Do you age as you eat? Glycation and 10 reasons it is bad for you

Glycation makes food taste good; It also forms AGEs.

The humble toast you had for breakfast today may seem like one of the simple pleasures of life, but did you realize that you were consuming 54 different flavors?

That’s right, and you have the Maillard’s reaction to thank!

In 1912, French chemist, Louis Camille Maillard, explained the principle behind the ‘browning’ in foods that makes it oh-so-delicious.

Uncooked bread contains carbohydrates (complex sugars), proteins and water. When the toaster heats it to 302oF, the carbohydrates start decomposing to free sugars. These sugars get added, irreversibly, to amino acids (building blocks of proteins) present in bread, in a chemical process called Glycation.

Chewing breaks down the sugar-added-proteins to yield amino acid-sugar complexes called Accumulated Glycation End products (AGEs), which have different chemical profiles governing flavor and taste.

Another result of an increased surface breakdown of carbohydrates is the generation of melanoidins (glycated protein polymers),1 that are colored, giving us the familiar and tempting browning on the toast.

And it is not just toasts that rely on the flavor resulting from glycation. The food industry relies extensively on glycated amino acids for flavoring (e.g., glycine in beer, cysteine in meat and valine in rye bread).

These flavor and color profiles attract us to certain foods and dictate both our eating and cooking habits.

AGEs come from diet and can also form within the body

AGEs from the diet are called dietary AGES, while those formed within the human body are called endogenous AGEs. In the body, carbohydrate metabolism creates sugar intermediates, such as methylglyoxal, which have a high propensity of getting added to proteins, fats, and DNA.

Since sugar-tagged amino acids, lipids or nucleotides can no longer retain their original shape (having chemically altered), their function is compromised, leading to poorly functioning cells. As a result, a slow systemic deterioration kicks in, a.k.a aging!

Science proves that AGEs cause aging

Dietary and endogenous AGEs circulate in the blood, binding to cell surfaces via receptors called RAGE (Receptors for AGE). AGE-RAGE binding dictates inflammation and disease fates, as described further below.

Our body has evolved an anti-AGE defense, in the form of detoxifying enzymes called glyoxalases (GLOs), which eliminate reactive glucose metabolites (e.g., methylglyoxal), saving cells from glycation. However, when dietary AGE intake is high, it increases the flux of reactive sugars towards enhanced glycation in the body.

Some of the best scientific proof for AGEs causing aging comes from studying GLOs. A studyusing genetically engineered worms (c. elegans) made to overproduce GLOs showed low levels of AGEs, decreased glycation of mitochondrial proteins and increased lifespan2.

When GLOs were deleted, AGEs increased, and worms died faster. Also, worms without GLOs died faster when fed on a high glucose diet3.  That’s some very cool science providing conclusive evidence.

AGEs influence diseases through oxidative stress, inflammation, and protein cross-links.

A research group studying 174 human subjects found that increased intake of dietary AGEs led to high blood levels of AGE-related markers (e.g., methylglyoxal and N-Carboxymethyl lysine), irrespective of participants’ age and physical fitness4.

Across all age groups, high circulating AGEs correlated with increased oxidative stress and inflammation.

When RAGEs bind with AGEs, they initiate signaling pathways6 increasing pro-inflammatory molecules7 that cause immune cells to attack the tissues.

Inflammation also leads to the formation of reactive oxygen species (ROS) that oxidize biomolecules and signal tissue damage. In addition to this, long-lived proteins (like collagen which degrade slowly in the human body) accumulate glycated amino acids, which now serve as nodes for cross-links in proteins, making them rigid with reduced elasticity.

Cross-linking decreases both protein turnover and functionality, causing them to persist longer in cells than is beneficial7.

These changes defy physiology, causing complications and diseases. Here are the top 10 reasons why AGEs are bad for your health.

1. AGEs propagate neurodegenerative diseases

AGEs worsen Alzheimer’s disease (AD) and Parkinson’s disease (PD). Both conditions are caused by protein clumps in the brain. Protein plaques from AD brain samples have increased glycation of the amyloid-beta protein, tau proteins, and a 3-fold increase in AGEs compared to healthy, similar-aged individuals8.

Research also suggests that glycation of amyloid and tau proteins increases cross-linking, promoting their fibrillar organization in the brain9.

Protein clumps in the brains of PD patients have higher AGEs than healthy individuals9. α-synuclein, the main protein in PD brain clumps, is extensively cross-linked and stabilized by AGEs10.

2. AGEs cause innate immunity defects

Innate immunity is the body’s first line of defense against pathogens. It kicks in before antibody-mediated immunity and consists of natural killer (NK) cells, dendritic cells (DC), and macrophages that recognize infected cells and clear them out to contain infection11.

In studies involving NK cells exposed to synthetic AGEs, glycation of NK cell proteins increased, leading to reduced immunity against tumors and virally infected cells12. Accumulated AGEs in DCs inhibited DC maturation and immune function13. Similarly, AGEs affect macrophages’ immune activity, reducing their ability to clear out RNA virus infections14.

3. AGEs lead to skin aging

AGEs glycate and extensively cross-link long-lived skin proteins such as elastin, fibronectin and collagen. This leads to a decrease in elasticity, skin permeability and skin repair while increasing stiffness and aging.

Accumulation of AGEs in the epidermis and dermis increases cell death, ROS, and inflammation-causing skin injury15.

4. AGEs negatively influence obesity, metabolic syndrome, and insulin resistance

It is well known that obesity, insulin resistance, and metabolic syndrome are linked to lifestyle disorders.

When experimental mice feed on dietary AGEs in their high-fat food, they develop non-alcoholic fatty liver disease symptoms. Besides weight gain, there is an increase of pro-inflammatory molecules in their adipose tissue, promoting obesity16.

This is similar to the standard Western diet’s effects that supply high dietary AGEs causing chronic inflammation, oxidative stress, and insulin resistance16. A clinical trial of obese individuals with metabolic syndrome showed that cutting out dietary AGEs from their food reversed insulin resistance17.

5. AGEs are toxic for persons with chronic kidney disease

Kidneys eliminate AGEs from the body. The reduced function of kidneys in chronic kidney diseases causes the accumulation of circulatory AGEs.

This increases AGEs present in the blood, consequently increasing glycation events. In this sense, AGEs pose as toxins. Their continued presence in the body and affinity for long-lived proteins could lead to added complications such as vascular pathologies in patients with chronic kidney diseases18.

6. AGEs promote atherosclerosis

Inflammation fromRAGE signaling and AGE-mediated protein cross-links cause injuries to blood vessel walls, making them stiffen19.

AGE build-up also leads to atherosclerotic plaques (narrowing blood vessels due to clogging) as glycation of low-density lipoproteins (LDL) prevents their uptake by cells. This increases LDL blood levels and their deposition on arterial walls 20.

More evidence linking AGEs to atherosclerosis comes from rodent experiments with intravenous injection of glycated albumin (an AGE proxy). Results showed a 6-fold increase of AGEs in rodent arteries, making them porous and unable to dilate.

Side note: The fluorescent properties of AGEs are now being used to monitor the atherosclerotic plaque burden in humans. Increased level of AGEs leads to glycation of skin proteins. Which results in autofluorescence of the skin correlating with the extent of atherosclerosis in elderly patients21.

7. AGEs worsen diabetes and related morbidities

Diabetes is a condition of chronic hyperglycemia or high blood glucose concentration.

Therefore, the body’s proteins are in constant contact with high circulating sugars, increasing glycation events in tissues. On a systemic level, this contributes to various diabetes-associated complications.

The AGE-RAGE axis of inflammation worsens diabetic nephropathy (damage of kidney blood vessels) by causing thickening of kidney compartments22 and increasing cell death in them23.

AGEs affect diabetic neuropathy (loss of sensation of touch and stimulus) by increasing blood vessels’ glycation in nervous tissues24. AGEs also glycate proteins within the eye (in the retina, lens and vitreous fluid). An inflammatory signal is initiated on binding with RAGEs (expressed on retinal pigment epithelial cells), leading to vision loss in diabetic retinopathy25.

90% of type 1 diabetics and 60% of type 2 diabetics suffer from diabetic retinopathy within 20 years of diabetes onset.

8. AGEs propagate autoimmune diseases

Autoimmune diseases occur when the body’s immune system is directed against self-antigens.

Pentosidine, an AGE formed by adding ribose sugar to the amino acids arginine and lysine, is implicated in rheumatoid arthritis progression.

Pentosidine concentrations found in the fluid at bone joints (synovial fluid) are markedly increased in rheumatoid arthritis patients compared to healthy individuals26.

Inflammatory signaling by RAGE drives myasthenia gravis, an autoimmune disorder causing skeletal muscle weakness27. AGE-modified proteins are highly reactive with the immune system, leading to self-destructive antibodies that cause tissue injury — a possible reason for AGE-induced autoimmunity28.

9. AGEs mediate osteoporosis

Bone health is maintainedby balancing cells that resorb old bone tissue (osteoclasts) and cells that lay new bone material (osteoblasts), a.k.a. bone remodelling.

Bone remodelling is a slow processthat gets hampered when circulating AGEs extensively glycate and cross-link proteins in the bone, like collagen I, altering biomechanical properties. Along with inflammation from AGE-RAGE signaling, this leads to an increase in osteoclasts’ destructive function while reducing the constructive functions of osteoblasts, weakening bones with age29.

10. AGEs enhance cancer malignancy

AGEs are now found to drive malignancy in cancers. In the lab, when lung cancer cells are incubated with glycated-albumin (an AGE proxy), they show migratory and invasive tissue properties30, causing metastasis.

A real-world study of 7800 middle-aged (55-74 years) cancer-free women established a correlation between AGEs and breast cancer. 1592 of these women who had a high dietary intake of AGEs went on to develop breast cancer31.

So, watch your dietary AGE consumption

A good start to controlling dietary AGE consumption is to avoid sugar-rich diets and processed foods and employ slow cooking methods for most of the week.

Braise, boil and poach as often as you would pan-fry or grill to welcome new flavors and textures to your dining table or in your take-out parcel. Moist heat in slow cooking and boiling methods reduces dietary AGE formation.

What’s more, fruits and vegetables are rich in antioxidants and phytonutrients (such as Iridoids) that lower AGEs. If you enjoy a grill, it can be made healthier using acid-based marinades as acidity dampens glycation.

So, feel free to enjoy your morning toast as long as you make more conscious choices of food and food preparation for lunch and dinner.

Written by Divyaanka Iyer, PhD and Pankaj Kapahi, PhD

References:

  1. Biological Properties of Melanoidins: A Review
  2. A Caenorhabditis elegans Model Elucidates a Conserved Role for TRPA1-Nrf Signaling in Reactive α-Dicarbonyl Detoxification
  3. Circulating Glycotoxins and Dietary Advanced Glycation Endproducts: Two Links to Inflammatory Response, Oxidative Stress, and Aging
  4. Oxidative Stress, Inflammation, and Disease
  5. Receptor for AGE (RAGE): signaling mechanisms in the pathogenesis of diabetes and its complications
  6. The role of advanced glycation end products in aging and metabolic diseases: bridging association and causality
  7. Advanced glycation end products contribute to amyloidosis in Alzheimer disease
  8. Potential implications of endogenous aldehydes in β‐amyloid misfolding, oligomerization and fibrillogenesis
  9. Glycoxidation and oxidative stress in Parkinson disease and diffuse Lewy body disease
  10. Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies
  11. Innate Immune Recognition
  12. Glycation interferes with natural killer cell function
  13. Advanced Glycation End Products Modulate the Maturation and Function of Peripheral Blood Dendritic Cells
  14. https://pubmed.ncbi.nlm.nih.gov/29051224/
  15. Advanced glycation end products- Key players in skin aging?
  16. Advanced glycation end products (AGE) and diabetes: cause, effect, or both?
  17. Oral AGE restriction ameliorates insulin resistance in obese individuals with the metabolic syndrome: a randomized controlled trial
  18. Serum Advanced Glycosylation End Products: A New Class of Uremic Toxins?
  19. Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications
  20. Identification of the major site of apolipoprotein B modification by advanced glycosylation end products blocking uptake by the low density lipoprotein receptor
  21. Skin autofluorescence as a measure of advanced glycation end product levels is associated with carotid atherosclerotic plaque burden in an elderly population
  22. Glomerular parietal epithelial cell activation induces collagen secretion and thickening of Bowman’s capsule in diabetes
  23. Glycation Damage: A Possible Hub for Major Pathophysiological Disorders and Aging
  24. Diabetic neuropathy
  25. The role of advanced glycation end products in retinal microvascular leukostasis
  26. Pentosidine in synovial fluid in osteoarthritis and rheumatoid arthritis: relationship with disease activity in rheumatoid arthritis
  27. Expression of receptor for advanced glycation end-products (RAGE) in thymus from myasthenia patients
  28. Diet and Autoimmunity: What is the connection?
  29. Advanced Glycation End Products Play Adverse Proinflammatory Activities in Osteoporosis
  30. Cancer Malignancy Is Enhanced by Glyceraldehyde-Derived Advanced Glycation End-Products
  31. Dietary Advanced Glycation End-products (AGE) and Risk of Breast Cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)

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