Advanced Glycation End Products, a Potential Link between Psoriasis and Cardiovascular Disease: A Case-control Study
Impact factor: 1.523
Level of evidence: IV
Type of study: case control to investigate if the high level of AGEs have any relation to premature atherosclerosis in psoriasis patients
Sample size: 52 psoriasis patients (ages 21-58) and 20 healthy controls (ages 25-48). Exclusion criteria is as follows: presence of diabetes, chronic renal or liver disease, malignancy, hypertension, or hyperlipidemia, having myocardial infarction, stroke, severe infection, sepsis, sunburn or tanning
Introduction: Chronic psoriatic inflammation indicates increased AGEs which has a prominent impact in pathogenesis of several diseases of every age. AGEs are endogenously formed and mediate reactive oxygen species and nuclear factor-kappa B. This production leads to IL-6 and TNF-α which are important in promoting endothelial dysfunction. This study was designed to identify the relation of increased skin AGEs and premature atherosclerosis in patients with psoriasis.
Important methods: Skin autofluorescence (SAF) analysis was used to determine AGEs. High sensitive C-reactive protein, carotid intima media thickness, physical activity, and dietary patterns were viewed. All measures of AGEs were performed by a single analyst. AGE levels and increased risk of CVD can be affected by exercise therefore physical activity was measured. Participants were placed in one of the following categories: sedentary, ≥30 min of moderate-intensity aerobic exercise ≥5 days/week, ≥25 min of vigorous aerobic exercise ≥3 days/week and moderate-to-high intensity muscle strengthening activity ≥2 days/week.
Statistical tests ran: Fisher’s exact test, two sample t-tests, Mann-Whitney-U-test, Pearson correlation, Spearman correlation, Wilcoxon test significant p- value < 0.05
Results: SAF was increased in psoriasis patients (P=0.057) and median CIMT was increased in psoriasis compared to control (P=0.001). As for treatment, 11 psoriasis patients were given methotrexate and were reevaluated after three months. The median AGEs decreased however was deemed insignificant (p=0.216)
Discussion/Conclusion: SAF and CIMT significantly higher in psoriasis patients indicates a correlation with AGEs and premature atherosclerosis. The increased amount of AGEs produces excessive amounts of oxidative stress and endothelial inflammation which decreases vasodilators such as nitric oxide and decreases the elasticity of the vessels. The treatment plan given, methotrexate alone, does not show significant efficacy in decreasing AGEs but allows for other methods such as dietary AGE reduction to occur. This case control study has shown there is a role of premature atherosclerosis in psoriasis patients and with further research more methods can be developed to control the AGEs levels.
Limitation: unable to detect non fluorescent AGEs, small sample size
Ergun T, Yazici V, Yavuz D, Seckin-Gencosmanoglu D, Ozen G, Salman A, Direskeneli H, Inanc N. Advanced Glycation End Products, a Potential Link between Psoriasis and Cardiovascular Disease: A Case-control Study. Indian J Dermatol. 2019 May-Jun;64(3):201-206. doi: 10.4103/ijd.IJD_396_18. PMID: 31148858; PMCID: PMC6537697.
The effects of advanced glycation end products (AGEs) on dermal wound healing and scar formation: a systematic review
Level of evidence: V
Type of study and any information related to it: This systematic review identified the influence AGEs have on dermal wound healing and scar formation in elderly and diabetic patients. The review further looked into therapeutic mechanisms.
Sample size: N/A
Introduction: The skin serves as a barrier to mechanical, thermal, microbial, and chemo-radial threats. As one of the largest organs of the body, it is extremely vulnerable to internal and external stressors. When injured, the body undergoes an inflammatory response releasing cytokines, platelet-derived growth factor, fibroblast growth factor, and interleukins. This response is diminished and the skin is replaced with collagen. In individuals with risk factors such as diabetes, smoking, malnutrition, or infection, there is a higher risk for impaired wound healing, aging, and scarring. In recent literature, AGE accumulation has shown a negative impact in altering the physiology of the skin.
Important methods: This study used qualitative analysis of 14 articles from Pubmed and Web of Science. Underwent a three-staged selection process with inclusion and exclusion criteria. Articles not containing AGEs, skin and scarring, or dermal wound healing were excluded.
Statistical tests ran: N/A
Results: AGEs led to dysfunctional collagen fibrils which led to decreased elasticity and scar formation with delayed wound closure.
Discussion/Conclusion: There was not enough evidence to concur the role of AGEs in the appearance or function of scar tissue but the scars tend to be more rigid with constant redness. The results do support the pathological role of AGEs in diabetic and elderly patients with aging and wound healing.
Van Putte, L., De Schrijver, S., & Moortgat, P. (2016). The effects of advanced glycation end products (AGEs) on dermal wound healing and scar formation: a systematic review. Scars, burns & healing, 2, 2059513116676828. https://doi.org/10.1177/2059513116676828
Is skin autofluorescence (SAF) representative of dermal advanced glycation endproducts (AGEs) in dark skin? A pilot study
Impact factor: 0.432
Level of evidence: IV
Type of study and any information related to it: Skin autofluorescence (SAF) is a common measure of advanced glycation end products (AGEs). Most studies use SAF to identify dermal AGEs in Caucasians and Asians; however, there is a lack of studies in dark skin subjects. This cross-sectional pilot study aimed to non-invasively identify SAF in dark-skinned subjects and see if it was representative of intrinsic fluorescence and AGE accumulation.
Sample size: 12 subjects with dark skin types (Fitzpatrick IV-VI). Six older subjects with diabetes mellitus (DM) (ages: 53-68 years), type 1 and 2, and six healthy young subjects (ages: 0-29 years).
Exclusion criteria: contraindications such as presence of tattoos and local skin disease on the targeted skin location and chronic kidney disease class 4 or higher. Non-fasting glucose was measured with blood glucose meter as well as cardiovascular risk profile and medical history.
Introduction: Advanced glycation end products (AGEs) are known for their pathogenic role in aging and chronic diseases. Skin autofluorescence (SAF) is used to identify dermal accumulation of AGEs. Most studies focused on Caucasians and Asians and have seen results with several AGEs such as NƐ-(carboxymethyl)lysine [CML] and pentosidine, correlations with increased SAF levels and diabetes, and as a predictor of cardiovascular disease development. Studies have focused on Caucasians and Asians due to the low SAF levels in subjects with dark skin versus light skin. These low SAF levels are not necessarily attributed to lower AGE levels but increased excitation and emission by melanin. SAF is an important tool in identifying skin biopsies but is unknown in localizing AGEs and intrinsic fluorescence in biopsies for dark skin people. This pilot study assesses AGE localization and SAF signaling in dark skinned subjects.
Important methods: AGE reader was used to noninvasively assess SAF. It is calculated by the ratio of emission light (420-560 nm) emitted by fluorescent molecules and reflected excitation light (300-420 nm), multiplied by 100. Two 3-mm punch skin biopsies, SAF measurement, and skin pigmentation were taken on the volar side of the forearm. Skin phototype to identify melanin and erythema index was performed.
Statistical tests ran: SAF measurements were assessed using Mann-Whitney U tests and correlations were assessed using Spearman’s correlations. Statistical significance: p<0.05
Results: The melanin index showed higher skin pigmentation in older subjects but there was no correlation between SAF and melanin index (r = -0.06, p = 0.86) or UV reflectance (r = -0.12, p = 0.72). SAF correlated with intrinsic fluorescence in the dermis 405 nm (r = 0.58, p < 0.05) and 440 nm (r=0.65, p<0.05) but not with 750 nm(r=0.47, p=0.12). Through immunohistochemistry, biopsies revealed high levels of CML surrounding collagen in dermis and blood vessels of older subjects.
Discussion/Conclusion: This study was the first of its kind. The first to take skin biopsies in dark skinned patients to compare non-invasive SAF with AGE levels. There is an association with SAF levels and intrinsic fluorescence but is not a reliable measurement on an individual level in dark-skinned subjects. This study did show results of AGEs in dark skin specifically with skin of older DM subjects.
Limitations would include small sample size. Recognizing the limitations will allow for more improvement with SAF measurement.
Atzeni IM, Boersema J, Pas HH, Diercks GFH, Scheijen JLJM, Schalkwijk CG, Mulder DJ, van der Zee P, Smit AJ. Is skin autofluorescence (SAF) representative of dermal advanced glycation endproducts (AGEs) in dark skin? A pilot study. Heliyon. 2020 Nov 12;6(11):e05364. doi: 10.1016/j.heliyon.2020.e05364. PMID: 33241137; PMCID: PMC7674296.
Expression of advanced glycation end-products on sun-exposed and non-exposed cutaneous sites during the ageing process in humans
Type of study and any information related to it: clinical
Sample size: 32 subjects were subdivided into four groups based on age. Group I (<20 years old), Group II (20-40 years old), group III (40-60 years old), group IV (>60 years old).
Introduction: Aging is related to an intrinsic and extrinsic glycation process. This affects endothelial cells, fibroblasts, and structural proteins (collagen). Specifically for the dermal extracellular matrix, glycation will further affect growth, enzymatic activity, cytokine response, and fibroblast motility. In elderly subjects, AGE accumulation will increase stiffening and decrease elasticity of skin. Extracellular matrix can be directly altered by ultraviolet (UVA), and in presence of AGEs can decrease the cell viability. This study focused on the effects of sun-protected versus sun-exposed regions of skin from different age groups through histological and immunological comparisons.
Important methods: Processing of tissue specimens, MAb against AGE-CML and Immunohistochemistry, Grading of CML immunoreactivity by scoring endothelial cells and fibroblasts separately.
Statistical tests ran: Correlations were assessed by Pearson correlation coefficient and intergroup mean variation was done by ANOVA
Results: AGE-CML expression was significantly different in both fibroblasts and endothelial cells between protected and non-protected samples. The correlation analysis supports AGE-CML percentage being proportional with patient’s age in endothelial cells and fibroblasts in protected and non protected regions.
Discussion/Conclusion: It is known that AGE accumulation is a part of normal aging, but in instances with oxidative stress such as ultraviolet exposure, it is more prevalent. This study determined AGE-CML patterns in skin biopsies and the histological data parallels literature showing structural and functional dermal changes start before the age of 35. AGEs have a huge impact by binding to fibroblast cell membrane receptors and interacting with vimentin filaments which will eventually contribute to the progressive skin aging. A report revealed RAGE expression was increased in sun-exposed skin, but interaction of AGEs and dermal fibroblasts are still ambiguous. This research concluded the glycation process interferes with fibroblasts at the ECM level and the AGEs increase with age but can be amplified with more sun exposure. This can open up new doors for anti-aging therapies, topical and systemic, and clarify the mechanisms of aging.
Crisan, M., Taulescu, M., Crisan, D., Cosgarea, R., Parvu, A., Cãtoi, C., & Drugan, T. (2013). Expression of advanced glycation end-products on sun-exposed and non-exposed cutaneous sites during the ageing process in humans. PloS one, 8(10), e75003. https://doi.org/10.1371/journal.pone.0075003
Nutrition and aging skin: sugar and glycation
Impact factor: 2.458
Type of study and any information related to it: Review
Discussion/Conclusion: Glycation is an important process that has a huge impact on skin. It is the process of cross-linking amino acids in collagen and elastin through sugars such as glucose and fructose to support the dermis. These cross-links can interfere with repairing collagen and elastin making it more difficult to repair. It has been noted that the North American diet is elevated in sugar and more recently discovered that this sugar is protein bound and has a huge role in glycation, better known as advanced glycation end products. Glycation occurs at a young age and can be heavily impacted by diet and ultraviolet exposure. These factors can decrease our defenses against free radicals and increase cross-links. It is extremely difficult to repair cross-links and is why preventative measures are emphasized. Reducing dietary sugar is important but also understanding pre-formed AGEs are present. In relation to a cosmetic procedure, long term results can be achieved more effectively if the diet was not composed of preformed AGEs and dietary sugar. A lot of cutaneous abnormalities are related to increased AGEs. Including dietary advice in practice that not only discusses healthier options but also healthier means of preparing the food can help reduce the levels of inflammation and oxidative stress that are a big contributor to skin diseases and other comorbidities.
Danby FW. Nutrition and aging skin: sugar and glycation. Clin Dermatol. 2010 Jul-Aug;28(4):409-11. doi: 10.1016/j.clindermatol.2010.03.018. PMID: 20620757.
Skin advanced glycation end-products evaluation in infants according to the type of feeding and mother's smoking habits
Type of study and any information related to it: cross-sectional
Sample size: 131 healthy Caucasian infants (aged <4 months). Categorized by breast fed or formula fed.
Important methods: sAF was assessed using AGE Reader device and expressed as arbitrary units (AU). It was measured in three positions on the lateral thigh. Mothers underwent a detailed oral interview to provide information about smoking. (i.e. “how many cigarettes did you smoke? Are you still smoking?”)
Statistical tests ran: Continuous variables were checked by Kolmogorov-Smirnov test, AGE levels of infants born to non-smokers were expressed by mean +- SD, gestational age, birth weight SDS, and infant AGEs were not normally distributed so Mann-Whitney test was used. Spearman’s correlation was used to explore infant AGE and continuous variables.
Results: Skin AGEs were significantly higher in formula-fed subjects than breastfed subjects. Among breastfed infants, the amount of AGEs found in infants from smoking mothers was significantly higher than those who have never smoked. Formula fed infants had similar skin AGEs amounts between infants with mothers who smoked during pregnancy and those who did not.
Discussion/Conclusion: Formula fed infants had higher amounts of skin AGEs which led to the discussion of food-derived AGEs and how infants who consume formula milk may have preconditions of metabolic and cardiovascular diseases. There was a high correlation between maternal and infant circulating AGEs and thus one could hypothesize smoking-derived AGE accumulated in mothers contributed to the effect of placental development disturbing fetal development. The data supported formula fed infants had increased skin AGEs and many rely on formula. Industries should make efforts to produce formulas with lower AGE levels. Skin AGEs in breastfed infants from smoking mothers were just as high as formula-fed but with the mothers who smoked, the increased AGEs during fetal life can affect fetal development. After delivery, smoke-related AGEs can still be transmitted through breast milk.
Federico, G., Gori, M., Randazzo, E., & Vierucci, F. (2016). Skin advanced glycation end-products evaluation in infants according to the type of feeding and mother's smoking habits. SAGE open medicine, 4, 2050312116682126. https://doi.org/10.1177/2050312116682126
Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases
Impact factor: 5.076
Type of study and any information related to it: review
Discussion/Conclusion: Aging is a progressive decline in physiological integrity and an increase in mortality. Since the 1950s, the oxidative stress theory, stating ROS accumulation can lead to cellular damage and alter cell function is the key to aging, has gained acceptance. Oxidative stress induces formation and accumulation of ALEs and AGEs. The two are results of lipid peroxidation and glycoxidation respectively and give rise to highly reactive electrophilic aldehydes which react with free amino groups. This interaction leads to cross-linking and aggregation which further leads to impaired cell function and ultimately cell death thus contributing to aging and age-related chronic diseases.
AGEs in connective tissue specifically covalently cross-link ECM adhesion proteins such as collagen elastin and laminin which will lead to degeneration of skin, cartilage, and ligaments. Age-related diseases are due to alterations in the AGE-RAGE pathway. AGE accumulation induces RPE/photoreceptor cell activation and aids in pathology in the human retina.
AGEs have a role in age-related chronic diseases. Normal aging and neurodegeneration can be determined by AGE measurement in brain tissue and CSF. AGE accumulation indicates excessive protein cross linking, pathological deposits like amyloid fibers, and neuronal cell death. AGEs lead to cellular dysfunction and tissue damage and lead to atherosclerosis and diabetes mellitus. Hyperglycemia can induce oxidative stress and further AGE formation. There has been an increase in age related chronic diseases and has become a major challenge in medicine and public health. More research needs to be conducted in order to explain the metabolic changes occurring with cell signalling with the involvement of ALEs and AGEs.
Moldogazieva, N. T., Mokhosoev, I. M., Mel'nikova, T. I., Porozov, Y. B., & Terentiev, A. A. (2019). Oxidative Stress and Advanced Lipoxidation and Glycation End Products (ALEs and AGEs) in Aging and Age-Related Diseases. Oxidative medicine and cellular longevity, 2019, 3085756. https://doi.org/10.1155/2019/3085756
The association between various smoking behaviors, cotinine biomarkers and skin autofluorescence, a marker for advanced glycation end product acc` 2``11umulation
Impact factor: 2.74
Level of evidence: IV
Type of study and any information related to it: cross sectional: Typically questionnaires are used when examining the risks of tobacco smoking on disease outcome. However, secondhand smoking may be undermined with questionnaires. This study examines active and secondhand smoking through SAF.
Sample size/ Important methods: participants were from the LifeLines Cohort Study and Qatar Metabolomics Study on Diabetes (QMDiab). LifeLines Cohort: assesses 8,905 individuals including 309 individuals with Tyoe II diabetes. QMDiab: biomarkers were saliva, plasma, urine in 364 individuals (188 had type II diabetes). SAF was measured non-invasively in all participants using AGE reader. Information in regards to smoking habits and ethnicity were assessed through questionnaires. Train technicians assessed participants in the study (BMI, blood tests).
Statistical tests ran: T-Test, ANOVA, etc. and what is considered significant (i.e., P value <.05)
Results: SAF increased with higher numbers of being exposed to secondhand smoking. Former smokers SAF levels approached SAF levels of people who never smoked after about 15 years of smoking cessation. Urinary cotinine N-oxide is positively associated with SAF in QMDiab (p=0.03). Mean SAF levels were significantly higher among current smokers compared to former and never smokers. In all smoking groups, those with type 2 diabetes had significantly higher SAF levels compared to those without diabetes. SAF levels were also assessed from different smoking classes according to how much tobacco was smoked per day. Those who were heavy smokers had higher SAF levels. Five markers were evaluated for tobacco smoke: cotinine in saliva, plasma and urine, cotinine N-oxide and hydroxy-cotinine in urine. Cotinine N-oxide was detected in 115/316 individuals who reported former or never smoker but cotinine in plasma (in 61 subjects) had the highest value for current smoking. Individuals who have been exposed to secondhand smoking for more than 11 hours/ day had higher SAF levels compared to those exposed 1-5 hours/ day, but not compared to those for 6-10 or 0.
Discussion/Conclusion: Secondhand smoking is associated with higher SAF levels and smoking cessation is beneficial. Cerami et al. has shown AGEs to be present in aqueous extracts of tobacco but Nicholl et al discovered higher levels of AGEs in blood vessels of smokers thus demonstrating smoke is an exogenous source of AGE. Tobacco smoke as an exogenous source may play a role in type II diabetes, cardiovascular diseases, coronary artery diseases, and peripheral artery disease. Cotinine N-oxide has been identified as the biomarker for environmental tobacco smoke exposure and is significantly associated with higher SAF levels. There were high levels of continine in non-smokers but this can be related to some non-smokers being indeed active smokers. Racial and ethnic background can have an impact on these results. Secondhand exposure in non-Caucasian non-smokers have slower nicotine metabolism which leads to elevated cotinine levels. Secondhand smoking can lead to increased risk of type 2 diabetes and CAD due to the increase of systemic inflammation and oxidative stress. Smoking cessation can reduce these risks and further studies can use SAF as a screening tool for comorbidities such as diabetes and cardiovascular disease.
van Waateringe RP, Mook-Kanamori MJ, Slagter SN, van der Klauw MM, van Vliet-Ostaptchouk JV, Graaff R, Lutgers HL, Suhre K, El-Din Selim MM, Mook-Kanamori DO, Wolffenbuttel BHR. The association between various smoking behaviors, cotinine biomarkers and skin autofluorescence, a marker for advanced glycation end product. PLoS One. 2017 Jun 20;12(6):e0179330. doi: 10.1371/journal.pone.0179330. PMID: 28632785; PMCID: PMC5478117.
Gromwell (Lithospermum erythrorhizon) root extract protects against glycation and related inflammatory and oxidative stress while offering UV absorption capability
Impact factor: 3.368
Type of study and any information related to it: in vitro: Gromwell root dates back to China’s Ming dynasty and has several skin benefits. In skin, GR protects against UVB- induced inflammation in human keratinocytes, increases ceramide production, promotes wound healing, and improves skin barrier function. Advanced glycation end products can be enhanced by reactive oxygen species and accelerate skin glycation. Skin AGEs reduce dermal thickness, cause skin discoloration, increase tissue damage, and accelerate the aging phenotype. Lip and facial skin are in constant exposure to extrinsic stressors such as pollution and solar radiation and it is plausible AGEs and subsequent oxidative stress can be detrimental to lip tissue at an earlier age. The objective is to evaluate GR and shikonin’s ability to provide UV absorption in lip and facial cosmetic applications.
Important methods: GR extract and shikonin were assessed by fluorometric, biochemical glycation assay, cell-based luciferase reporter to assess nuclear factor erythroid 2-related factor 2, and ELISA for TNF-alpha. UV predictive performance was assessed by UV-A solar stimulation and transmitter analyzer.
Statistical tests ran: Data are represented by mean inhibition (SEM) and dose dependent curves.
Results: GR extract and shikonin dose-dependently inhibited glycation intermediate formations. Maximum inhibition for GR extract and shikonin were 87% and 83% respectively. Both activate the Nrf2/ARE pathways and suppressed IL-1B and TNF- alpha production.
Discussion/Conclusion: Elevated levels of AGEs are detrimental for skin health. The lips and face are constantly exposed allowing skin to be susceptible to tissue damage and thinning. The results show that GR extract can inhibit the glycation reaction and potentially offer protective skin benefits by boosting oxidative defenses through the Nrf2/ARE pathway and suppressing TNF-alpha and IL-1B production. Activating the Nrf2 pathway prior to glycation promotes detoxification of glycation-related carbonyls. Shikonin has antioxidant benefits which can activate this pathway and this study has further shown GR extract possesses similar activation of this pathway. GLO1, ARE-containing glycation detoxification gene, was significantly upregulated by GR extract and shikonin in keratinocytes. Following GR extract and shikonin treatment, GCLC and GCLM, rate limiting enzymes for glutathione production were also significantly upregulated. The anti inflammatory properties of these extracts are well documented and low dose treatments of them suggest they are potent inhibitors of inflammatory signaling. In regards to AGE, RAGE activation induces a cascade of inflammatory markers and this prolonged inflammation is correlated with age acceleration. UV exposure can also contribute to glycation related ageing and topical applications are needed to protect the skin. Although this is in vitro, GR extract and shikonin provide desirable lip and facial skin benefits.
Glynn, K. M., Anderson, P., Fast, D. J., Koedam, J., Rebhun, J. F., & Velliquette, R. A. (2018). Gromwell (Lithospermum erythrorhizon) root extract protects against glycation and related inflammatory and oxidative stress while offering UV absorption capability. Experimental dermatology, 27(9), 1043–1047. https://doi.org/10.1111/exd.13706
The Relationship between the Soluble Receptor for Advanced Glycation End Products and Oxidative Stress in Patients with Palmoplantar Warts
Impact factor: 1.205
Type of study and any information related to it: Oxidative stress and inflammation are involved with HPV-related lesions. sRAGE is stated to have a protective factor against the interconnected processes of inflammation and oxidative stress and has never been researched before.
Sample size: Participants were divided into two groups : those with palmoplantar warts (n=24) and controls (n=28).
Inclusion criteria: 18 years or older, non-smoker, no treatment for warts
Exclusion criteria: chronic alcohol use, drug abuse, treatment with corticosteroids, pregnancy, breastfeeding
Important methods: Analyze the role of sRAGE in warts. Serum levels of sRAGE, oxidative stress parameters, and markers of inflammation were evaluated. sRAGE was measured by ELISA. Oxidative stress was assessed by total antioxidant status 9TAS), total oxidant status (TOS), and oxidative stress index (OSI).Based on the number of lesions, participants were stratified into three groups: less than 5 lesions, between 5-10 lesions, and more than 10 lesions and then separated by duration of less than 1 month, between 1-6 months, and history longer than 6 months.
Statistical tests ran: This data was carried out using t-test. When multiple groups were compared Kruskal-Wallis was used. The relationship between two parameters was assessed by Spearman’s correlation coefficient. Significance level p=0.05 and CI = 95%
Results: The serum levels of sRAGE were significantly lower in patients with warts compared to the controls.
Discussion/Conclusion: Warts are lesions caused by human papillomavirus (HPV). Multiple factors contribute to the pathogenesis and oxidative stress and inflammation are interrelated processes that exacerbate the effects. In this study, patients with palmoplantar warts had lower serum levels of sRAGE compared to controls. sRAGE downregulation can be a contributing factor to HPV pathogenesis, and act as a negative regulator and represent an early mediator in the onset of warts. There are multiple mechanisms to the decrease of sRAGE. HPV induction increases keratinocyte proliferation which results in a higher rate of glucose metabolism which stimulates the synthesis of AGEs. Thus the AGE accumulates and interacts with sRAGE. Another mechanism is disrupting the AGE-sRAGE axis which induces a low synthesis of soluble receptors. This study reveals the imbalance between prooxidants and antioxidants in patients with warts. It is postulated that sRAGE is a biomarker for warts but more importantly acts as a decoy for GAEs, blocking AGEs-RAGE axis and furthermore preventing the augmentation of oxidation.
Mitran, C. I., Nicolae, I., Tampa, M., Mitran, M. I., Caruntu, C., Sarbu, M. I., Ene, C. D., Matei, C., Ionescu, A. C., Georgescu, S. R., & Popa, M. I. (2019). The Relationship between the Soluble Receptor for Advanced Glycation End Products and Oxidative Stress in Patients with Palmoplantar Warts. Medicina (Kaunas, Lithuania), 55(10), 706. https://doi.org/10.3390/medicina55100706
Advanced Glycation End Products are Increased in the Skin and Blood of Patients with Severe Psoriasis
Impact factor: 4.016
Level of evidence: IV
Type of study and any information related to it: This cross-sectional case control study investigates if psoriasis is associated with accumulation of AGEs in skin and serum and if skin and serum AGEs correlate with psoriasis severity.
Sample size: Involves a series of 80 patients with chronic plaque psoriasis and 80 controls that matched for age, sex, and BMI. Inclusion criteria were between the age of 18-60 years, had been diagnosed with chronic plaque psoriasis, and lacked systemic treatment for at least 6 months. The control group consisted of healthy patients or patients with chronic eczema.
Important methods: Total cutaneous content of AGEs was evaluated by AGE Reader mu: a non-invasive fluorescence technique which measures tissue AGEs. Venous samples were collected as well and centrifuged. Serum levels were measured using ELISA.
Statistical tests ran: Results are presented using basic parameters of statistics: mean value, SD, and standard error. Normal distribution was measured using Shapiro- Wilk, dependent data was classified by student’s t-test, and independent data was compared using Mann-Whitney tests. p<0.05 was considered statistically significant.
Results: Levels of skin AGEs were significantly higher in patients with severe psoriasis compared to those with mild psoriasis (2.87 vs. 2.15, p = 0.04), severe eczema (2.87 vs. 1.90, p = 0.02), and healthy controls (2.87 vs. 1.86, p = 0.01). There were no differences in AGE levels between normal skin and lesioned skin in eczema patients. Cutaneous levels of AGEs paralleled serum levels and positively correlated with disease severity. However, serum levels of RAGE were significantly lower in patients with psoriasis compared to those with eczema or healthy controls. RAGE levels had an inverse correlation with disease severity.
Discussion/Conclusion: AGEs are formed via a non-enzymatic glycation between reducing sugars and free amino groups of proteins, lipids, or nucleic acids. These products can be metabolized endogenously or exogenously from foods or tobacco. This study included patients selected based on not having conditions associated with AGE accumulations, and the results showed those with severe plaque psoriasis have an increased amount of cutaneous and serum AGEs. Cutaneous AGE levels directly correlated with psoriasis severity and serum AGEs. These results parallel previous studies showing a similar trend in patients with other inflammatory diseases. There was a discrepancy with AGEs and mild psoriasis which can have been attributed to higher sun exposure since UV radiation promotes skin AGE accumulation. AGEs mechanism of function relies on the membrane receptor RAGE. RAGE is a transmembrane receptor that is localized on many cell types but it has been seen that HMGB1 levels are increased in moderate- to- severe psoriasis. HMGB1 favors the shift of T regulatory cells to TH17 which is crucial in psoriasis induction. This AGE-RAGE interaction amplifies inflammation and favors cytokine release and has a role with hyperglycemia and vascular homeostasis. This study has strengths including the strong correlation between cutaneous and serum levels of AGEs and severity of disease, inclusion and exclusion criteria. Intensified protein glycation in skin may have a role in psoriasis inflammation and this connection needs further research to identify the severity of increased cardiovascular and metabolic risks.
Papagrigoraki, A., Del Giglio, M., Cosma, C., Maurelli, M., Girolomoni, G., & Lapolla, A. (2017). Advanced Glycation End Products are Increased in the Skin and Blood of Patients with Severe Psoriasis. Acta dermato-venereologica, 97(7), 782–787. https://doi.org/10.2340/00015555-2661
An evaluation of the effect of a topical product containing C-xyloside and blueberry extract on the appearance of type II diabetic skin
Impact factor: 1.621
Level of evidence:
Type of study and any information related to it: This clinical trial evaluated the effects of a topical product containing blueberry extract, AGE inhibitor, C-xyloside, GAG synthesis stimulator, on the hand, face and arm.
Sample size: 20 female type II diabetics older than 55 with mild to moderate hyperpigmentation, fine lines, and wrinkles on face and hands. Those with hypersensitivity to the product were excluded. Participants were not allowed to use any other products, topical retinoids, or moisturizes in this 12-week period.
Important methods: Subjects used the product on their face, hand, and forearm twice a day for 12 weeks. At weeks 4,8, and 12 subjects were graded on a four point scale ( 0=none, 1= mild, 2= moderate, 3= severe) for fine lines, wrinkles, radiance, skin tone, hyperpigmentation, skin smoothness, sagging and overall appearance. The investigator and subjects also performed skin tolerability exams with the same four point ordinal scale identifying edema, dryness, stinging, tightness, itching, tingling. Digital high resolution photography documented baseline photos. Pin probe corneometry assessed hydration and suction devices measured skin elasticity. Advanced glycation end products (AGEs) were measured on the left forearm through an AGE reader to assess increased glycated proteins in the subjects.
Statistical tests ran: A two tailed unpaired Mann-Whitney test was used to analyze nonparametric ordinal data. A value of p<0.05 was considered statistically significant.
Results: Nineteen of the twenty subjects completed the clinical trial. One subject was unable to complete the trial due to unrelated hospitalization. The 12-week duration did not sufficiently measure change in skin AGEs, however with longer application the product may produce different results. Facial measurements showed a statistically significant increase in skin thickness and skin hydration. Skin rigidity is common in diabetic patients. Skin elasticity results were averaged after five suction and relaxation cycles. The amount of force to stretch the skin decreased at each checkpoint, therefore becoming more elastic and less rigid. However, the data was not deemed significant. The efficacy of the product on the hand was assessed. A statistically significant improvement in hand skin smoothness and overall appearance was noted at week 4 and had significant improvement in week 8 and 12. No tolerability issues were noted and stinging and burning decreased which is consistent with an excellent tolerability.
Discussion/Conclusion: Diabetes is a disease that has multisystem effects. Of the products that affect virtually every organ, advanced glycation end products (AGEs) are irreversible products due to molecular rearrangements which can increase tissue rigidity. Carboxymethl-lysine and pentoside are irreversible AGEs which create this cross linked induced rigidity which can alter growth factors such as fibroblast growth factor, diminish vascular barrier function. These effects account for the accelerated aging and poor wound healing which is often found in diabetic patients. Efficacy of the blueberry extract was evaluated by several methods. A positive trend towards skin flexibility and elasticity was demonstrated. Visually there was a noted improvement in skin roughness, radiance, fine lines, and overall appearance. However, a larger sample size and more time were needed to achieve statistical significance. Prior to this study, skin products were designed by skin needs: dry, normal, or oily skin. With the increasing prevalence of diabetes, more research and awareness needs to be noted for their skin and the premature protein glycation they face.
Draelos, Z. D., Yatskayer, M., Raab, S., & Oresajo, C. (2009). An evaluation of the effect of a topical product containing C-xyloside and blueberry extract on the appearance of type II diabetic skin. Journal of cosmetic dermatology, 8(2), 147–151. https://doi.org/10.1111/j.1473-2165.2009.00428.x
Oxidation products are increased in patients affected by non-segmental generalized vitiligo
Impact factor: 2.339
Level of evidence: IV
Type of study and any information related to it: case control
Sample size: Forty-seven patients (25 females and 22 males) affected by non-segmental generalized vitiligo were examined over a 12-month period. 47 aged matched individuals with no history of vitiligo or autoimmune disease were enrolled by convenience sample.
Exclusion criteria: segmental vitiligo, use of systemic immunosuppressive drugs, alcohol consumption, smoking, taking any form of antioxidant agents or vitamin supplements
Important methods: AGEs and AOPPs were assessed using spectrofluorimetric and spectrophotometric methods. AGEs determination: 1:50 dilution of serum with phosphate-buffered saline at pH=7.4Fluorescence intensity was expressed in arbitrary units (AU).
Statistical tests ran: Analysis was performed with SPSS for Windows (version 13.0, SPSS Inc). Data was analyzed using Mann-Whitney test and correlations by Spearman’s rank correlation coefficient. Statistical significance was p<0.05.
Results: Both AOPPs and AGEs serum levels were significantly higher (p<0.0001) in patients with vitiligo compared to controls. There was a positive correlation of AOPPs with duration of vitiligo and disease activity (p=0.48, 0.37, and 0.55) and a similar correlation was observed between AGEs serum levels and the same clinical parameters. AGE levels were significantly higher in vitiligo patients with older lesions (p<0.01) , or those suffering from Hashimoto thyroiditis (p<0.01). Levels were higher in concomitant diabetes or psoriasis.
Discussion/Conclusion: Vitiligo is a depigmentating cutaneous disease with high levels of reactive oxygen species. Due to skin being exposed to both endogenous and exogenous injuries, serious pathological alterations can occur. In vitiligo, there are increased levels of H2O2 and peroxynitrite and poor antioxidant defense in the epidermis. Early stages indicate increasing levels of lipid peroxidation which suggests ROS as a potential initiating factor in inducing disease and controlling the melanocyte levels decreasing. Oxidative stress is seen with other autoimmune skin diseases such as pemphigus vulgaris, psoriasis, and alopecia areta. The main ROS is seen as H2O2 in these diseases, but results are contrary for vitiligo. In this study, AOPPs and AGEs were two oxidative markers that were significantly higher in vitiligo patients compared to controls. Higher AOPP levels were associated with disease activity while AGEs were associated with older lesions or concomitant autoimmune diseases (psoriasis, diabetes, Hashimoto thyroiditis).
This was the first study evaluating the role of AGEs in vitiligo patients. Glycation and oxidation of macromolecules could have a role in pathogenesis of vitiligo. ROS can directly damage cell membranes and cause mitochondrial alterations leading to irregular survival and proliferation of melanocytes.
Understanding the roles of AOPPs and AGEs is crucial to clarify the pathogenesis of vitiligo and the therapeutic target.
Vaccaro, M., Bagnato, G., Cristani, M., Borgia, F., Spatari, G., Tigano, V., Saja, A., Guarneri, F., Cannavò, S. P., & Gangemi, S. (2017). Oxidation products are increased in patients affected by non-segmental generalized vitiligo. Archives of dermatological research, 309(6), 485–490.
Advanced Glycation End Products in the Pathogenesis of Psoriasis
Impact factor: 4.556
Level of evidence: V
Type of study: Review article
Results: Cutaneous and serum levels of AGEs in patients with severe psoriasis were significantly higher compared to patients with mild psoriasis or severe eczema and healthy control patients. Levels of skin AGEs had a positive correlation with serum AGEs in all patients (r=0.93). Levels of skin AGEs also had a positive correlation with severity of psoriasis in patients (r=0.91). Serum levels of RAGE were lower in psoriatic patients as compared to patients with severe eczema or healthy individuals; this displayed an inverse correlation between RAGE levels and disease severity (r=-0.71).
Discussion/conclusion: This review article investigated the possible role of intensified glycation of proteins in psoriasis skin. Methylglyoxal (MG), an important mediator involved in the formation of AGEs such as CML and CEL, was found to be increased in serum levels of patients with severe psoriasis. Studies showed that the AGE-RAGE bond leads to activation of NF-KB, a nuclear transcription factor that modulates numerous inflammatory genes. In addition to the binding of AGE, RAGE can also bind to other ligands such as HMGB1; this ligand may favor the shift of T regulatory cells to Th17 cells, which has been proven to be significant in the induction of psoriasis. Chronic inflammation and oxidative damage are associated with the induction of keratinocyte apoptosis; this dysregulated pathway is pertinent to the pathogenesis of psoriasis.
Papagrigoraki A, Maurelli M, Del Giglio M, Gisondi P, Girolomoni G. Advanced Glycation End Products in the Pathogenesis of Psoriasis. Int J Mol Sci. 2017 Nov 20;18(11):2471. doi: 10.3390/ijms18112471. PMID: 29156622; PMCID: PMC5713437.
Ameliorating effect of akebia quinata fruit extracts on skin aging induced by advanced glycation end products. nutrients.
Impact factor: 4.546
Level of evidence: IV
Protocol: Spectrofluorometry, ELISA, spectrophotometry, Leica optical microscope, 3D image analysis.
Statistical Analysis: One way ANOVA; p<0.01 was considered statistically significant.
Study Type: Retrospective/case control; ex vivo, in vivo.
Results: Aminoguanidine (AG) and akebia quinata fruit extract (AQFE) were incorporated into a neutral gel at 1% and applied topically to the surface of human skin explants. Fibrillin-1 degradation via methylglyoxal-induced glycation (MG) was decreased with the use of AG. AQFE applied topically also protected fibrillin-1 from glycation and showed similar staining to the control batch without glycation. CML staining was decreased in the glycated explants that were treated with AG and AQFE as compared to the explants treated with MG. The AQFE-treated batch induced by MG showed complete inhibition of CML expression that was induced by MG.
An in vivo experiment was conducted using 0.5% AQFE applied to the periorbital region of 17 volunteers over a period of 8 weeks. Crow’s feet wrinkles that were analyzed using 3D image analysis and showed a decrease in the depth of deep furrows (p<0.05).
Discussion/Conclusion: In this study, akebia quinata fruit extract (AQFE) was demonstrated to possess antioxidant and antiglycation activity, which could aid in the prevention of AGEs accumulation. The use of AQFE was clinically validated as a possibility for use as an anti-skin aging agent and the in vivo experiment results show that AQFE possesses an anti-wrinkle effect.
Shin S, Son D, Kim M, Lee S, Roh KB, Ryu D, Lee J, Jung E, Park D. Ameliorating Effect of Akebia quinata Fruit Extracts on Skin Aging Induced by Advanced Glycation End Products. Nutrients. 2015 Nov 12;7(11):9337-52. doi: 10.3390/nu7115478. PMID: 26569300; PMCID: PMC4663606.
Regulation of human melanoma growth and metastasis by AGE-AGE receptor interactions.
Impact factor: 7.143
Level of evidence: IV
Protocol: Immunohistochemical staining, western blot, RT-PCR, modified MTS assay after incubation.
Statistical Analysis: Student’s t-test; Wilcoxon analysis for in vivo survival assays.
Study Type: Retrospective/case control; in-vitro; in-vivo
Results: This experiment showed that AGE2 (glyceraldehye-derived AGE) and AGE3 (glycoaldehyde-derived AGE) induces melanoma cell growth in vitro (p<0.01); through this study, it was determined that AGE2 and AGE3 significantly enhanced melanoma cell migration and invasion by 138% (AGE2) and 108% (AGE3) (p<0.005). Additionally, an in vivo human melanoma experiment performed in this study showed that AGE2 was strongly present within cytoplasm of melanoma cells and in the extracellular matrix; AGE and CML were hardly detected in normal skin.
Discussion/Conclusion: This study demonstrated that AGE2 and AGE3 enhanced proliferation, migration, and invasion of human melanoma cell lines in vitro. As a result, it was concluded that an abundant accumulation in extracellular AGE in skin could cause melanoma cells to proliferate and invade.
Abe R, Shimizu T, Sugawara H, Watanabe H, Nakamura H, Choei H, Sasaki N, Yamagishi S, Takeuchi M, Shimizu H. Regulation of human melanoma growth and metastasis by AGE-AGE receptor interactions. J Invest Dermatol. 2004 Feb;122(2):461-7. doi: 10.1046/j.0022-202X.2004.22218.x. PMID: 15009731.
Advanced glycation end products: Key players in skin aging?
Level of evidence: V
Study Type: review article
Protocol: CML was histochemically detected in human epidermis, mainly upper epidermal layers, from healthy donors. Cytokeratin 10 (CK10) was found to be a target protein for CML modification; younger donors expressed weaker levels of CML in comparison to older donors. This study had restrictions in that the sample size was small and heterogenous, but it indicates that there may be involvement of AGEs in epidermal physiology. In an in vitro reconstructed organ skin model, it was shown that glycation modification both the epidermis and dermis.
Results: The accumulation of AGEs has been observed to be increased in sites of sun-exposed skin, exhibiting that UV irradiation may contribute to the formation of AGEs in vivo. Areas of sun-protected skin in young individuals showed no significant accumulation in AGEs.
Smoking was found to be an aggravating factor of skin aging. Not only does it accelerate the formation of AGEs, but it also increases the deposition of AGEs in various tissues such as the skin.
Extracellular matrix (ECM) proteins have been found to be one of the major target proteins of glycation. Collagen is one of the strongest proteins and is found in abundance in the ECM. With glycation of collagen, the function is impaired in numerous ways. Collagen glycation leads to changes in its biomechanical properties which leads to stiffness and decreased flexibility. Additionally, modified collagen resists degradation by MMPs, which leads to impaired tissue permeability and turnover. Elastin and fibronectin were also found to be targets of glycation. In in vitro studies, it has been shown that glycated skin samples result in impaired biomechanical properties. In vivo studies show decreased skin elasticity in diabetic patients as compared to healthy controls.
AGEs displayed various effects on functions of skin cells in vitro such as decreased proliferation and enhanced apoptosis of human dermal fibroblasts. Additionally, in vitro studies showed that AGEs were capable of inducing premature senescence in human dermal fibroblasts and in normal human keratinocytes. In extrinsic aging, UVA irradiated fibroblasts and keratinocytes exhibited decreased viability after exposure to AGEs, showing that AGEs affect cells by making them more sensitive to external stimuli.
Pyridoxamine, a naturally occurring vitamin B6 isoform, showed favorable results in a phase II clinical trial against diabetic neuropathy. Data showed that oral intake of pyridoxamine leads to potent inhibition of skin collagen CML formation in diabetic rats; however, further investigation must be performed to determine its potential against skin aging. Natural nutrients and vitamins showed to be beneficial as well; supplementation of vitamin C in healthy human subjects showed a significant decrease in serum protein glycation. Moreover, blueberry extract, an AGE-inhibitor and C-xyloside, a glycosaminoglycan synthesis stimulator, were tested in female diabetic subjects for 12 weeks. This treatment resulted in improvement of skin firmness, wrinkles, and hydration but did not show a significant decrease in cutaneous AGEs content.
Studies in mice showed that restriction of caloric intake increased lifespan and delayed many age-related dysfunctions. Therefore, dietary restrictions such as a restriction in intake of dietary “glycotoxins”, could decrease levels of AGEs in skin collagen.
Discussion/Conclusion: Several in vitro and in vivo studies have shown the great impact of AGEs on skin aging. These studies displayed the effects of AGEs on the epidermal and dermal skin in addition to potential triggering factors for AGEs accumulation. An important target of AGEs was found to be ECM proteins; these proteins provide structural support and function in cellular signaling, which inevitably lead to skin aging when glycated. Possible paths for further research and investigation were discussed in terms of treatment and prevention of skin aging such as pyridoxamine, vitamin/nutrient intake, and dietary restrictions. The autofluorescence of skin in terms of AGEs skin deposition increases with chronological aging thus, making this a potential method of research on the various anti-aging products in the cosmetic industry.
Gkogkolou P, Böhm M. Advanced glycation end products: Key players in skin aging? Dermatoendocrinol. 2012 Jul 1;4(3):259-70. doi: 10.4161/derm.22028. PMID: 23467327; PMCID: PMC3583887.
Novel facial cream containing carnosine inhibits formation of advanced glycation end-products in human skin.
Level of evidence: IV
Type of Study: Retrospective/case-control; Ex-vivo human living skin explants.
Sample size: Each condition of treatment and control was tested in triplicate (3 explants per batch).
Methods: Immunostainings assessed by microscopical observation and image analysis.
Statistical Analysis: Student t-test with Bonferroni adjustment for multiple comparisons; p<0.05 was stated to be significant.
Results: Methylglyoxal (MG) exposure in ex vivo human skin explants results in increased CML and pentosidine. Groups treated with aqueous solution of 0.2% carnosine (AQ-CARN) showed antiglycation effect with CML: -64% (epidermis) and -41% (reticular dermis); pentosidine: -48% (epidermis) and -42% (reticular dermis). Groups treated with a face cream formulation with 0.2% carnosine (FC-CARN) had antiglycation effect with CML: -150% (epidermis) and -122% (reticular dermis); pentosidine: -108% (epidermis) and -136% (reticular dermis).
Discussion/Conclusion: This study confirmed that MG leads to the increased formation of CML and pentosidine in the epidermis and dermis of human skin. Carnosine has been studied and associated with anti-aging and cell longevity by suppressing cell senescence, induction of rejuvenating effects, and protection against shortening of telomeres. Antiglycating effects of AQ-CARN in the reticular dermis were not significant. FC-CARN showed a higher antiglycating effect than AQ-CARN; this is possibly due to the increased cutaneous delivery of carnosine and/or the antiglycation effects of other ingredients in the cream such as bacterial exopolysaccharides and niacinamide. A limitation to this study was that the results were derived from skin from a single donor. A previously published clinical study from the same authors indicated that in a sample size of 33 women (45-65 years of age) using FC-CARN, there was improvement in facial contour characteristics and increased hydration, firmness, elasticity, and improved skin texture after 56 days of use. Therefore, it can be inferred that use of FC-CARN would result in improvement of signs linked to AGEs accumulation in the skin that cause skin aging. Further research should be conducted to study the antiglycation effects of FC-CARN without carnosine to determine the cream’s antiglycation activity.
Narda M, Peno-Mazzarino L, Krutmann J, Trullas C, Granger C. Novel Facial Cream Containing Carnosine Inhibits Formation of Advanced Glycation End-Products in Human Skin. Skin Pharmacol Physiol. 2018;31(6):324-331. doi: 10.1159/000492276. Epub 2018 Sep 10. PMID: 30199874; PMCID: PMC6262686.
Glycation and the role of diet in aging skin.
Level of evidence: V
Study Type: Review
Results: Immunostaining used as a method of AGE detection has shown the prevalence of glycation in aged skin. Glycation and the accumulation of its products, AGEs, results in structural, morphological, and functional changes in the skin; this process is also known as “sugar sag” due to the prominent role that glucose and fructose play in the mechanism. Studies have shown that the consumption and accumulation of AGEs is not only linked to the sugar content of food, but also correlates to the method of cooking. Proteins like collagen with slow turnover rates are more susceptible to glycation modification. Glycated collagen is highly resistant to degradation by matrix metalloproteinases (MMPs), which further slows the process of collagen turnover and replacement with functional proteins. Fibroblast filaments and keratinocytes, which are essential for maintaining cytoskeletal stability and cellular functions, are also highly susceptible to glycation modification.
In vitro human dermal fibroblasts show higher rates of premature senescence and apoptosis, which is a possible explanation for the diminished collagen and ECM protein synthesis in cell culture and aged skin biopsies. Keratinocytes that have been exposed to AGEs express higher levels of pro-inflammatory mediators, show decreased mobility, and also suffer premature senescence.
Diets low in AGEs correlated with a reduced number of inflammatory biomarkers such as TNFa, IL-6, and C-reactive protein in addition to an improvement in wound healing. Because glycation is accelerated in the presence of ROS, antioxidants can be effective in limiting the production of new AGEs and possibly affecting AGE-induced tissue damage.
Discussion/Conclusion: Ingestion of foods high in AGEs affects skin collage, fibroblasts, and keratinocytes. As a result, these cells show premature senescence and apoptosis with decreased mobility, tensile strength, and cellular function. Several in vitro and in vivo studies show that dietary therapies can influence and reduce “sugar sag”. However, limitations when attempting to study the impact of vitamin C supplementation on skin health include: designing an ethical study requiring a control group to adhere to a diet poor in vitamin C without supplementation; ensuring participant compliance to diet and supplementation protocol.
Nguyen HP, Katta R. Sugar Sag: Glycation and the Role of Diet in Aging Skin. Skin Therapy Lett. 2015 Nov;20(6):1-5. PMID: 27224842.
Diet and dermatology: the role of a whole-food, plant-based diet in preventing and reversing skin aging: a review.
Impact factor: 1.43
Level of evidence: V
Type of study: review
Results: The Ornish et al study showed that lifestyle and diet modifications affected telomerase activity that could slow the aging process and possibly reverse it. In a 5 year follow up study, those who consumed a whole food plant based (WFPB) diet had telomeres that increased in length; in contrast, the control group had shortened telomeres. The accumulation of AGEs in the skin can lead to rapid stiffening of collagen, elastin, vitronectin, and laminin; this results in skin ulcers and delay skin healing. Additionally, increased AGEs decreases the cell’s ability to produce nitric oxide from L-arginine, which is needed for the cross-linking of collagen fibers and repair of collagen and elastin. As a result, the skin shows reduced tensile strength such as those in older individuals. Uribarri et al measured the AGE units in meats and processed foods and WFPB products; this study found that meats and processed foods had the highest number of AGE units. In addition, cooking foods using high, dry heat increased AGE content. Vitamins E, C, and A were found to maintain skin health and acted as important antioxidants to prevent and reduce damage from oxidative stress.
Discussion: This review discusses the benefits of a WFPB diet and its role on skin aging. WFPB products have lower AGE units than meat and processed foods, which can aid in the prevention of AGEs accumulation in the skin. Furthermore, WFPB products contain several vitamins such as vitamin A, C, and E, which are imperative in repairing and reducing oxidative damage caused by AGEs. As a result, a WFPB diet can reduce skin aging and possibly reverse some of the detriments caused by AGEs.
Solway J, McBride M, Haq F, Abdul W, Miller R. Diet and Dermatology: The Role of a Whole-food, Plant-based Diet in Preventing and Reversing Skin Aging-A Review. J Clin Aesthet Dermatol. 2020 May;13(5):38-43. Epub 2020 May 1. PMID: 32802255; PMCID: PMC7380694.
Association between small fiber neuropathy and higher skin accumulation of advanced glycation end products in patients with type 1 diabetes.
Sample Size: 178 patients with type 1 diabetes (99 men, average age 43)
Protocol: Accumulation of AGEs was assessed via skin autofluorescence. Intraepidermal nerve fiber density was assessed by counting PGP 9.5-immunoreactive nerve fibers.
Statistical Analysis: Skin autofluorescence- Mann-Whitney U, P-value: 0.001; intraepidermal nerve fiber density- Mann-Whitney U, P-value: 0.005
Correlations were assessed via Spearman’s correlation.
Type of study: Cross-sectional.
Results: Type 1 diabetic patients with diabetic neuropathy had significantly higher skin autofluorescence than the type 1 diabetic patients without neuropathy. They also had significantly lower intraepidermal nerve fiber density. A positive correlation was observed between skin autofluorescence and both patient age and diabetes duration, while a negative correlation was observed between skin autofluorescence and intraepidermal nerve fiber density.
Discussion/Conclusion: Small fiber diabetic peripheral neuropathy in type 1 diabetes is associated with higher levels of skin AGEs.
Araszkiewicz A, Gandecka A, Nowicki M, Uruska A, Malińska A, Kowalska K, Wierusz-Wysocka B, Zozulińska-Ziółkiewicz D. Association between small fiber neuropathy and higher skin accumulation of advanced glycation end products in patients with type 1 diabetes. Pol Arch Med Wewn. 2016 Nov 22;126(11):847-853. doi: 10.20452/pamw.3649. Epub 2016 Nov 22. PMID: 27906877.
Skin beautification with oral non-hydrolized versions of carnosine and carcinine: Effective therapeutic management and cosmetic skincare solutions against oxidative glycation and free-radical production as a causal mechanism of diabetic complications and skin aging.
Level of evidence: II
Type of study: Retrospective/case control; randomized, double blind control study
Sample size: 42 persons
Important methods: Objective skin surface evaluation with Visioscan VC 98; visual assessment of skin appearance parameters
Statistical tests ran: p<0.05 was stated to be significant; student t-test
Results: In the group treated with Can-C Plus, the parameter surface constantly decreased on the forearm during the 1st 3 months (-16%), which showed improvements in surface structure and smoothing effects. When Can-C Plus was stopped in the 4th month, the surface value increased on the forearm (87% of forearm’s baseline value). Placebo group showed surface evolution analogous to the group treated with Can-C Plus however, amplitudes were ½ of it. Skin surface was reduced by 8% on the forearm in the placebo group. The contrast parameter in the group treated with Can-C plus during the first 3 months of active supplementation showed a 23% decrease. Final data after the 4th month showed 82% of the forearm’s baseline value. Placebo group showed lower results that were not significant. Circular roughness after 4 months showed lowest values in the active group: -18% (p<0.01). Placebo group showed decreased values for circular roughness compared to baseline values, but was not significant.
Discussion/conclusion: This study shows that the supplementation of oral non-hydrolyzed versions of carnosine and carcinine are effective therapeutic managements and treatments for skin aging and diabetic complications due to oxidative glycation. Carnosine and carcinine provide specific antioxidant activities and protection of proprietary antioxidant enzymes in the skin throughout the process of skin aging and diabetic lesions. Oral supplementation of Can-C Plus proved a continuous and significant improvement in the skin parameters that were investigated as compared to the placebo group. Visual inspection of the skin after supplementation showed improvement in overall skin appearance and reduction of fine lines.
Babizhayev MA, Deyev AI, Savel'yeva EL, Lankin VZ, Yegorov YE. Skin beautification with oral non-hydrolized versions of carnosine and carcinine: Effective therapeutic management and cosmetic skincare solutions against oxidative glycation and free-radical production as a causal mechanism of diabetic complications and skin aging. J Dermatolog Treat. 2012 Oct;23(5):345-84. doi: 10.3109/09546634.2010.521812. Epub 2011 Jul 14. PMID: 21756141.
Advanced glycation end products (AGEs) promote melanogenesis through receptor for AGEs.
Level of evidence: IV
Type of study: Retrospective/case control; ex vivo skin organ culture and in vitro melanocyte culture
Important methods: Western blot and immunofluorescence
Statistical tests ran: p<0.05 was stated to be significant; student’s t-test used between 2 groups; ANOVA used for comparing multiple groups
Results: Ex vivo experiments using human skin resulted in increased melanin content in skin cultures 5 days after AGE exposure. The ratio of pigmented epidermal area to total epidermal areas was significantly greater in AGE exposed skin as opposed to non-exposed controls. In vitro studies with melan-a cells with 4 day incubation time showed significant increase in melanin content (17%) compared to control cells; AGEs treatment on melan-a cells for 2 weeks showed more melanin contents in comparison to 4 day incubation.
Discussion/conclusion: The existence of AGE-RAGE interactions in melanocytes leads to increased melanin production in ex vivo skin organ culture and in vitro melanocyte culture. This shows that AGE-RAGE plays a role in AGE-mediated melanogenesis in primary human epidermal melanocytes, which results in a means of altering skin pigmentation. Keratinocytes exposed to UV irradiation showed increased secretion and production of AGEs.
Lee EJ, Kim JY, Oh SH. Advanced glycation end products (AGEs) promote melanogenesis through receptor for AGEs. Sci Rep. 2016 Jun 13;6:27848. doi: 10.1038/srep27848. PMID: 27293210; PMCID: PMC4904211.
Skin intrinsic fluorescence is associated with hemoglobin A1c and hemoglobin glycation index but not mean blood glucose in children with Type 1 diabetes.
Impact Factor: 16.02
Level of Evidence: IV
Sample Size: 110 children between 5-20yrs with at least 1 year of type 1 diabetes diagnosis
Protocol: Skin intrinsic fluorescence (SIF) was recorded at the time of each patient’s visit to the clinic. A 30 day history of mean blood glucose (MBG) was documented after in clinic confirmation that the patient’s glucose meter was working normally. Blood was drawn at the visit to test HbA1c and current glucose level (cBG). Hemoglobin glycation index (HGI) was calculated as the difference between the observed and expected HbA1c from MBG. Associations were determined between SIF (as a measure for skin AGEs) and MBG, HbA1c, cBG and HGI levels.
Statistical Analysis: Pearson correlation analysis was used between variables. A multivariate regression model was used to evaluate associations between SIF and the variables of interest, controlling for demographic variation.
Study Type: Case-control
Results: HbA1c was correlated with MBG (p<0.001) and HGI (p<0.001). After adjustment for age, duration of diabetes, race, sex and BMI, SIF was significantly associated with HbA1c and HGI. Age, duration of diabetes and female sex were all associated with higher SIF.
Conclusion: SIF readings evaluate AGE levels in the skin. This study showed that AGE levels increased with age, duration of diabetes and being female vs. male. HGI calculation intended to create a MBG independent variable. The association between SIF and HGI shows that MBG does not significantly impact AGE levels, even though high HbA1c is associated with AGE deposition.
Felipe DL, Hempe JM, Liu S, et. al. Skin intrinsic fluorescence is associated with hemoglobin A1c and hemoglobin glycation index but not mean blood glucose in children with Type 1 diabetes. Diabetes Care. 2011;34:1816-1820. doi:10.2337/dc11-0049.
Excess body fat increases the accumulation of advanced glycation end products in the skin of patients with type 1 diabetes.
Impact factor: 2.7
Level of evidence: IV
Type: Case Control, In vivo
Summary: A study was done on 227 Type One Diabetic patients (121 women and 106 men) and patients that had other chronic diseases in addition to the T1D were excluded from the study. This study evaluated the correlation of AGE deposits in the skin and its correlation to body fat in these patients. The normal body fat had 123 patients and the elevated body fat had 104 patients. The mean age of these patients was 31 ( +/- 9.2 years) with a mean HbA1C of 8.9 (+/- 1.8). In order to obtain the AGE level in each patient they used AGE reader Type 214D00102 and they assessed the adipose tissue by electrical bioimpedance method. The study concluded that the elevated body fat had a significantly ( p value < 0.05, evaluated by Mann- U whitney) higher level of AGE. THis subsequently puts them at greater risk for complications.
Zawada AE, Naskret D, Niedźwiecki P, Grzymisławski M, Zozulińska-Ziółkiewicz DA, Dobrowolska A. Excess body fat increases the accumulation of advanced glycation end products in the skin of patients with type 1 diabetes. Adv Clin Exp Med. 2020 Oct;29(10):1193-1199. doi: 10.17219/acem/126050. PMID: 33064379.
Systemic lupus erythematosus and glycation process
Impact Factor: 1.415
Level of Evidence: V
Type of Study: critically appraised articles
Results: This paper was a synopsis of research performed by other researchers.
Discussion/conclusions: Reference data shows a link between oxidative stress, AGEs formation, and autoimmune diseases such as systemic lupus erythematosus. Advanced glycation end products examined in patients included pentosidine, carboxymethyllysine (CML), and its homologue carboxyethyllysine (CEL). There was a positive correlation between the accumulation of AGEs in the skin of people with SLE as well as a positive correlation between the accumulation of AGEs and the duration of the disease. No correlation was found between SLE and the amount of AGEs in blood.
Nowak A, Przywara-Chowaniec B, TYRPIEń-Golder K, Nowalany-Kozielska E. Systemic lupus erythematosus and glycation process. Cent Eur J Immunol. 2020;45(1):93-98. doi:10.5114/ceji.2018.77875