Advanced Glycation Endproducts (AGEs) are a family of compounds resulting from a series of non-enzymatic reactions between proteins, lipids, or nucleic acids, and sugars. The initial step, known as glycation, involves the binding of a sugar molecule to an amino group and is reversible. However, as the glycated compound undergoes subsequent reactions, culminating in the formation of AGEs, the final product becomes irreversible.
Advanced Glycation End Products play a significant role in various health and biological processes, with implications for both aging and the development of chronic diseases.
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How do AGEs form?
The key aspect of advanced glycation endproducts formation is the reaction between an amino group from a protein, nucleic acid or lipid and a sugar molecule, like glucose. For this reason, during high glycemic states, AGE formation accelerates, leading to an exacerbated accumulation of AGEs in the lifetime of individuals with type 2 diabetes mellitus (T2DM). Glycated hemoglobin or HbA1C is one of the many AGEs identified in humans.
In addition to being formed through reactions within our bodies, AGEs can also originate from exogenous sources such as food and smoking. The well-known Maillard reaction, occurring during the cooking process of food due to heat exposure (also known as browning), not only produces chemicals we associate with good taste but also results in the production of advanced glycation end-products.
Exogenous Advanced Glycation End-Products
Food processing with high heat or under high pH levels also promote the formation of AGEs which are then absorbed in the intestinal tract.
Apart from food sources, cigarette smoke is also a major source of AGEs as it contains highly reactive glycation products that, after entering the human body, lead to the formation of these compounds.
Exogenous and endogenous AGEs may act synergistically, magnifying their harmful effects on health.
AGEs’ Impact on Health, Aging and the Development of Chronic Diseases
While further research is necessary, current studies seem to support the idea that Advanced Glycation End-products contribute to oxidative stress and inflammation. Increased inflammatory markers, such as C-Reactive protein and TNF-alpha, as well as endothelial disfunction, hepatic inflammation, cognitive decline, and decreased kidney function are some of the findings from early studies.
The crosslinking of AGEs with other proteins is one possible reason these compounds contribute to aging and the development of diseases, such as:
- Crosslinking of AGEs with nucleic acid: this alteration causes DNA strands breaks and mutations.
- Crosslinking of AGEs with structural proteins in tissues: this alteration can affect their mechanical properties leading to consequences such as:
- Stiffening of blood vessels, causing high blood pressure and other cardiovascular complications
- Hardening of cartilage and the extracellular matrix, contributing to the development of osteoarthritis and impaired joint function.
- And many more consequences to lungs, skin, kidneys, and other organs.
- Crosslinking of AGEs with enzymes, affecting many metabolic processes.
- Crosslinking of AGEs with receptors, making them irreversibly non-functional and disrupting pathways.
Moreover, crosslinking of AGEs potentially may occur with hormones, immunoglobulins, and many more fundamental pieces of our organisms that contain amine group, altering their functions. However, more research is needed to better understand the extent of damage they can cause.
Receptors for Advanced Glycation End-Products (RAGE)
The Receptors for AGEs, known as RAGE, of which many variations have already been identified, can be found on cell membranes: when ligands bind to them, they trigger a cascade of intracellular events, resulting in inflammation, the formation of reactive oxygen species (ROS aka free radicals), and causing cellular proliferation and apoptosis.
Overexpression of RAGE are linked to Alzheimer’s disease and other neurodegenerative conditions, as well as liver disease, kidney disease, cardiovascular disease and cancer.
Measurement and Detection of AGEs in tissues
Tissue biopsy is the gold standard method for measuring advanced glycation end-products. While the advantages of a biopsy lie in its high accuracy and the additional insights it provides into the disease process beyond AGEs, the downside is its invasiveness and time-consuming nature.
Other traditional methods for AGE measurement include ELISA, liquid chromatography (HPLC), mass spectrometry, and, more recently, the use of autoantibodies engineered to target specific AGEs. However, these methods lack universal standards among laboratories, making it challenging to compare results.
Skin autofluorescence is a novel technology that allows for a quick and non-invasive measurement of AGEs by using a commercially available device: a specific wavelength of light is emitted on the skin, and the reflected light is then measured by the device and processed by software to provide a reading. According to some research, there’s good correlation between skin autofluorescence and skin biopsies in terms of AGEs readings.
Importance of Monitoring AGEs Levels and their Implications
An accurate measurement and detection of AGEs levels could offer valuable diagnostic information and allow us to implement preventive strategies. By understanding the extent of AGE accumulation in tissues and biological fluids, healthcare professionals could tailor interventions to mitigate the impact of AGEs on health. Early detection of elevated AGE levels may prompt lifestyle modifications, dietary changes, and targeted therapies to slow down the progression of AGE-related complications.
Precision in measuring specific AGEs could contribute to personalized medicine approaches. Tailoring preventive strategies based on individual AGE profiles would allow for more effective and efficient interventions, potentially reducing the risk of age-related diseases, such as cardiovascular complications, neurodegenerative disorders, and diabetes-related complications.
Mitigation and Prevention Strategies against AGEs
Research extends beyond comprehending how Advanced Glycation End-Products form and their role in biological processes and disease development; it also explores measures to mitigate their effects, prevent their formation, and eliminate them once formed. Potential strategies include:
- Lifestyle interventions. Lifestyle changes, such as abstaining from smoking, regular exercise, and diets low in sugars, along with caloric restriction, seem effective in reducing AGEs levels and lowering the risk of AGEs-related diseases. Avoiding high-temperature cooking methods appears to lessen exogenous AGE intake, and vegetables emerge with the lowest AGE levels compared to other food types. Embracing these well-established lifestyle recommendations aligns not only with common wisdom but also offers a rational approach to mitigating AGEs-related risks.
- AGEs Inhibitors. Inhibiting AGEs formation is another possible way to proactively reduce their accumulation in tissues and the harm they cause. One established way to do that is by taking supplements or drugs known to lower glucose levels, like berberine and metformin. Other ways to inhibit AGEs formation would be to block one or more of the reactions that lead to their formation, like by using compounds with anti-glycation activity. However, extensive research is needed not only to discover such compounds, but also to evaluate their safety and efficacy in humans and in the long term.
- AGEs Breakers. As highlighted earlier in this article, once AGEs form, they accumulate as our bodies lack the ability to break down these compounds. Researchers aim to find molecules that facilitate the breakdown of AGEs, allowing our bodies to metabolize and eliminate them.
- RAGE antagonists. Targeting the receptors for AGEs could also offer another strategy to limit their harmful effects. By intervening at the receptor level, it could be possible to effectively reduce the downstream effects of AGEs, offering an additional path for potential therapeutic interventions.
Research and Future Directions
High concentrations of AGEs have been observed in numerous conditions, measured in various tissues of patients affected by diseases spanning different systems, from Alzheimer’s Disease and other neurodegenerative disorders to cardiovascular diseases, liver disease, infertility, and cancer. Our understanding of advanced glycation end-products remains limited, primarily derived from observational studies and basic research. Some studies even present contradicting evidence to others, challenging the assumed role of AGEs in predicting disease risk. Interventional studies, often confined to limited timeframes, may not accurately reflect lifelong exposure to AGEs and the efficacy of long-term interventions, particularly in chronic health conditions.
In the evolving landscape of longevity medicine, the focus on preventing AGEs accumulation and moderating exogenous AGEs intake emerges as a promising strategy. As research progresses, these proactive measures may emerge as key components for enhancing healthspan and lifespan.
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