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Advanced Glycation End Products: What they are and how they influence our health and aging

Advanced glycation end products, or AGEs for short, can influence our health and attribute to the acceleration of aging. When sugar reacts with protein molecules in food and drinks, it can lead to the production of AGEs which accumulate over time within the body. This process is also known as glycation–the reaction between sugars and proteins that creates damaging compounds called advanced glycated end products (AGEs). These end products have been linked to many age-related diseases including diabetes complications such as kidney disease and eye disease. There are things you can do to reduce your exposure to these harmful compounds which we will be exploring on this week’s blog.

Advanced glycation end products are products of chemical reactions between sugar molecules and protein or fat molecules. This process is called the Maillard Reaction, named after French chemist Louis Camille Maillard who discovered it in 1910 while working on food chemistry. Maillard’s work shows how sugar can brown and add flavor to cookies and bread, but it can also produce some very harmful compounds that studies show contribute to age-related diseases. AGEs are a general term that describes a number of compounds that result from this reaction. The Maillard Reaction showed how amino acids react with reducing sugars at elevated temperatures. AGEs are formed when these sugars become covalently bonded to proteins or lipid compounds without the controlling action of an enzyme. AGEs are found in all organisms and foods, but their concentration increases with cooking time and temperature. AGEs work in the human body by reacting with DNA and RNA, AGEs form a complex series of reactions that result in cross-linking AGEs to proteins. This reaction is not optimal as it increases AGEs ability to bind with AGE receptors in tissues. AGE additively increases the concentration of AGE receptor sites, resulting in an increase in AGE-mediated signal transduction between cells. This process is exacerbated by the fact that glucose also enhances AGE formation. Thus, it is believed that AGE stimulation of AGE receptors results in the human body moving from a homeostatic AGE receptor activity to AGE-mediated AGE receptor dysregulation. Homeostatic AGE receptor activity refers to a state in which a certain concentration of AGE receptor sites is present and a certain level of glucose is present, resulting in a specific amount of signal transduction between cells. AGE-mediated AGE receptor dysregulation refers to a situation where an increased concentration of AGE receptors results in an increased number of signals being transmitted between cells within the. Maintaining homeostatic AGE receptor activity is essential for cellular regulation (the process in which cells replicate, proliferate, and grow) and homeostatic function in healthy adults. 

HOW ARE WE EXPOSED TO AGEs?

Now that we know what AGEs are, let’s go over how we are exposed to them. Modern diets are largely heat-processed and as a result contain high levels of advanced glycation end products (AGEs). AGEs can be found in everyday consumables such as food products, but the main source of these products is from cooking and processing methods.

Cooking at high temperatures changes some of the sugars to AGEs. 

AGEs occur when sugars and proteins (in the case of food) come together in a process called glycation. These two substances can also interact with environmental factors such as UV radiation, oxidative stress, pollution, and smoking to form AGEs. AGEs are created through AGE-receptor interactions with AGEs found within foods, resulting in AGE-receptor dysregulation. AGE-receptor dysregulation refers to the processes by which AGEs affect AGE-receptor activity.

This interaction occurs by the body’s normal metabolic process, which is different than the glycation process. However, when excessively high levels of AGEs are reached in tissues this becomes harmful to the body.  

Thousands of AGEs have been identified from the glycation of proteins and lipids on y-positioned amino groups of lysine residues or oxygen-containing groups such as the following: aldehydes, ketones, and reducing sugars.  

  • Aldehyde is a compound containing a functional group with a carbon atom double-bonded to an oxygen atom and single bonded to -CHO. This carbon and oxygen is called a carbonyl group. 
  • A ketone contains a carbonyl group bonded to two other atoms such as the following: R-COCH= O (R= alkyl, aryl, etc.). 
  • Reducing sugars is a term used for monosaccharides and some disaccharides that can be oxidized to form aldehydes or ketones.

Some of the AGEs that can be found in our bodies are N ε -(carboxymethyl)lysine (CML), pentosidine, and others. CML and pentosidine are considered reliable biomarkers for oxidative stress and damage to DNA, RNA, and protein. Additionally, Pentosidine and CML is a biomarker for type 2 diabetic retinopathy. Oxidative stress refers to the damage produced in cells and tissues by non-neutralized free radicals. Oxidation is a process in which the structure of an organic compound is altered by the addition or removal of electrons to its molecules or atoms, causing it to become oxidized. Oxidation is dangerous to the body because it creates a chain reaction of oxidative stress.

Impact of AGEs on inflammation, oxidative stress, and insulin resistance

AGEs can disrupt cellular communication. Cellular communication refers to the internal biochemical messengers that carry information from cell to cell. Cellular communication makes up an important part of normal body function, allowing cells to ‘talk’ to one another and coordinate various functions necessary for the body as a whole (like growth, tissue repair, and organ function). AGEs interfere with cellular communication by binding to the surface molecules on cells. Examples of this include altering cell surface receptor function (such as the insulin and/or IGF-1 receptor), increasing cellular inflammation (via NFκB), and increasing oxidative stress.

AGEs have a direct impact on proteins and the extracellular matrix. The extracellular matrix is our body’s natural scaffolding that supports our cells (cells are attached to the extracellular matrix, AGEs accumulate in this area) AGEs cause damage to cellular proteins and the extracellular matrix by oxidative stress. AGE crosslinks have been documented to contribute to retinal capillary cell death, diabetic nephropathy, atherogenesis, etc. Additionally, AGEs can alter cell intracellular signaling by AGE-RAGE ( AGE receptor AGE ). AGEs have been suggested to be the cause of oxidative stress, inflammation, and insulin resistance. AGEs are linked to inflammatory markers like C-reactive protein (CRP) present in the blood, which is an indicator of systemic inflammation. 

MOBILITY AND AGING

Mobility is one of the most common problems that elderly people face. Mobility refers to the ability to perform the basic activities of daily living that are necessary for independence and is a core indicator of health and quality of life in aging. In older adults, the decline in physical function is a major determinant of frailty and loss of independence. The age-related decline in physical function results from a number of changes that occur at the cellular, organ system, and whole-body levels. AGEs are linked with the degradation of skeletal muscle function in older adults. AGEs are also known to play a role in the pathogenesis of arterial stiffness and hypertension, both strong predictors of cardiovascular disease which is one of the leading causes of death among elderly people.

REVERSE AGEs

Reversing AGEs requires reversing AGE modifications at the molecular level.  Since AGEs are modified by sugars, avoiding foods high in sugar and avoiding processed sugar are generally recommended. In addition to reducing or eliminating sugar intake, antioxidant-rich foods should be consumed to reduce oxidative stress. Additionally, supplements that promote healthy blood circulation may reduce the body’s exposure to AGEs. Some supplements that can support reverse AGE modification include carnosine, aminoguanidine known as Pimagidine, and benfotiamine. Unfortunately, there has been a challenge in reverse AGE at the molecular level but this challenge has led to the development of AGE inhibitors. Such inhibitors are now being developed for therapeutic use in order to manage diabetic complications and other diseases that result from AGE modifications at the molecular level. Examples include therapies targeting collagen cross-linking, glyoxalase I inhibition or amadoriase gene expression.

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Before taking any medications, over-the-counter drugs, supplements or herbs, consult a physician for a thorough evaluation. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

References

https://pubmed.ncbi.nlm.nih.gov/20544678/

https://pubmed.ncbi.nlm.nih.gov/24624331/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949097/

https://pubmed.ncbi.nlm.nih.gov/23525877/

https://www.sciencedirect.com/science/article/abs/pii/S0024320504009233

https://pubmed.ncbi.nlm.nih.gov/16280650/

https://pubmed.ncbi.nlm.nih.gov/8949973/

https://pubmed.ncbi.nlm.nih.gov/25786107/

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GUT-BRAIN AXIS

The gut-brain axis is a term that refers to the two-way communication system between the gastrointestinal tract and the central nervous system. The gut-brain axis can be disrupted by many different factors, including stress. With an unhealthy gut microbiome (bacteria) in your digestive tract, you are more susceptible to many health conditions. These include inflammation, metabolic syndrome, obesity, type 2 diabetes, depression or anxiety disorders, and neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease.

The purpose of this blog post is to share information on how a healthy diet can help heal your gut microbiome by providing proper nourishment for good bacteria while helping remove bad bacteria from your body through natural detoxification pathways.

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WHAT IS THE GUT-BRAIN AXIS?

The Gut-Brain Axis has recently been coined as the new “Central Nervous System”, which is a complex system of communication between the enteric nervous system in the gut and the central nervous system (CNS) in your brain. The Gut-Brain Axis is responsible for maintaining homeostasis between the autonomic nervous system and the immune system, regulating substances that may act as neurotransmitters. When the Gut-Brain Axis is not functioning optimally, this can lead to a range of problems including depression, anxiety, and stress-related disorders. Gut bacteria are responsible for maintaining the Gut-Brain Axis by producing neurotransmitters that can stimulate specific cells in the gut which can then send signals back to the brain through various neurological pathways.

Strong evidence suggests that gut microbiota has an important role in bidirectional interactions between the gut and the nervous system. It interacts with CNS by regulating brain chemistry and influencing neuro-endocrine systems associated with stress response, anxiety, and memory function. Gut microbiota can also influence brain function through the hypothalamic-pituitary-adrenal axis and autonomic nervous system. The hypothalamic-pituitary-adrenal axis is the major neuroendocrine system that mediates the stress response. Our autonomic nervous system is made up of the sympathetic nervous system (SNS) which is activated by stress and can stimulate colonic relaxation, vasoconstriction, and ileocaecal transit. Gut microbiota also interacts with immune cells in the gut, and these interactions have been shown to affect brain function. This has implications for mood disorders such as anxiety and depression that we will discuss later in this blog. Gut microbiota can also influence brain function through the autonomic nervous system, which regulates all of our unconscious actions (our heart rate, breathing pattern, etc).

Another factor worth mentioning is neurotransmitters. Neurotransmitters are essentially electrical signals in the brain that help us communicate and regulate many bodily functions including mood, emotions, ability to handle stress, and more. When our gut-health axis is off, our neurotransmitter signals can be disrupted which causes a cascade of brain issues. To make this simple, we are going to focus on serotonin as an example of what our gut-health axis can do for us. Serotonin is a neurotransmitter that regulates mood and behavior. When serotonin levels get messed up, it not only causes anxiety but also disrupts sleep patterns and more.

GUT HEALTH AND MENTAL HEALTH

Gut health is essential to mental health because it affects our mood, emotions, ability to handle stress, and symptoms of conditions such as Autism Spectrum Disorder (ASD). The Gut-Brain Axis is a two-way street, and both of these ‘roads’ are connected. When one road is in bad condition it affects the other road as well. This can cause inflammation, stress, and disease. As we learned in our inflammation series, inflammation can cause an increase in the release of cortisol from the adrenal glands. This is not good for us because too much cortisol disrupts our body and brain functions.

Stress also plays a large role in our gut-brain axis. Not only does stress cause our adrenal glands to release cortisol, but it can also lead to poor diet decisions that throw off your gut bacteria. Anxiety and depression are associated with changes in microbiome composition, as well as with increased gut permeability allowing lipopolysaccharides.  (LPS) refers to metabolic endotoxemia. LPS are not only harmful to your gut, but they are also a primary cell wall component of gram-negative bacteria. So as stress and anxiety increase your gut permeability and release lipopolysaccharides into the bloodstream these can cause inflammation in the brain leading to more cortisol production and an overall increase in inflammation throughout the body.

IMPORTANCE OF OPTIMAL GUT HEALTH

Maintaining good gut health is important as the gut microbiome may help with stress responses by influencing the synthesis of neurotransmitters and neuropeptides that have an impact on homeostasis, neuroinflammation, and neuronal plasticity. Recent research shows that the gut microbiome may also have an impact on neurogenesis. Neurogenesis is a vital process to maintaining mental health and is the generation of neurons from neural stem cells. Gut microbiota close to the enteric nervous system (ENS) exerts substantial influence over it. The gut microbiome can stimulate vagal afferent neurons by releasing transmitters such as 5-HT, acetylcholine, and norepinephrine. The gut microbiome can also stimulate afferent neurons in the submucosal and myenteric plexus of the ENS to release a range of chemicals including neuropeptides (e.g., substance P, cholecystokinin)

HOW IS THE GUT-BRAIN AXIS BEING USED IN MEDICINE TODAY?

Research is still underway on how to improve the balance of gut microbiota or modulate the gut-brain axis. Gut microbiome therapy may be used in some future medical therapies for psychiatric disorders, autism, and neurodegenerative disease.

Biological psychiatry is currently studying the Gut-Brain Axis by focusing on how metabolites from the microbiome can impact neurotransmitter function, synaptic plasticity, and neuroinflammation. The Gut-brain axis is being studied in clinical psychiatry for treating conditions like depression, anxiety disorders, and autism spectrum disorder (ASD). Although research is still underway on how to improve the balance of gut microbiota or modulate the gut-brain axis, some recent studies have been completed for Gut microbiome therapy.

WHAT CAN YOU DO AT HOME TO IMPROVE OUR GUT-BRAIN AXIS

Diet is one of the most important modifying factors of the microbiota-gut-brain axis. If you are experiencing any gastrointestinal symptoms (gas, bloating, stomach pain) as well as mental health issues such as anxiety or depression then a Gut-Brain Axis evaluation is recommended to determine if there is an imbalance in neurotransmitters due to the Gut-Brain Axis not functioning efficiently. The most important thing that you can do if you’re not feeling like yourself is to visit your Provider and get these tests done!

In the meantime, it is important to improve your Gut-Brain Axis by trying the following tips to get back on track:

  • Get enough fiber in your diet from fruits and vegetables
  • Get rid of the bad bacteria’s and yeast with beneficial bacteria
  • Reduce stress as much as possible and practice self-care!
  • Exercise regularly
  • Practice mindfulness

 The Gut-Brain Axis is the intersection of your gut and brain that affect each other. When your Gut-Brain Axis isn’t set up correctly it can be harmful to your overall well-being. This new discovery has been coined as the “central nerve” for all three major organ systems–the CNS, endocrine, and immune systems. It’s not just about digestion anymore! If you want to learn more about how this process works or if you’re looking to improve health with an integrative approach to optimal gut health – check out our most recent blogs.  Follow us next week as we take on: Metabolic Endotoxemia.

At the Institute for Human Optimization, we understand that what starts in the gut impacts the entire body. No two patients are the same, so we work with you and create a personalized and individual approach to your gut health issues. What can that look like? Would you plant grass seed or kill the weeds first? Weeds should be killed first. Similarly, we will work directly with you to reduce or remove the weeds, aka factors that are driving dysbiosis. After that, we can work together to restore balance in your gut microbiome.

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

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LEAKY GUT & MORE: THE IMPACT OF DYSBIOSIS

We recently discussed the importance of nurturing a healthy gut. Gut health has been linked to many health issues including autoimmune disease, heart disease, mood, obesity, endocrine disorders, cancer, and more. When dysbiosis in the gut occurs, it can lead to further gut problems. This week we will be discussing in more depth gut health issues such as leaky gut, SIBO, and what you can do at home to optimize your gut microbiome.

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Leaky Gut Syndrome

The term “leaky gut” has been a buzz term on social media lately. In fact, leaky gut is a more recently known term within the conventional medical community. Leaky gut, also known as increased intestinal permeability, refers to when food particles and other things such as bacteria and toxins, “leak” through the intestinal wall that otherwise shouldn’t. Your gut is lined by the intestinal wall, think of it as a patio screen door. Ideally, the screen door in your home is free of damage providing a barrier from the outdoor elements from coming inside the house. The screen acts as a filter and allows only certain things of certain sizes to enter your home. However, if your screen door is damaged and/or has holes, over time it is easier for large bugs, debris, and other critters to enter your home. With time, the screen door is no longer functioning as a barrier. Similarly, in our gut when our intestinal wall is damaged, the small holes become larger which now allows for harmful substances to enter our system. Naturally, we all have some level of leaky gut as the barrier is a screen and therefore not completely impermeable.

What causes Leaky Gut Syndrome?

Your bio-individuality may make you more sensitive to changes in the digestive system, but your DNA does not determine your gut health destiny. Let’s look at a few common causes of leaky gut:

  • Dysbiosis
  • Diet
  • Alcohol use
  • Stress
  • Food Allergies and Sensitivities

Dysbiosis

Dysbiosis occurs when pathogenic microbes (viruses, bacteria, mycobacteria) and symbiotic microbes that are beneficial to the microbiota by regulating our immune system, can no longer coexist in the gut in harmony. This is the leading cause of leaky gut syndrome.

Diet

Diet can determine the composition of gut microbiota, favoring the growth of organisms that are best suited for metabolizing commonly consumed food groups. Western diets are rich in a complex mixture of fats and are high in simple sugars, which significantly impacts the gut microbiome composition, and often leads to the development of gut inflammation and other related diseases, including intestinal disease [12].  

A diet rich in processed foods or foods you are highly sensitive to (we will discuss this later) can lead to leaky gut. Unfortunately, I see more times than not how the American diet impacts patient health outcomes. Studies continuously show how ultra-processed foods adversely affect our gut microbiome which in turn, drives inflammation. The rationale is that the nutritional composition of ultra-processed foodstuffs can induce gut dysbiosis, promoting a pro-inflammatory response and consequently, a “leaky gut”. 

Alcohol Use

Alcohol and its metabolites specifically promote intestinal inflammation through its influence on intestinal microbiota, immune function, and more. In large amounts, alcohol and its metabolites can overwhelm the gastrointestinal tract (GI) and liver and lead to damage both within the GI and in other organs.  Alcohol disrupts the epithelial cells, cells that line the surfaces of your body, and disrupts the space between the cells which allows increased gut leakage.

Stress

Stress is a health disruptor on your body, mood, and behavior. In the case of leaky gut, it can increase gut barrier permeability which can result in “leaky gut”. There are many stress management strategies that you can try to incorporate from the comfort of your home such as physical activity, meditation, relaxing music, and yoga. If you are unsure where to start and/or have taken steps to manage your stress with no results, your healthcare provider can work with you to create a stress management care plan.  

Food Allergies & Sensitivities

There is a difference between food allergies and food sensitivities. Food allergies are typically an acute hypersensitivity reaction that typically takes place within 2 hours of consuming the allergenic food. The symptomatic presentation can vary ranging from anaphylaxis, hives to respiratory or gastrointestinal distress. Food allergies are mediated by IgE immunoglobulin activity and cause a profound histamine release. Treatment can range from needing an epinephrine pen, steroids, and antihistamines. In contrast to Food Sensitivities, or intolerances which is typically more of a delayed hypersensitivity reaction which can take place upwards of 72 hours post-consumption which a varying symptomatic presentation which includes postprandial fatigue, migraines or body aches to common GI symptoms of gas, bloating, diarrhea or constipation. Food sensitivities are typically mediated by IgG and trigger inflammation. The problem is that foods that we are intolerant can present themselves very mildly compared to an allergy and cause chronic gut inflammation thereby increasing gut permeability. Additionally, it is important to keep in mind that 80% of our immune system resides in the digestive tract in the form of Gut Associated Lymphatic Tissue (GALT), and chronic exposure to larger food particles can ultimately lead to immunological programming and intolerances to foods that we commonly consume. Ultimately, this can trigger immunological dysregulation and autoimmunity.

SIBO

Another unassuming condition that often goes underdiagnosed and undetected is, Small Intestinal Bacterial Overgrowth (SIBO) occurs when excess bacteria are growing in the small intestine, disrupting the balance, and causing dysbiosis in your gut microbiome. Clinically, SIBO is an often-neglected mechanism for have patients presenting with weakened nutrition. Normally, you would find very little bacteria in the small intestine compared to the large intestine. SIBO has negative consequences on the structure and function of the small intestine and can cause mounting issues, including:

  • Osteoporosis
  • Kidney Stones
  • Incomplete Digestion
  • Vitamin Deficiency

Osteoporosis

Our bones are constantly undergoing continuous recycling throughout our lives. This process is known as bone remodelingand involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized. In other words, old bone is broken down and new bone is formed. For this to occur, our bones need a steady supply of protein, vitamins, minerals, and healthy fats to be properly absorbed. Healthy digestion is needed for optimal bone health. Over time, SIBO can cause poor calcium absorption which in turn drives bone loss.  

Kidney Stones

If you know anyone who has had kidney stones, you’ve heard enough to hope you never have one. Kidney stones are a multifactorial complex disorder between the gut, liver, bone, and kidney. If you have SIBO, you have an increased risk of kidney stones because of the absorption issues that are a result of bacterial overgrowth.

Incomplete Digestion

Our small intestine continues the process of digestion that begins in the stomach and runs to your large intestine. But unlike the stomach, which has minor absorptive properties, 90% of food absorption occurs in the small intestine. Whatever is not absorbed is then passed on to the large intestine. Bacterial overgrowth disrupts conjugated bacterial cells, and dihydroxylation of bile salts, which are needed to digest fats, resulting in incomplete digestion of fats and diarrhea. 

Vitamin Deficiency

The adverse effects of SIBO on nutrition involve several factors but one of the most common clinical manifestations is malabsorption. Vitamin B12 deficiency occurs in SIBO as the bacteria take up the vitamin. Vitamin A, D, and E are also commonly seen in SIBO due to the malabsorption of fat-soluble vitamins. 

How can you optimize your Gut Health? 

The health of our gut determines the health of the rest of our bodies. What are simple steps you can do at home to optimize your gut health?

At the Institute for Human Optimization, we understand that what starts in the gut impacts the entire body. No two patients are the same, so we work with you and create a personalized and individual approach to your gut health issues. What can that look like? Would you plant grass seed or kill the weeds first? Weeds should be killed first. Similarly, we will work directly with you to reduce or remove the weeds, aka factors that are driving dysbiosis. After that, we can work together to restore balance in your gut microbiome.

Disclaimer: The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Additionally, the information provided in this blog, including but not limited to, text, graphics, images, and other material contained on this website, or in any linked materials, including but not limited to, text, graphics, images are not intended and should not be construed as medical advice and are for informational purposes only and should not be construed as medical advice. Always seek the advice of your physician or another qualified health provider with any questions you may have regarding a medical condition. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this or any website.

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