Toxic Effects of Advanced Glycation End Products

1. Toxic Effects of Advanced Glycation End Products Greg Lieberman March 3, 2014 RE|NOUS

2. http://www.pnas.org/content/early/2014/02/19/1316013111.abstracthttp://www.pnas.org/content/early/2014/02/19/1316013111.abstract • “Oral Glycotoxins are a Modifiable Cause of Dementia and the Metabolic Syndrome in Mice and Humans” • Conducted by researchers from the Icahn School of Medicine at Mount Sinai in NY • Published in Proceedings of the National Academy of Sciences of the United States of America, February 24th, 2014

3. Glycotoxins • Advanced Glycation End Products (AGEs) • Promote Oxidative Stress—imbalance in reactive oxygen species/redox states of cells (toxic production of peroxides/free radicals). • Methyl-glyoxal-imidazolone-H1 (MG-H1) • Amplify proinflammatory properties of Aβ and tau • Linked to cognitive decline in elderly patients

4. Glycation • “Non-Enzymatic Glycosylation”: • Sugar covalently bound to protein or lipid without enzymatic catalysis—lacks specificity • Leads to formation of AGEs (amyloid proteins are side products in intermediate reactions) • Exogenous glycation also occurs when sugars are cooked with proteins/fats

5. Advanced Glycation End Products (AGEs) • Exogenous: abundant in foods as flavor enhancers and colorants (browning/caramelization) • “Western Diet”: high in saturated fats, red meats, and “empty” carbohydrates, and low in seafood, poultry, whole grains, fresh fruit and vegetables • Important what we eat, but also how it is prepared—lower heat in presence of water • Barbecued/fried meats, donuts, cake, dark colored soda, french fries, dairy products all high in AGEs

6. Effect of AGEs in Mice • Low AGE diet (MG-): • delayed metabolic/vascular diseases and longer lifespans • Improved insulin resistance and reduced inflammation • MG Supplemented Low AGE Diet (MG+): • developed Metabolic Syndrome (MS), kidney/cardiac fibrosis, inflammation, and SIRT1 depletion

7. NAD-Dependent DeacetylaseSirtuin1 (SIRT1) • Intracellular regulatory protein, but exact function not determined; positively regulates neuronal, immune, and endocrine responses • Linked to metabolic regulatory transcription factors • Downregulation of SIRT1 associated with insulin resistance • Could increase insulin sensitivity in cells

8. AGEs as a Modifiable Risk Factor • Expanded MG+/MG- mouse model to test whether AGEs predispose individuals for dementia in addition to causing MS • 3 Groups: • (MG-): low AGE • (MG+): MG supplemented to low AGE diet • (Reg): controls; fed regular chow (high AGE)

9. AGEs as a Modifiable Risk Factor

10. Systemic/Brain Changes Caused By MG+ • Elevated Oxidative Stress: • Higher serum AGEs—sMG and sCML (N-carboxymethyl-lysine) • Higher plasma 8-isporostanes • Lower adiponectin • Resistance to Insulin: • Higher fasting insulin levels • Higher leptin levels

11. Systemic/Brain Changes Caused By MG+

12. Systemic/Brain Changes Caused By MG+ • Protein levels: • Reduced SIRT1 • Reduced [NAD+/NADH]-regulating nicotinamidephosphoribosyltransferase (NAMPT) • Receptor levels: • Reduced AGE Receptor 1 (AGER1) • Consistent with higher receptors for AGEs (RAGE), AGEs, and reactive oxygen species (ROS) levels • Reduced PPARγ • Promotes Aβ clearance

13. Systemic/Brain Changes Caused By MG+

14. Systemic/Brain Changes Caused By MG+ • Analyzed hippocampal areas of mice: • MG+ mice had AGE-positive aggregates in areas of dense glial populations • MG- mice had fewer glia and no AGE clusters

15. Systemic/Brain Changes Caused By MG+

16. How MG+ Causes Aβ Accumulation • SIRT1 regulates A DisintegrinAnd Metalloproteinase Binding Protein 10 (ADAM10): • “modulates amyloid precursor protein (APP) and soluble APP-beta (sAPP-β) levels, limiting the accumulation of Aβ1–42” • MG+ leads to: • Suppressed SIRT1 causes lower levels of ADAM10 • Higher levels of sAPP-β and higher ratio of sAPP-β:APP • Higher levels of Aβ accumulated in brain

17. How MG+ Causes Aβ Accumulation

18. Chronic MG+ Impairs Learning and Memory • Rotarod test for motor coordination/balance learning skills: • MG- mice performed for longer distance & at higher speed before falling off rod • Object Recognition: • MG- mice had higher discriminatory capacity between familiar vs. novel objects (~70% of time spent exploring new object; MG+ showed poor exploratory behavior)

19. Chronic MG+ Impairs Learning and Memory

20. Dietary AGE in Humans: SIRT1 Suppression • Observational Study: n = 93, ≥60 y old, educated, 68% female • Normal baseline metabolic function, cognition, and calorie/dietary AGE intake (dAGE) • Baseline sMG levels correlated positively with dAGE intake and inversely with SIRT1 levels

21. High MG Correlated With Decreased Cognition • High baseline sMG predicted cognitive decline when tested 9 months later (CDR and MMSE testing) • Remained significant after adjusting for age, sex, education, and baseline MMSE

22. MG Correlated With Reduced Insulin Sensitivity • Higher levels of sMG (as wellassCML) correlated with increases in Homeostasis Model Assessment (HOMA)-IR: • Marker of insulin resistance

23. MGDecrease in Cognition & Insulin Sensitivity

24. Summary • Possible mechanism to explain causal link between dementia and metabolic syndrome: • Dietary AGEs (specifically MG)  Oxidative Stress (inflammation)  suppression of SIRT1 suppression of ADAM10  accumulation of Aβ (also insulin resistance)

25. Summary • Since lower MG levels in MG- mouse brains are associated with lower Oxidative Stress, limiting external dAGEs could be a new therapeutic approach for neuroprotection and delaying onset of dementia • Warrants further research and larger clinical trials to solidify connection between mouse models and clinical benefits