Advanced Glycation End Products (AGEs) and scar formation A systematic review Lennert Van Putte¹, Sofie De Schrijver¹, Peter Moortgat² ¹ University of Antwerp, Faculty of Medicine and Health science, Antwerp, Belgium ² Oscare, Organisation for Burns, Scar After-care and Research, Antwerp, Belgium

Conflicts of Interest None declared

1. AGEs = Advanced Glycation End Products Collective term for all degenerated protein/lipid/nucleic acid molecules, damaged because of anchored sugar molecules Formed by multiple reactions Role in aging and age-related complications Best known AGE = HbA1c Skin relevant AGE = Collagen

2. AGEs: Formation Sugars Oxidative stress Time IRREVERSIBLE AGEs Figure: Khera PK, Joiner CH, Carruthers A, et al: Evidence for interindividual heterogeneity in the glucose gradient across the human red blood cell membrane and its relationship to hemoglobin glycation. Diabetes 2008 Sep;57(9):2445-2452 Sugars Oxidative stress Time

And you, how AGE’d are you?

3. AGEs: Glycation Targets When & where does accumulation occur? From the age of 20 years old! In skin, joints, skeletal & vascular muscle, glomerular basement membrane How does accumulation occur? Balance between formation and removal Formation: Exogenous (ingestion) & endogenous (DM, smoking, …) Removal: Kidneys (GFR as indicator) Which proteins? Collagen Albumin LDL Hb

4. AGEs : consequences Crosslinking collagen  Directly ↓ function RAGE  Inflammation  Oxidative stress Binding lipoproteins  Atherosclerosis

5. AGE: consequences in skin Figure: Gkogkolou P, Böhm M. Advanced glycation end products: Key players in skin aging? Dermatoendocrinol. 2012 Jul 1;4(3):259-70.

6. AGEs: Skin and Wound Consequences ↓ Skin thickness ↓ Elasticity ↑ Contraction ↑ Time of inflammation ↑ Time of wound closure ! All drawn conclusions concerned studies on diabetics only !

7. AGEs: scar formation in elderly “What is the effect of AGEs on scar formation in elderly?” “What can we learn from the elderly in relation to AGEs and scarring?” Figure: “Scar”, from the movie The Lion King, Walt Disney Pictures 1994.

7. AGEs: Scar Formation in Elderly Simple deduction… Diabetic  ↑ AGEs in skin Older  ↑ AGEs in skin AGEs & diabetic wound healing ≈ AGEs & elderly wound healing?

7. AGEs: Scar Formation in Elderly But NOT simpler… Paradoxically: Elderly apparently heal better than younger people after cutaneous surgery Elderly vs. Healthy adults Faster “Normalization” Less red Less hypertrophic Increased contraction Diabetics vs. Healthy adults Delayed wound closure Prolonged inflammation & redness Reduced thickness of dermis Increased rigidity

Anti-AGE strategies 3. Nutriceuticals 4. Dietary measures 1. AGE Formation Inhibitors 3. Nutriceuticals 4. Dietary measures Aminoguanidine Ascorbic acid (vitamine C) Caloric restriction Pyridoxamine (isoform vitamine B) α-tocopherol Niacinamide 5. Targeting RAGE Pyridoxaln 2. AGE breakers Sodium selenite siRNA Dimethyl-3-phenayl-thiazolium chloride (ALT-711) Selenium yeast Putative small molecular inhibitors against RAGE-induced signalling Trolox N-phenacylthiazolium Rivoflavin N-phenacyl-4,5-dimethylthiazolium Zinc FAOXs 6. Molecular chaperones Manganese FN3K Alfa lipoic acid Carnosine The enzymatic system of Glo

8. Conclusions Abundant evidence supports: ↑ Skin AGEs in both elderly and diabetics Pathological role of AGEs in wound healing Effectiveness of possible therapeutic strategies Similar trends in wound healing in both elderly and diabetics However, some unexplained paradoxical dissimilarities  Further research is required to conclude the definite role of AGEs in scar formation and therapy

9. Future Investigations Correlation of scar characteristics (thickness, redness, elasticity etc.) with the amount of AGEs Anti-AGE strategies: Diet (e.g. more antioxidants, less carbohydrates) Antioxidant cream (e.g. Q10) Topic Metformin (Glucophage®) Diphtheria toxin (very experimental but promising)

Thank you for your attention!