Download AGEs - The Medical University of South Carolina

SCTR Scientific Retreat on Health Disparities
November 9, 2016
The molecular implications of lifestyle
associated metabolites (AGEs) to cancer
disparity
=
+
Sugar
Protein
David Turner PhD
Assistant Professor,
Hollings Cancer Center,
Medical University of South Carolina
AGEs
Cancer
Disparity
Advanced Glycation end-products -AGEs
+
HC=O
NH2
Protein crosslinks
Proteolytic
degradation
DNA damage
Cell signaling
AGE Formation
Maillard reaction
Reducing
sugars
+
Amino acids
DNA
Schiff's
base
Amadori
products
Oxidation
Glycolytic
intermediates
Reactive carbonyl species
Oxidation
Amino acids
-
Glyoxal, methylglyoxyl
3-deoxyglucosone
Perpetual
chronic activation
of stress repsonse
pathways
Oxidation
Reactive oxygen
species
Lipids
NAPDH
oxidase
Immune cell
recruitment/activation
AGEs
(CML, CEL
Pentoside
Glucosepane)
NFkB, TNF, HIF1, cytokines, chemokines
Endogenous & Exogenous AGEs
High fat/
high sugar
diet
Sedentary
lifestyle
Fried/grilled
foods
Processed
foods
Low income
Socioeconomic &
Environmental Risk Factors
 Exogenous AGE pool
Protein
AGEs
 Endogenous AGE pool
Tumor Specific
Biology
Glycolysis
Renal
&
enzymatic
clearance
=
+
Sugar
Endogenous
production &
exogenous
intake
Stress
response
Ancestry
HyperGlucose
glycemia
metabolism
Imbalance in this “steady state”
leads to increased AGE accumulation,
accelerated aging and earlier disease
onset and complications
Health Disparity
Exogenous AGE - lifestyle
Source: J. Am. Dietetic Ass. 2010:p911-916
•
•
Consuming foods that
are high in sugar/fat or are highly
processed substantially increases the
levels of AGEs in our bodies
Dietary AGE’s are naturally present in
raw animal-derived foods but grilling,
broiling, roasting, searing, and frying
propagate and accelerate new AGE
formation
•
Smoking and consumption of alcohol
increase AGE levels in the body
•
A sedentary lifestyle may increase AGE
accumulation in the body. Moderate
exercise can maintain a constant AGE
level and may even lower it
Bacon
91,577 AGE kU/100g
Carrots
10 AGE kU/100g
Big Mac
7,801 AGE kU/100g
Raw chicken
800 AGE kU/100g
Fried chicken
Poached chicken
1,000 AGE kU/100g 8,000 AGE kU/100g
VS
Dietary-AGE affect
mammary development
AGE
H&E
H&E
AGEs inhibit chemotherapy
MCF7 & T47D breast cancer cells
A
B
- Phosphorylation of Era at S167 is associated with tamoxifen resistance
C
D
C
MCF7
T47D
AGE levels are increased
in cancer patients
ELISA of circulating AGE levels in serum
AGE levels are increased in tumors
Control
Non-cancer
EA-LG
AA-LG
EA-HG
AA-HG
N=8
IHC staining of tumor AGE levels
AGEs increase cancer
associated pathways
AGES and cancer prevention
Tumor Biology
Increased glycolysis,
Hyperglycemia
Elevated stress
responses
Sugar
+
Lifestyle
intervention
Protein
=
AGEs
AGE
targeted
therapies
Chronic
diseases
Health Disparity Factors
Race, Poor diet, Obesity
Sedentary lifestyle,
Alcohol, Smoking
=
Increased AGE
pool in tissues
and organs =
aberrant cell
signaling
Target AGE
signaling
pathway
Cancer
Associated
Pathways
Lifestyle intervention
Antioxidant procyanidin complex
Dr. Michael Lilly
Mary Berkaw
Marvella Ford
Gayenell Magwood
Lindsay Peterson (Wash U)
Matt Gregoski
Liz Garret-Mayer
Kent Armeson
Measures We Can All Take!!
• Avoid/cut down on foods high in protein, sugar and fat as well as
processed foods
• Increase intake of natural whole grains, fresh fruit and vegetables
• Change how we cook foods:
 Cook foods at lower temperatures for longer periods of time (slow
cookers are great for lowering A.G.E.s and maintaining flavor)
 Cook over ceramic surfaces instead of metal, which will lower
A.G.E. formation during cooking
 Use a food thermometer to ensure you don’t overcook meats
X
•
 When preparing dishes that call for browning meat, such as stews
or roasts, skip the browning step
Substitute high-sugar, oil-based marinades with lemon juice, vinegar, and
tomato juice and experiment with different spices and rubs for flavor
SUMMARY
•
AGES are lifestyle linked metabolites which are associated with many if not all
chronic diseases
•
In relation to cancer our studies indicate that AGEs:
- alter mammary gland development in mice
- promote resistance to chemotherapeutic drugs
- are elevated in African American men with PCa
- promote cancer associated pathways
- Both lifestyle and pharmacological intervention may
are effective strategies to reduce AGE levels in patients
Multidisciplinary, collaborative research teams are needed involving
behavioral intervention experts, dieticians as well as basic, translational
and population scientists in order to fully comprehend the link between
lifestyle, chronic disease and AGE accumulation
Acknowledgements
Co-investigators
Michael Lilly
Steve Savage
Thomas Keane
Laura Spruill
Victoria Findlay
Marvella Ford
Gayenell Magwood
Lindsay Peterson (Wash U)
Liz Garret-Mayer
Kent Armeson
Stefan Ambs (NCI)
Scott Cramer (U of Colorado)
Jaime Uribarri (Mount Sinai)
Funding –
NIH/NCI P20 CA157071
NIH/NCI R21 CA194469 (provocative question)
NIH/NCI R21 CA176135
NIH/NCI R21 CA176135 supplement
HCC disparities research pilot project
Students/Technicians
Lourdes Nogueira
Danzell Smith
Brad Krisanits
Narges Anbardar
Jamie Randise
Katie Walter
Dion Foster
Van Phan
Gleb Fedarovich
Lifestyle
Metabolism
Sugar
+
AGEs
Protein