, Pyropia plicata, Champia novaezelandiae, Bostrychia scorpioides) or cyanobacteria (e.g., Aphanothece halophytica), flavonolignans derived from plants (e.g., Silybum marianum), alkaloids derived from plants (e.g., Ocotea paranapiacabensis), polysaccharides derived from mushrooms (e.g., Pholiota nameko) or bacteria (e.g., Klebsiella pneumonia, Klebsiella planticola), fish (e.g., Pangasius hypophthalmus)-derived collagen hydrolysates, and Lactobacillus fermentum-fermented soy milk have been studied for their applications in similar contexts.
Extracts from various plants have been studied with respect to glycation-induced skin aging, including Akebia quinata (Chocolate vine) fruit, Argania spinosa (Argan), Agastache rugose (Korean mint), Camellia sinensis (Green tea), Carica papaya (Papaya) fruit, Cecropia pachystachya (Ambay pumpwood) leaf, Chenopodium formosanum (Djulis), Cirsium japonicum (Japanese thistle) flower, Corylus avellana skin (Hazelnut), Davilla rugosa (Davilla), Ficus carica (Fig), Helianthus annuus (Sunflower) sprout, Jasminum sambac (Arabian jasmine) cell, Lycium chinense (Goji berry), Manilkara multinervis (African Manilkara), Nigella sativa (Black cumin) seed, Rosmarinus officinalis (Rosemary) leaf, Schizonepeta tenuifolia (Japanese catnip), Silybum marianum (Milk thistle) flower, and Vaccinium angustifolium (Blueberry). Additionally, microalgae, such as Dunaliella salina (Dunaliella) and Parachlorella beijerinckii (Chlorella), have also been studied for their antiglycation and anti-aging properties.
Although the therapeutic potential of many natural products on skin glycation and aging has been supported by previous studies, there have been exceptional observations as well [138,139]. In addition, since the experimental data of each natural product have been provided in individual studies, it is difficult to make a relative comparison between their efficacies. Furthermore, clinical trials to verify their skin anti-aging efficacy are mostly lacking.

5.3. Mechanistic Insights and Therapeutic Applications

Skin aging due to glycation stress can occur in both the epidermis and dermis [19,41]. Glycation stress increases the level of fluorescing yellowish AGEs in the epidermis and the cross-linking between the dermal matrix components, such as collagen, elastin, and hyaluronan. As a result, the skin color turns more yellowish and darker, the skin surface becomes rougher, and wrinkles increase and deepen. In addition, the dermis layer becomes thinner and harder, and elasticity decreases. Glycation stress can damage the skin barrier and increase TEWL rates [53,97,156], with some exceptional cases [54,56]. Therefore, skin aging due to glycation stress is recognizable by the aesthetic, physical, and functional changes of the skin.
If we divide the process of glycation causing skin aging into two parts, the first step is the production of new AGEs through chemical reactions, and the second step is the occurrence of biological effects induced by existing AGEs (Figure 2). In the first step, when a glycation agent reacts with a substrate, the reaction is affected by oxygen, catalytic metals, UV rays, etc. [157,158]. In the second step, AGEs cause oxidative stress and stimulate RAGE-mediated cell signaling pathways, resulting in the upregulation of inflammatory cytokines and the downregulation of collagen. Overall, glycation stress leads to cell death or senescence, inflammation, and skin aging. Therefore, various treatment strategies against glycation-induced skin aging can be envisioned, such as strategy 1 to prevent the production of AGEs, strategy 2 to remove the preformed AGEs, strategy 3 to control RAGE-mediated cell signaling pathways leading to the upregulation of inflammatory gene expression and downregulation of collagen gene expression, strategy 4 to assist or enhance cellular antioxidant defense, and strategy 5 to regenerate cells and matrix environments.
Figure 2. Potential therapeutic targets and treatment strategies against glycation-induced skin aging. Sharp (↓) and blunt (⊥) arrows indicate stimulation and suppression, respectively.
For the successful clinical application of these strategies, the discovery and development of synthetic compounds, natural products, or other preparations suitable for each individual strategy must be a prerequisite. It is recommended that dietary supplements or topical formulations applied for human anti-aging purposes include at least one active component optimized for each strategy. Furthermore, it is also advantageous to apply multiple strategies in combination. Additionally, if possible, it may also be advantageous to apply oral supplements and topical formulations simultaneously. In any case, it is essential to check safety in advance. In clinical trials, the analysis of skin AGE levels along with various skin parameters should be conducted to verify whether the antiglycation intervention was performed properly. The level of AGEs in the skin can be conveniently quantified by measuring skin autofluorescence [66,143,159,160,161]. This method has the advantage of being noninvasive and minimally affected by the interference of other skin pigments such as melanin [162,163].

5.4. Future Tasks and Prospects

Developing technologies to implement the five therapeutic strategies to alleviate glycation-induced skin aging will be an important and necessary future task. Various glycation inhibitors for strategy 1 have been discovered in separate studies, making it difficult to know which one is better. An integrated study comparing their efficacy and safety with a set of criteria in the same experimental model is needed. For strategy 2, due to the questionable safety and efficacy of existing synthetic AGE-breakers [101,155], future studies are needed to develop alternative innovative therapies involving deglycating enzymes [115,164], oxidized protein hydrolases [165,166], or physical disruption of AGEs [167,168,169]. Additionally, we anticipate the development of drugs that promote the removal of AGEs by cell-mediated phagocytosis [103]. For strategy 3, although various synthetic and natural modulators are known to modulate the RAGE-mediated cell signaling pathways [170,171], many tasks remain to be implemented, including the assessment of safety, efficacy, pharmacodynamics, and pharmacokinetics in vivo. For strategy 4, various types of synthetic or natural antioxidants [172] and modulators of nuclear factor erythroid 2-related factor (NRF) 2 may be used to assist or enhance cellular antioxidant defense systems [173]. Future studies are needed to verify their efficacy in vivo before clinical application. Strategy 5 is the most challenging, but various attempts have already been made to help the regeneration of cells and matrix environments by injecting cells [129,130], matrix components [174], or skin boosters [175]. Developing advanced nanomaterials for the control of glycation stress is also an important future task for implementing these treatment strategies [73,134,176].
It is predicted that future skin anti-aging treatments will be led by targeted and tailored therapies that are supposed to vary by the specific cause of skin aging and the individual health condition of the subject. Such glycation-targeting treatments will be particularly important for patients who are more affected by glycation stress. In other words, the treatments will have a significant impact on skin aging only in subjects with a high skin AGE level. Therefore, for the best outcomes, the selection of the right treatment subjects is as important as the selection of the right treatment options. It is also important to measure skin AGE levels before and after treatments to check the quantitative changes due to the applied intervention. The data will be essential to claim the skin-anti-aging effects of a certain intervention targeting AGEs. The glycation-targeting technologies would have expanding applications in various skin inflammatory conditions (e.g., psoriasis, atopic dermatitis), metabolic complications (e.g., diabetic dermopathy, impaired wound healing), and age-related pathologies (e.g., elastosis, dyschromia).

6. Conclusions

Many pieces of experimental and clinical evidence support the significance of glycation-induced skin aging. Several synthetic and natural agents with antiglycation or antioxidant activity reduce skin AGE levels, oxidative damage, and skin aging symptoms caused by chronological aging, diabetes, high-carbohydrate diets, UV radiation, or oxidative stress. Therefore, it is suggested that glycation-targeting dietary supplements or topical formulations containing these agents may provide therapeutic options to mitigate glycation-induced skin aging.

Author Contributions

Conceptualization, Y.C.B.; investigation, J.Y.C.; writing—original draft preparation, J.Y.C. and Y.C.B.; writing—review and editing, N.G.H. and W.J.L.; supervision, Y.C.B. and W.J.L.; project administration, N.G.H.; funding acquisition, W.J.L., Y.C.B. and N.G.H. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2024-00437643).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The original contributions presented in this study are included in the article, and further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AGDaminoguanidine
AGEadvanced glycation end-product
AKTprotein kinase B; AKT
BSAbovine serum albumin
CATcatalase
CCRC-C chemokine receptor
CELNε-(carboxyethyl)lysine
CKcytokeratin
CMANω-(carboxymethyl)arginine
CMLNε-(carboxymethyl)lysine
COLcollagen
COXcyclooxygenase
DTPAdiethylenetriaminepentaacetic acid
ELISAenzyme-linked immunosorbent assay
ERKextracellular signal-regulated kinase
GPXglutathione peroxidase
Hbhemoglobin
HDFhuman dermal fibroblast
HEKhuman epidermal keratinocyte
HUVEChuman umbilical vein endothelial cell
Igimmunoglobulin
IκBinhibitor of NF-κB
ILinterleukin
ITAoindividual topology angle
JNKc-Jun N-terminal kinase
KLFkrüppel-like factor
LTleukotriene
MAPKmitogen-activated protein kinase
MCPmonocyte chemoattractant protein
MDAmalondialdehyde
MG-H1methylglyoxal-derived hydroimidazolone 1; Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine
MMPmatrix metalloproteinase
MPOmyeloperoxidase
NBTnitroblue tetrazolium
NFnuclear factor
NRFnuclear factor erythroid 2-related factor
PBSphosphate-buffered saline
PECAMplatelet endothelial cell adhesion molecule
PGprostaglandin
PMSFphenylmethylsulfonyl fluoride
RAGEreceptor for advanced glycation end-products
ROSreactive oxygen species
RTroom temperature
SA-β-galsenescence-associated β-galactosidase
SDS-PAGEsodium dodecyl sulfate-polyacrylamide gel electrophoresis
SIRTNAD-dependent deacetylase sirtuin
SODsuperoxide dismutase
TEWLtransepidermal water loss
TNFtumor necrosis factor
UVultraviolet
VEGFvascular endothelial growth factor

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Role of Reactive Oxygen Species in Collagen-Induced Platelet Activation and the Protective Effects of Antioxidants
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