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Advanced Glycation End Products (AGEs):

  • Writer: David S. Klein, MD FACA FACPM
    David S. Klein, MD FACA FACPM
  • Jan 16
  • 4 min read

A Silent Driver of Atherosclerotic Cardiovascular Disease


Introduction


If you are truly interested in a healthy diet, if you are truly interested in learning the why and how of nutrition and nutritional medicine, this is article is an important investment of your valuable time. While it seems like a very dry, academic topic, it is likely to change your behavior in a meaningful and healthy way. Please share this one with your friends and family, it may change them, for the better, as well.


Background


Atherosclerotic cardiovascular disease (ASCVD) is often framed as a problem of cholesterol alone. While lipoproteins remain central, this view is incomplete. A growing body of evidence points to advanced glycation end products (AGEs) as a powerful, under-recognized contributor to vascular aging, endothelial dysfunction, inflammation, and plaque instability.


AGEs accumulate slowly and quietly over decades. By the time ASCVD becomes clinically evident, the biological damage has often been underway for years. Understanding AGEs changes how we think about cardiovascular risk, prevention, and longevity.


What Are Advanced Glycation End Products?


Educational infographic illustrating how advanced glycation end products (AGEs) contribute to cardiovascular disease, diabetes, kidney disease, neurodegeneration, and eye damage through chronic inflammation and vascular injury.
Advanced glycation end products causing cardiovascular disease, diabetes, kidney disease, neurodegeneration, and eye damage

AGEs are harmful compounds formed when sugars react non-enzymatically with proteins, lipids, or nucleic acids, a process known as the Maillard reaction. This reaction accelerates under conditions common in modern life:


  • Chronic hyperglycemia

  • Insulin resistance and diabetes

  • Oxidative stress

  • High-temperature food preparation (grilling, frying, roasting)


Once formed, AGEs are biologically persistent. They accumulate in long-lived tissues such as vascular collagen, myocardium, kidney, retina, and neural tissue¹².



Endogenous vs Exogenous AGEs


Endogenous AGEs


Produced within the body as a consequence of:

  • Elevated glucose exposure

  • Mitochondrial oxidative stress

  • Aging-related metabolic inefficiency


Exogenous AGEs


Absorbed directly from food, particularly:

  • Charred meats

  • Fried foods

  • Baked and roasted products

  • Ultra-processed foods


Dietary AGEs significantly raise circulating AGE burden and inflammatory markers, independent of calories or macronutrient composition³⁴.


Diagram showing non-enzymatic glycation leading to advanced glycation end product formation
How Advanced Glycation End Products Form

AGEs contribute to atherosclerosis through multiple converging mechanisms:


1. Endothelial Dysfunction


AGEs cross-link collagen within the arterial wall, increasing stiffness and impairing nitric oxide signaling. The result is reduced vasodilation and increased shear stress⁵⁶.


2. Chronic Inflammation via RAGE


Illustration of AGEs binding to RAGE receptors causing endothelial inflammation
AGE RAGE Pathway and Vascular Damage

AGEs bind to the Receptor for Advanced Glycation End Products (RAGE), activating NF-κB and sustaining low-grade vascular inflammation. This signaling loop perpetuates oxidative stress and cytokine production⁷⁸.


3. LDL Modification and Foam Cell Formation


Glycated LDL is more readily oxidized and less efficiently cleared, promoting macrophage uptake and foam cell formation, a hallmark of early plaque development⁹.


4. Plaque Instability


AGE accumulation weakens fibrous caps and promotes metalloproteinase activity, increasing the risk of plaque rupture and thrombosis¹⁰.


AGEs, Diabetes, and “Residual Risk”


Even in well-controlled diabetes, AGEs persist due to prior glycemic exposure, a phenomenon known as metabolic memory¹¹. This explains why cardiovascular risk often remains elevated despite improved A1c levels.

Importantly, AGE burden also rises in non-diabetic individuals with insulin resistance, visceral adiposity, and sedentary lifestyles, making this a broader cardiometabolic issue¹².


Clinical Markers and Assessment


While AGEs are not yet part of routine cardiovascular screening, several surrogate indicators raise suspicion for elevated AGE burden:


  • Elevated fasting insulin

  • Increased HbA1c within “normal” range

  • Oxidative stress markers

  • Vascular stiffness (pulse wave velocity)

  • Skin autofluorescence (research and select clinical settings)¹³


Reducing AGE Burden: Practical Strategies

Nutrition


  • Favor steaming, boiling, poaching over grilling or frying

  • Emphasize whole, unprocessed foods

  • Reduce refined carbohydrates and fructose exposure


Glycemic Control

  • Optimize insulin sensitivity

  • Address post-prandial glucose excursions


Antioxidant and Nutrient Support

  • N-acetylcysteine (NAC)

  • Alpha-lipoic acid

  • Vitamin C and E

  • Polyphenols (curcumin, resveratrol)¹⁴


Lifestyle

  • Regular aerobic and resistance exercise

  • Weight optimization

  • Sleep and stress regulation


What you can do, right now:

Visual comparison of steamed foods versus grilled foods and AGE formation
Dietary Sources of Advanced Glycation End Products

  1. Control your sugar intake: Limit refined sugars, soft drinks, alcohol

  2. Modify cooking: Boil and steaming food is healthier than baking, frying and grilling (particularly over open flame)

  3. Eat whole (unprocessed) foods: A good start is the Mediterranean diet.


These interventions reduce AGE formation, enhance clearance, and blunt RAGE-mediated inflammation¹⁵.


Why This Matters Clinically


AGEs provide a unifying mechanism linking aging, diabetes, oxidative stress, and ASCVD. Addressing them shifts cardiovascular care from reaction to prevention and reframes risk assessment beyond cholesterol alone.


For patients focused on longevity, vascular health, and cognitive preservation, AGE reduction represents a meaningful and actionable target.



REFERENCES



The medical references cited in this article are provided for educational purposes only and are intended to support general scientific discussion. They are not a substitute for individualized medical advice, diagnosis, or treatment. Clinical decisions should always be made in consultation with a qualified healthcare professional who can account for a patient’s unique medical history, medications, and circumstances.

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