WHAT IS MITOPHAGY?

Mitophagy is a process that occurs in cells, and it’s essentially the destruction of old or dysfunctional mitochondria. It’s important to know about mitophagy because as we age, our bodies lose their ability to carry out this process properly. When mitophagy does not occur properly it can lead to mitochondrial disease which has been linked to neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. This blog post will provide an overview of what mitophagy is and why it matters.

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WHAT IS MITOPHAGY

The word ‘mitophagy’ was coined in 2007 by the researchers who discovered this process. The prefix mit- means thread and phage means eat, so we define mitophagy as the destruction of mitochondria via a cellular mechanism called autophagy. Autophagy is a process that involves the degradation and recycling of cellular components. Mitophagy is the selective kind of autophagy mechanism that removes mitochondria.  A cell can digest its own organelles through this process, but it will only remove damaged structures and not healthy structures. This selective quality is what makes mitophagy so unique because most other forms of autophagy just degrade cellular components indiscriminately.

There are two other forms of autophagy: chaperone-mediated autophagy and micropexophagy. [i]

  1. Chaperone-mediated autophagy is a process that degrades damaged proteins and this type of degradation occurs in the lysosome or sac like structure.
  2. Micropexophagy on the other hand targets  mitochondria for degradation.

MITOPHAGY & MITOCHONDRIA

The mitochondria is an organelle that is responsible for converting energy into a form of molecules that our cells can use.[ii] Inside the mitochondria are enzymes called electron transport chains (ETCs) which take electrons and try to pair them with hydrogen atoms to produce chemical energy. This process also creates free radicals as by products, so our cells must have an enzyme called superoxide. Superoxide dismutase (SOD) eliminates superoxides and turns them into hydrogen peroxide. Hydrogen peroxide (H2O2) is broken down by catalase and glutathione peroxidase into water and oxygen gas.

This cellular structure is responsible for helping generate ATP (Adenosine triphosphate) which stores energy in the form of phosphate bonds. Cells need ATP to get rid of excess calcium ions that build up due to metabolism, and also to open up calcium ion channels for muscle contraction. Severing of the mitochondria from the rest of a cell triggers apoptosis, which is a programmed form of cellular death. The lack of a link to other organelles and its proximity to calcium ions makes it susceptible to damage. Because of this susceptibility, cells have developed a mechanism which allows them to dispose of defective mitochondria.

HOW DOES MITOPHAGY WORK

Mitophagy is a type of autophagy and there are three steps that must occur for this mechanism to carry out successfully:[iii]

1. The first step is the creation of an isolation membrane which surrounds the mitochondria, so the rest of the cellular components aren’t degraded.

2. The isolation membrane which elicits the form of selective degradation known as mitophagy is created by a multi-protein complex called PINK1 and Parkin.

3. The last step involves the elimination of the mitochondrion through fusion with lysosomes (the cellular structure responsible for degrading other organelles) via a double membrane structure called an autophagosome.

TYPES OF MITOPHAGY

There are two types of mitophagy that exist: Macro-autophagy and Micro-autophagy.

Macroautophagy begins with the formation of an isolation membrane around the mitochondria from a multi-protein complex composed of several proteins such as Nix, Parkin, AIFm2 and FUNDC1.

This isolation membrane then fuses with a lysosome which creates an autophagosome. The autophagosomes carry the mitochondria to the cytoplasm for degradation into amino acids, fatty acids, and nucleotides.

Microautophagy is a process that creates a small isolation membrane around the mitochondria from a single protein called Ulk1. This process is often used in response to stress, but there hasn’t been direct evidence of this process occurring in mammalian cells.

HOW IS MITOPHAGY REGULATED?

A protein complex called PINK1-Parkin is believed to be the primary regulator of mitophagy.  This complex is required for creating the isolation membrane that leads to mitophagy.

PINK1 has been found to regulate this process by promoting mitochondrial fission, imparting an isolation membrane around the mitochondria, and recruiting Parkin which becomes phosphorylated in response. When PINK1 is degraded or loses function through mutations, it can lead to PINK1-associated Parkinson’s disease.

Parkin is also required for mitophagy, and it acts in a parallel pathway to that of the PINK1-Parkin complex by creating an isolation membrane around mitochondria through phosphorylation of proteins involved in fission which leads to the formation of an autophagosome.

This suggests that PINK1-Parkin play a major role in the regulation of mitophagy.

MITOPHAGY IN DISEASE

Mitophagy is often found to be defective in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease[iv]. This is because faulty mitochondria are not properly eliminated, leading to cellular damage.

Since mitophagy is important in neuronal function, it follows that this process would be affected in cancer disorders. Cancer cells often have uncontrolled mitochondrial biogenesis, and this leads to extreme energy demands in cancerous cells which can be exploited. Mitochondrial biogenesis refers to the creation of new mitochondria from the division of existing ones.[v] This process is regulated by a protein complex that includes PGC1α and NRF1, which are often over-activated in tumor cells.

Cancer cells also need the ability to oxygenate themselves, so putting selective pressure on these cells through drugs that inhibit mitochondrial function can lead to their death. Inhibiting mitophagy could potentially decrease the effectiveness of such chemotherapy treatments, however research has shown that some chemotherapy drugs stimulate mitophagy so it may still have some use.

In addition, mitophagy is important for cardiovascular function and the development of stem cells. Mitochondrial biogenesis is a crucial process for stem cell formation and differentiation into progenitor cells. Mitophagy also ensures that damaged mitochondria are eliminated in cardiovascular cells.

Mitophagy is important to our longevity and healthspan because it allows the removal of faulty mitochondria that could potentially lead to cell death. Cell death leads to the death of the organism, so this process is critical for cellular health. Maintaining optimal cellular health is a key component in healthy aging, and efficient mitophagy is necessary for elimination of damaged mitochondria. We would love to see you next week on another blog post – Tune in then!

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.

[i] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900761/

[ii] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630798/

[iii]

[iv] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017092/

[v] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883043/

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FISETIN: Why are people taking this supplement?

Fisetin is a flavonoid found in many fruits and vegetables. It has been shown to have anti-inflammatory, antioxidant, and anticancer effects. Because of the potential health benefits it may provide, fisetin supplements are becoming more popular as people look for alternatives to other medications that they may not be comfortable with or want to take long term.  In this blog post we will explore what fisetin is, why people are taking it, potential benefits and discuss current research being done around Fisetin and how this could impact future treatments available for those looking to improve their health naturally.

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Origins & History of Fisetin

Fisetin is a naturally occurring flavonoid compound. Flavanoids are water-soluble compounds found in plants and have antioxidant properties. Water-soluble means that Fisetin can dissolve in water. Fisetin is not found to be fat-soluble, which means it cannot dissolve into fats or lipids that are normally soluble in oils. Fisetin was isolated from the Fruiting bodies of a Fungus called Fomes Fomentarius. The Fruiting body of this fungus is responsible for producing all of the spores that are used to reproduce. Fisetin can also be found in many plants including Ginko Biloba, strawberries, persimmons. Fisetin’s chemical structure was first identified chemical formula was first described by Austrian chemist Josef Herzig in 1891. Fisetin can be found throughout the plant kingdom, where it acts as a photosynthesis inhibitor and UV protectant. Fisetin has even been isolated from insects, including ants, aphids, and wasps.

Fisetin is also said to be one of the many flavonoids that are found abundantly in the plant subfamily Cornoideae, which includes Foeniculum vulgare, Foeniculum dulce, and Coriandrum sativum. Fisetin was first isolated from Foeniculum vulgare, Fennel. Fisetin was first isolated from the bark of the Pacific wax myrtle tree and has since been found in many fruits and vegetables. Fruits and vegetables that are high in fisetin include:

– Strawberries; specifically, they are Fisetin’s highest food source.

– Red grapes

– Apples

– Asian pear

– Fennel seeds  (Foeniculum vulgare) Fisetin is a member of the flavonoids, which are plant pigments produced by many plants to help protect themselves from outside stressors, such as ultraviolet light, insects, and herbivores.

Why are people taking Fisetin?

Natural supplements are becoming increasingly popular in the health and wellness community. There are a number of different types of natural supplements such as probiotics, prebiotics, digestive enzymes, amino acids and herbal extracts that all serve their own specific purposes. There are many reasons why people take natural supplements. Some people want to support their bodies’ natural processes, others want natural help with a specific health concern, and some just want to maintain good health. Dietary supplements have been one way that consumers have sought to fulfill unmet dietary needs. Fisetin is one of many supplements like this that people are turning to attempt to make themselves feel better. Many of my patients opt to take supplements to make sure they get enough essential nutrients and to maintain or improve their health.

POTENTIAL BENEFITS

Fisetin is a naturally occurring antioxidant found in many fruits and vegetables. Fisetin is known as a neuroprotective agent, meaning it has been shown to have potential benefits in helping the body fight against both acute and chronic neurological diseases.  Fisetin is one of the most common and bioactive flavonoids which possesses potential neuroprotective effects. Fisetin also enhances learning and memory, decreases neuronal cell death, and suppresses oxidative stress.  Fisetin has been shown to have significant protective effects on the body from oxidative stress, which is why Fisetin may be taking it as it can potentially be beneficial for those looking to improve their health or prevent disease. Oxidative stress refers to the level of damage done to cells in the body by free radicals. Fisetin has been shown to have some effect against oxidative stress, but it is not yet known whether Fisetin itself can actually reduce oxidative stress or if Fisetin can enhance antioxidants that are already present in the body. It is also unknown how Fisetin works as an antioxidant. Fisetin may work as a scavenger, Fisetin can bind to free radicals, Fisetin could be regenerating the antioxidants that it is acting with, or Fisetin itself may act as an antioxidant. There is still much to learn about Fisetin.

FISETIN AND LONGEVITY

As we age, we accumulate damaged cells. Damaged cells can cause tissues to function improperly or not work at all. Fisetin has been shown to reduce senescent cell burden in mice by activating the body’s enzymes that clear out senescent cells. Senescent cells are cells that have stopped dividing to replicate themselves. Senescent cells can accumulate in all tissues with age and secrete pro-inflammatory cytokines and chemokines. Fisetin has been shown to increase the lifespan of mice. In a recent study, Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.

FISETIN & and mTOR

mTOR is responsible for controlling cell growth, division, and metabolism. Recent research shows how Fisetin inhibits the mTOR pathway. When you inhibit the mTOR pathway you are essentially slowing down the aging process.

Fisetin & Inflammaging

Inflammaging refers to the chronic low-grade inflammation that is caused by cellular damage, oxidative stress, and mitochondrial dysfunction. Fisetin is believed to be able to reduce inflammation because Fisetin has shown an ability to reduce cellular (nuclear) damage in animal studies. This is accomplished by Fisetin’s ability to inhibit by inhibiting pro-inflammatory enzymes and substances, like lipoxygenases and NF-kB.

FUTURE RESEARCH

As research continues on this compound more information about how fisetin could be used for medicinal purposes will be revealed. Fisetin holds great potential for multiple applications in medicine, and research studies have shown Fisetin’s positive anti-inflammatory and anticancer effects on different cell types. Over the last two decades, much attention has been drawn to plant-derived bioactive compounds as novel therapeutic agents for treatment of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The current research suggests that the benefits of Fisetin may be worth considering for those looking for natural options to improve their health.

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.

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EXTRACELLULAR MATRIX

The extracellular matrix is a network of proteins and other molecules in the space between cells. It helps cells attach to one another and move around. You can think about this like scaffolding for building a house: it provides support and structure for all kinds of activities inside the cell without getting too involved in how those things happen. When there’s damage or injury, it also sends signals to help repair or replace damaged parts of tissue by recruiting stem cells from elsewhere in the body. In this blog post, we will explore how extracellular matrix regulation works to maintain homeostasis from birth to death so you can better understand your body’s natural aging process!

WHAT IS THE EXTRACELLULAR MATRIX?

The extracellular matrix (ECM) is a dynamic structure that provides a structural framework for cellular organization and movement. It is a three-dimensional space, extending between cells that are defined by components produced by the cells themselves as well as cells that they neighbor.

The ECM consists of a dynamic mixture of structural proteins which are typically secreted from the cell into the extracellular environment. The extracellular matrix is made up of many components, including molecules like collagen and elastin, macromolecules like glycoproteins or proteoglycans, proteins like adhesion proteins that allow cells to bind to each other, growth factors that signal new tissue formation, and others.

Collagen is one of the most prominent components of the extracellular matrix. It provides strength and stability to tissues and is primarily responsible for wound healing and tissue repair.

There are many types of glycoproteins, or proteoglycans, which give the matrix its winding appearance, similar to DNA’s iconic double helix. These macromolecules allow cells to recognize and bind to the matrix components.

Several types of adhesive proteins promote cell-to-cell contact, which can be found on either side of a plasma membrane where they’ll spread out from the cell’s surface towards the extracellular matrix. These proteins will crosslink, or bond together with other adhesive proteins to form a mesh that reinforces the adhesive bond between cells.

4 Major Purposes of the Extracellular Matrix:

Containment of cell growth: This refers to how the matrix can “wrap” around cells while still allowing them to grow in size while confined by the surrounding ECM.

Cell signaling and communication: Cell signaling and communication refer to how cells can send signals through the matrix so that growth and development happen in the right place at the right time.

Binding cells together to form tissues or organs:  The adhesion proteins that hold cells together can also link them to the extracellular matrix.

Removal of dead or damaged cells from the body:  Cells are constantly dying and being replaced, so the ECM will send signals to attract stem cells that can migrate towards their location within tissue in order to repair or replace damaged cells.

HOW DOES THE EXTRACELLULAR MATRIX REGULATE CELL BEHAVIOR?

The extracellular matrix is a critical mediator of cell behavior. In fact, cells respond to their environment by changing shape and altering gene expression in order to perform their job properly. 

Cell adhesion: This refers to how cells bind together very tightly with adhesive proteins that can crosslink with other adhesive proteins across the plasma membrane so they strengthen the bond between cells.

In order for cells to join together correctly at the right times and places, they need to be able to sense their environment and respond by sending signals through a network of proteins that bind together in a very specific way. So if a developing embryo is going to form into multiple layers that will eventually become distinct tissues or organs, cells in each layer will need to bind to the ECM and pass signals through it to be able to change shape and function into whatever they’re supposed to become.

3 Types of Cell Adhesion:

Integrin: These proteins anchor cells to the extracellular matrix, primarily binding between adhesive proteins on one side of a plasma membrane and “integrin-binding sites” on the other side of the plasma membrane.

Cell-matrix adhesion: This refers to how cells can bind directly to ECM components, which involves integrins as well as other types of adhesion proteins.

Compartmentalization/Segregation: This refers to how cells can create closed boundaries that will separate different tissues from each other.

In order for cells to be able to create compartments, they need to regulate the way substances enter and exit the local environment. In fact, many types of tissue have a limited list of molecules that can diffuse across their borders in one direction or another – this is called “selective permeability”, and it’s a feature of many cell types.

2 Main Features of Selective Permeability:

1) Pores in the plasma membrane allow solutes to move through them but prevent water from moving freely through those pores, due to the presence of lipid bilayers. This allows cells to selectively control which molecules can enter or exit their local environment.

2) Cells can have a different level of permeability in different directions, so some proteins will move freely across the cell membrane while others cannot – this is called “anisotropy”.

HOW DOES SELECTIVE PERMEABILITY WORK?

Different types of cells can adjust how permeable their plasma membranes are to help create local boundaries and also take in the right molecular nutrients for their job. In regards to the extracellular matrix, the ECM can bind to integrins on the plasma membrane of cells, which helps create a boundary that separates tissues from each other. Integrins are the major cell adhesion proteins, which means they bind cells to the ECM. Cells will be able to pass molecules through the border into neighboring tissues, but if the molecule is too large it won’t fit through the pores of the membranes and therefore cannot go across. All cells have distinct levels of permeability in different directions to help create a very specific environment for each cell type.

EXTRACELLULAR MATRIX & LONGEVITY

Part of what allows cells to remain differentiated is the extracellular matrix. It provides cells with the appropriate molecular signals to maintain their state, and when they move to a different tissue it also helps ensure that they will behave correctly in their new local environment – which is why this system breaks down when there is damage or disease. Abnormalities in the extracellular matrix are linked with age-related diseases. When ECM is broken down, it releases many different molecules that can cause inflammation. Inflammation is an immune response meant to eliminate threats to the body, but chronic inflammation can be very harmful and eventually result in death. When this happens over time the extracellular matrix will degrade and build up in ways that are detrimental to our health. When this happens, it causes “inflamm-aging” which is when inflammation builds up over time due to wear and tear on the body.

As we age, the extracellular matrix continues to degrade in many ways. The aging process involves many deleterious changes in the cells and tissues of an organism, which can affect how it functions. Lifestyle factors may accelerate the degradation of the extracellular matrix. Since ECM is responsible for cellular differentiation, preventing this degradation could lead to greater longevity because it would allow cells to maintain their state and continue functioning properly.  

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.

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CELL DANGER RESPONSE: What it is and why its important

The body’s immune system is a complicated, elegant machine that protects us from the outside world. It does this by recognizing invaders through amazing sensing mechanisms and responding to them with incredible precision. In the case of cell danger response (CDR), our cells do their best to protect themselves as they are being attacked by viruses or bacteria. Yet CDR can be dangerous if it overreacts and causes inflammation – which can lead to chronic diseases such as diabetes or even cancer. In this week’s blog post we will not only explain what CDR is but also how we minimize its risks so we may live a healthy life.

WHAT IS THE CELL DANGER RESPONSE?

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. 

How it works is by the cell senses that it is being attacked, then using specialized proteins to monitor our metabolism. When CDR is activated, the body will use available energy sources and switch its focus to self-defense rather than growth and reproduction. CDR is a mechanism that allows cells to sense ‘danger’ that may be caused by viruses or bacteria. This danger can also come in the form of molecules such as DNA, RNA, and proteins – all of which are components found inside our cells.  When these substances get leaked into the extracellular environment, CDR kicks into gear.

The activated CDR will then enter into a cascade – this is where it gets its name, the danger response cascade (DRC). The danger response cascade can be broken up into five steps that occur in succession: 

1. Detection: Detection of PAMPs (e.g., pathogen-associated molecular patterns like lipopolysaccharides) or damage-associated molecular patterns (DAMPs). PAMPs are substances that can be recognized by specialized receptors, such as Toll-like receptor (TLR), NOD-like receptor (NLR), and RIG-I like helicases (RLH). DAMPs refer to the cellular debris or damage that results from being attacked. 

2. Activation of MAPKs, IKKɛ, TBK1, PKA, and PKR. Next these activated enzymes activate transcription factors (which refers to a biochemical process by which a particular gene’s instructions are copied into RNA) that then activate or suppress inflammation-promoting genes while suppressing other essential genes involved in repair pathways. When we discuss activated enzymes, this refers to enzymes that have been phosphorylated, which means a phosphate group has been added to the enzyme.  

3. Activation of transcription factors such as NF-kB, FOXO3a, and HIF1α. These transcription factors then go on to stimulate or suppress the transcription of genes that regulate inflammation and also cell survival. 

4. Activation of MDA5 & RIG-I: MDA5 and RIG-I are critical to the CDR response because they activate an antiviral pathway known as type I interferon production. Type I interferon production is a pathway that allows our body’s immune system to help fight infections. 

5. Secretion of inflammatory cytokines to induce downstream immune cells to take action against the infection. Inflammatory cytokines are a group of signaling proteins that trigger inflammation at sites of infection. The cells which release these cytokines are called antigen-presenting cells (APCs) and include monocytes, macrophages, dendritic cells, and B lymphocytes. This cascade is what allows CDR to induce inflammation – yet it can have negative consequences if activated over and over again.

In addition, CDR can also occur in response to non-infectious stresses such as heat, UV irradiation, and oxidative stress. These stresses have been shown to activate IKKɛ (which is one of the last components in the cascade) and cause it to activate NF-κB (Nuclear factor-kappa B). When activated, this protein moves into the nucleus where it works with other transcription factors to promote the expression of genes that trigger inflammation. It is important to note that these events happen within minutes of your body detecting CDR triggers. 

WHAT IS THE DANGER RESPONSE CAUSED IN THE BODY?

Inflammation is a vital part of the CDR cascade. It’s what helps cells fight off disease, but there are consequences if it goes on for too long or isn’t properly regulated.  Left unchecked, inflammation can lead to several chronic conditions. 

 Inflammation has been linked to cardiovascular disease, arthritis, atherosclerosis, type 2 diabetes, Alzheimer’s disease, and even depression. One of the most well-known links between inflammation and chronic illness comes from the research of Dr. Robert Ader. In 1974 he conducted a study in which two groups were given an antitoxin to protect against poison. 

 Group A only received the treatment, while group B also had their spleens removed beforehand to prevent their immune systems from mounting an inflammatory response. After receiving the antitoxin both groups were then injected with the poison. However, unbeknownst to them this second injection was not actually poisonous but just saline solution therefore they should not have gotten sick. 

To the surprise of the researchers, group B got just as sick as group A even though they did not have an immune system. Basically, because their bodies had already mounted an inflammatory response when injected with the saline solution it was interpreted by their brains to be a poison so they could become ill. This example is just one of many that illustrate how chronic inflammation can lead to the development of disease.

HOW CAN WE AVOID THE DANGER RESPONSE?

The answer to this question is multifactorial. First, it’s important to avoid or control infections with your immune system because that is what triggers the response in the first place.  

Second, it’s also best to take care of your body. This means eating a healthy diet, exercising regularly, practicing stress management, and more. 

Third, optimizing your immune system is important.  The better it functions the less likely you are to succumb to disease and the more effective it will be at fighting off infections.

Fourth, protect your cells from damage and stress by limiting exposure to toxins and sources of oxidative stress such as UV radiation and environmental pollutants. This includes using antioxidants that can directly neutralize free radicals before they do damage: vitamin C, vitamin E, manganese, selenium, copper, zinc, and more.

Finally, genetic variation also determines how many times your immune system can mount a CDR response before producing dysfunctional cells. This means that although the danger responses in everyone are the same there is a big difference in their potential scope because of individual genetics. Different SNPs have also been linked to an impaired danger response.

Although the danger response is an important part of fighting infections, it can also be responsible for chronic inflammation which has been linked to many health problems. Fortunately, there are things you can do to prevent this from happening. By implementing lifestyle changes you can help your body fight off disease while simultaneously protecting your cells from damage. 

How can the Institute for Human Optimization help you? At IfHO, we utilize a personalized, precision-based approach to medicine. Precision Medicine acknowledges individual differences in genes.  By having a better understanding of the individual’s genes and making therapeutic decisions based on their genetics, we can work together to drive CDR in a desirable direction.   

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.

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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.

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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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