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About AGEs (Advanced Glycation Endproducts)

In 1912 Louis-Camille Maillard, a French chemist, conducted a simple experiment in his lab that turned out to be a shortcut that created meat flavor and aroma through heating sugar and amino acids. This chemical reaction has thus been called Maillard Reaction or Browning Reaction. Following extensive researches on the Maillard Reaction across diverse fields from food, nutrition to therapeutics, the term Advanced Glycation Endproducts or AGEs was introduced to describe the end products of the Maillard Reaction that are formed under normal physiological conditions in living organisms.

Accumulation of AGEs

AGEs accumulate over a person’s lifetime, but this process occurs more rapidly in patients with conditions such as diabetes mellitus, renal failure and cardiovascular disease. Accumulation of AGEs is an important factor in the development of chronic complications of these conditions. Tissue AGEs correlate closely with early kidney, eye and nerve disease in patients with diabetes mellitus. Moreover they are valuable predictors of future cardiovascular morbidity and mortality. New drugs, aimed at preventing formation of AGEs or breaking AGEs, are currently in (late) clinical development.

Role of AGEs

AGEs play a pivotal role in the development of chronic age-related diseases such as diabetes, renal failure and cardiovascular disease. The level of AGEs in long-lived tissues (not in blood!) serves as a memory of glycometabolic and oxidative stress and is a valuable predictor of cardiovascular complications.

Measuring AGEs

Until now it has been complicated to measure tissue AGEs in patients because existing methods are expensive, time consuming, lack specificity, are poorly reproducible and/or are invasive. The AGE Reader is the answer to the need for measuring AGEs without the disadvantages of the existing methods. This state of art device provides a simple non-invasive solution which allows clinicians to determine the AGE level within 12 seconds.

Many advanced glycation endproducts (AGEs) have a characteristic fluorescence. Moreover, tissue fluorescence in (invasive) biopsies has an established association with chronic complications. The AGE Reader is able to easily, quickly and noninvasively measure this tissue fluorescence.

The AGE Reader has a light source which illuminates the tissue of interest. This light excites fluorescent moieties in the tissue which will emit light with a different wavelength. In the used wavelength band the major contribution in fluorescence comes from fluorescent AGEs. The emitted light is detected using a spectrometer or photodiodes. By using specific technical adaptations including selection of specific wavelength, modulated or pulsed light sources, a more selective discrimination of specific AGEs can be obtained.

Measurement validation

Since its development stage, the AGE Reader has undergone extensive methodological and clinical validation studies and the results of these studies have been published in various international journals.

The AGE Reader has been validated against classical and newer methods for AGEs determination in skin biopsies. The AGE Reader autofluorescence values were found to be closely correlated to collagen-linked fluorescence and to specific AGEs in skin biopsies taken at the same site as the AGE Reader measurement. (Meerwaldt et al. 2004)

Clinical validation

Diabetes
Initial clinical studies were performed in diabetes mellitus, because it is the classical example of increased formation and accumulation of AGEs. Skin AF was indeed found to be approximately 30% higher in patients with type 1 or type 2 diabetes mellitus compared with age-matched controls. In a large cohort of well controlled primary care patients with type 2 diabetes, the presence and degree of microvascular and macrovascular complications were associated with a graded increase in skin AF (Lutgers 2006). Gerrits et al. (2008) reported that skin AF is not only associated with diabetic nephropathy and neuropathy, but is also a predictor of its development.

The UK Prospective Diabetes Study (UKPDS) risk score has emerged as the most widely used tool to predict complications in type 2 diabetes. Although many type 2 diabetes patients are nowadays controlled tightly according to guidelines for their classic risk factors (for example cholesterol, blood pressure, smoking and HbA1c), they still develop cardiovascular complications. Additionally, risk calculators may underestimate CV risk in patients already treated with antihypertensive or lipid-lowering drugs. Consequently there is a need for additional markers among clinicians to identify patients at high risk for developing CV complications.

The publication by Lutgers et al. (2009) in Diabetologia showed that the AGE Reader is of additional value in determining CV risk besides the classic risk factors. Within a group of almost 1000 well controlled (HbA1c: 7%) type 2 diabetes patients in primary care it was shown that the AGE Reader measurement, apart from age, was the best single predictor of CV mortality and total mortality. Furthermore this publication demonstrated that the AGE Reader measurement in combination with the UKPDS risk score adds prognostic information and often leads to reclassification from low-intermediate risk to high risk (27%) and vice versa. Thus, without using the AGE Reader, 27% of the patients was incorrectly classified and therefore possibly not treated as desired.

Renal disease
The AGE Reader has also been extensively tested in renal disease which led to the following important conclusions:

• Skin AF is an independent predictor of cardiovascular disease associated mortality in hemodialysis patients.
• Skin AF is a strong and independent predictor of mortality and chronic graft loss in renal transplant recipients.
• Skin AF correlates to arterial elasticity and diastolic function in both hemodialysis and peritoneal dialysis patients.

Cardiovascular disease
Clinical research on the AGE Reader in cardiovascular led to the following findings:

• Skin AF is an independent marker for acute myocardial infarction.
• Skin AF is a non-invasive marker for inflammatory stress in stable coronary artery disease.
• Skin AF predicts future cardiovascular morbidity and mortality in STEMI patients.

Since the introduction of the AGE Reader over 125 peer reviewed papers have been published. These papers supply an extensive clinical validation. Below you can find the key publications and the most recent publications regarding the AGE Reader. If you would like to see the complete list of publication, please download our publication list.

Key publications

• Skin Autofluorescence and the Association with Renal and Cardiovascular Risk Factors in Chronic Kidney Disease Stage 3. McIntyre N. et al. Clin J Am Soc Nephrol. 2011 Sep 1. Epub
   
• Skin-Autofluorescence Is an Independent Predictor of Graft Loss in Renal Transplant Recipients. Hartog J. et al. Transplantation, Volume 87, Number 7, April 15, 2009
   
• Skin autofluorescence provides additional information to the UK Prospective Diabetes Study (UKPDS) risk score for the estimation of cardiovascular prognosis in type 2 diabetes mellitus.  Lutgers H. et al, Diabetologia, 2009; 52(5): 789-797
   
• Simple non-invasive assessment of advanced glycation endproducts accumulation. Meerwaldt R et al, Diabetologia, 2004; 47:1324-1330

Recent publications

• • Skin Autofluorescence Is a Predictor of Cardiovascular Disease in Chronic Kidney Disease Patients. Furuya F. et al. Ther Apher Dial. 2014 Dec 29. 

  • Relationship between cardiac tissue glycation and skin autofluorescence in patients with coronary artery disease. Hofmann B. et al. Diabetes Metab. 2014 Dec 29. Epub

  • Association of advanced glycation end products and chronic kidney disease with macroangiopathy in type 2 diabetes. Rigalleau V. et al. J Diabetes Complications. 2014 Oct 30. Epub

  • Advanced glycation end products (AGEs) and the soluble receptor for AGE (sRAGE) in patients with type 1 diabetes and coeliac disease. Bakker S.F. et al. Nutr Metab Cardiovasc Dis. 2014 Nov 1.Epub

  • Associations of advanced glycation endproducts with cognitive functions in individuals with and without type 2 diabetes. Spauwen P.J. et al. J Clin Endocrinol Metab. 2014 Dec 2

  • Tissue advanced glycation end products (AGEs), measured by skin autofluorescence, predict mortality in peritoneal dialysis. Siriopol D. et al. Int Urol Nephrol. 2014 Nov 26. 

  • Skin autofluorescence as a novel marker of vascular damage in children and adolescents with chronic kidney disease. Makulska I. et al. Pediatr Nephrol. 2014 Nov 20.

  • Skin autofluorescence associates with vascular calcification in chronic kidney disease.
    Wang A.Y. et al. Arterioscler Thromb Vasc Biol. 2014 Aug;34(8):1784-90.

  • Advanced glycation end products in the skin are enhanced in COPD. Hoonhorst S.J. et al. Metabolism. 2014 Jun 13. Epub

  • Type 2 diabetes mellitus, skin autofluorescence and brain atrophy. Moran C. et al. Diabetes. 2014 Jul 22.

  • Life-long endurance running is associated with reduced glycation and mechanical stress in connective tissue. Couppé C. et. al. Age (Dordr). 2014 Aug;36(4):9665. 

  • Relationship of Skin Autofluorescence to Severity of Retinopathy in Type 2 Diabetes.
    Yasuda M. et al. Curr Eye Res. 2014 May 28:1-8.

  • Skin Autofluorescence and All-Cause Mortality in Stage 3 CKD. Fraser S.D. et al. Clin J Am Soc Nephrol. 2014 May 29. Epub

  • GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence. Eny K.M. et al. Diabetologia. 2014 Aug;57(8):1623-34. 
     
  • AGEs and chronic subclinical inflammation in diabetes: disorders of immune system.
    Hu H. et al. Diabetes Metab Res Rev. 2014 May 20. Epub
     
  • Correlation between diabetic retinopathy severity and elevated skin autofluorescence as a marker of advanced glycation end-product accumulation in type 2 diabetic patients. Hirano T. et al. J Diabetes Complications. 2014 Mar 10. Epub
     
  • Advanced glycation end products are associated with arterial stiffness in type 1 diabetes.
    Llauradó G. et al. J Endocrinol. 2014 Jun;221(3):405-13. 
     
  • Skin autofluorescence, 5-year mortality, and cardiovascular events in peripheral arterial disease: all that glitters is surely not gold. Schmidt AM. Arterioscler Thromb Vasc Biol. 2014 Apr;34(4):697-9. 
     
  • Skin Autofluorescence Is Associated With 5-Year Mortality and Cardiovascular Events in Patients With Peripheral Artery Disease. de Vos LC. et al. Arterioscler Thromb Vasc Biol. 2014 Feb 13. 

For a complete overview of all publications please download our publication list.