Not all regenerative medicine is created equal.

We have recently obtained another key weapon in our office. This weapon is a true Class 4 COLD LASER. But this is not like the typical class 4 laser. Many people know about lasers but are not exactly sure how they achieve their goals. The basic science of lasers is that they use the principle of Photobiomodulation. The following illustration shows this concept. Photobiomodulation is defined as a form of light therapy that utilizes non-ionizing light sources. These include near ultraviolet, visible light, infrared, microwave, radio waves, and low-frequency radio frequency (long-wave) are all examples of non-ionizing radiation. By contrast, far ultraviolet light, X-rays, gamma-rays, and all particle radiation from radioactive decay are ionizing light sources. Photobiomodulation is a NON-THERMAL process involving endogenous chromophores. The first law of photobiology explains that for a low power visible light to have any effect on a living biological system, the photons must be absorbed by electronic absorption bands belonging to some molecular photo-acceptors, which are called chromophores. Here is a good explanation of chromophores. A chromophore is the part of a molecule responsible for its color. The color that is seen by our eyes is the one not absorbed by the reflecting object within a certain wavelength spectrum of visible light hence the objects steal the objects from the wheel. Chromophores will elicit reactions at various biological sites. This process results in beneficial therapeutic outcomes including but not limited to the alleviation of pain or inflammation, immunomodulation, and promotion of wound healing and tissue regeneration. We can see this principle in the following illustration: What we are able to see is that a very important aspect of laser therapy involves the mitochondria. The mitochondria produce ATP which is the body's energy currency. It does this by stimulating the Cytochrome C Oxidase which is an enzyme in the electron transport chain of the Krebs cycle. Laser therapy produces a shift in overall cell redox potential in the direction of greater oxidation and increased Reactive Oxygen Species (ROS) generation. In a biological context, ROS are formed as a natural byproduct of the normal aerobic metabolism of oxygen and have important roles in cell signaling and homeostasis. ROS are well known to stimulate cellular proliferation of low levels, but inhibit proliferation and kill cells at high levels. Nitric oxide is also involved in laser therapy. It may be photo-released from its binding sites in the respiratory chain and elsewhere. Nitric oxide will increase vasodilation and thus increasing blood supply. Nitric oxide may also act as a neurotransmitter helping with pain control. Also, not to be overlooked is the fact that the mitochondria have many important tasks in many other aspects of cell biology and cell signaling pathways. It has been proposed that the redox state of a cell regulates cellular signaling pathways that control gene expression. Modulation of the cellular redox state can activate or inhibit signaling pathways. When we start affecting the various pathways and affecting gene expression we have now crossed into the field of Epigenetics. Several regulation pathways are mediated through the cellular redox state. Changes in redox state induce the activation of numerous intracellular signaling pathways, such as nucleic acid synthesis, protein synthesis, enzyme activation and cell cycle progression. When all is said and done the application of a therapeutic dose of light to impaired or dysfunctional tissue leads to a cellular response mediated by mitochondrial mechanisms that reduce pain and inflammation, speed healing, and cell hemostasis. These cellular mechanisms responsible for the effect of visible light on cells include cytochrome c oxidase. Mitochondria are thought to be a likely site for the initial effects of light, leading to increased ATP production, modulation of reactive oxygen species, induction of transcription factors, and possible changes in mitochondrial DNA. These effects in turn lead to increased cell proliferation and migration particularly by fibroblasts. Fibroblasts are responsible for the production of collagen which is a basic building block for many of the bodys tissues including bone, cartilage etc. The lasers overall effect is that it will bio stimulate cells to increase cellular growth and regenerative activity, while simultaneously deactivating 7 or the 9 enzymes that cause inflammation by up to 70%. Another unique aspect of lasers is that they are considered to be monochromatic, coherent and collimated. Monochromatic means that there is a single wavelength which stimulates particular human tissues that will only respond to that specific wavelength being utilized. Coherent means that it minimizes the photon scatter as light interacts with the tissue. Lastly, because lasers have a higher power that works with a specific wavelength, they are collimated which allows it to actually reach the deep tissues. The following illustration drives home these points. HOW ARE LASERS CLASSIFIED? One may ask how are the lasers classified? The FDA classifies lasers from I to IV. For instance, a Class IV Laser is any laser device that the FDA has determined is powerful enough to pose a significant risk of injury to the eye. Consequently, being Class IV does not necessarily make a laser more effective, as that would depend upon what you intend to do with it and how you use it. Some Class IV lasers are used in health and medical settings for a wide range of therapeutic applications. Others are used for construction, cutting, burning and by hobbyists such as high-powered laser pointers. Let us look at some further perimeters of the Class IV Lasers. Hot lasers are known as Class IV lasers. Class IV lasers have a power output above 500 milliwatts (mW). At a lower power range, hot lasers are used for therapeutic purposes. Class IV lasers can cut tissue during surgical procedures. Most Class IV lasers are called hot lasers because they can rapidly increase tissue temperatures. The one common tread with class IV lasers is that they have higher power outputs and most translate the energy to heat. On the other hand, most, cold lasers are also known as low-level lasers, they are among Class II and Class III lasers. Cold lasers have a power output of less than 500 mW. These lasers are called cold because they do not generate a thermal effect. But we must realize that the decreased power will also decrease the penetration depth of the laser. The vast majority of lasers in medical use are not true class IV cold lasers but class III lasers. Many of them are advertised as a Class IV lasers but in reality, they are Class III lasers. If they happen to a Class IV laser then most of the energy is expended as heat. They may have some bells and whistles and other gimmicks. But it does not make them any more effective. As we can see in the following illustration, typically a Class IV laser will need much less treatment time than a Class III laser. Also, we will obtain a much greater depth of penetration with the Class IV laser. What most medical professionals do not seem to understand is that a laser with many medical benefits produces it benefits with LIGHT ENERGY NOT HEAT. Thus, when one is looking to derive benefits from the laser, heat should not be a consideration. THE PHOTONIC ENERGY IS WHAT ONE NEEDS TO BE CONCERNED ABOUT. The following illustration will give an idea about the difference. The most significant difference in the various types of lasers is the depth of penetration. There is a misunderstanding that a more efficient laser will produce heat. This is simply not the case. Most of the time when we are utilizing a laser we are interested in the depth of penetration. We also do not wish to subject the patient to long hours of treatment. So, if we can eliminate the heat and get penetration of depth than we may have something special. When all is said and done IT IS THE PHOTONIC ENERGY WHICH ACCOMPLISHES THE REPAIR. WHAT WOULD BE MY CHOICE FOR AN OPTIMAL LASER? I have used lasers for many years. The use of lasers for musculoskeletal conditions has long passed the point of being experimental. There are many different types of lasers in use. In our clinic we have been very happy with our laser sleeves and our original hand-held Class IV type laser. The original Class IV laser which we have been using requires eyewear protection and it will produce heat which could burn the skin. Nevertheless, it was efficient but at the same time there was a risk of thermal injury and because of the thermal considerations I believe the penetration was limited. If I were able to design a laser I would want one to be a Class IV laser that essentially did not cause any thermal damage. To be effective, the laser would have to have a power output of greater than 500 milliwatts. It would need to be monochromatic and have a wavelength of approximately 680 mM which is the ideal wavelength to stimulate the mitochondria. This is the sweet spot in the red spectrum range. It obviously requires eyewear. Also, it is cold laser. What are the differences between and hot and cold laser? Again, Cold Lasers are therapeutic lasers that produce an insignificant amount of heat and are extremely safe for use by professionals. Let us take a look at the specs of the new laser. The output of the new laser is 750 milliwatts. Remember, the energy output for the Class IV laser is above 500 milliwatts. So, we definitely classify as a Class IV laser by power output. The new laser is monochromatic so it essentially stays on one wavelength and its wavelength is 680 nM which is the sweet spot for mitochondrial stimulation etc. The wavelength is 680 nm. This is the sweet spot in the red spectrum range. This provides both a large safety margin and potent force. If we were to lower the wavelength we could lower the safety margin. The last aspect to an ideal laser is what is called lumen intensity. We need to look at some physical aspects of light when looking at lumen intensity. There are three terms we want to know when assessing lumen intensity. These are lumens, lux and candela. A good way to remember the differences between terms is: Lumens are how much light is given off Lux is how bright your surface will be Candela measures the visible intensity from the light source. The lumen intensity of the new laser is 550 lumens per millimeter of tissue radiated. The beam profile is one millimeter. This last spec will allow the user to pinpoint targeting tissue. Example would be a meniscus tear located posteriorly in the medial compartment, or a tear in the supraspinatus located inferior to the acromion for example. This later spec you can only utilize the function of when the laser is a true class four. You need the power of penetration without the heat damaging aspect. This is a very important aspect and the one important principle which needs to be conveyed and understood - not easy to do! True photonic intervention is dependent on absorption of the light force or energy. Not in the heat transmission normally incorporated into laser modules. The light is the energy! Again, we see a picture of our new Class IV laser. Notice it is a hand-held laser. It is battery powered. Many times, simplicity is a goal strived for but many times seldom achieved. The next illustration is a summation of all the benefits our new Class IV laser is able to achieve while at the same time being extremely safe to the patient as long as the proper eye precautions are taken. The last two illustrations are videos comparing the new class IV cold laser with a typical Class IV laser. The differences between the two are remarkable. The last two items really drive home the point of what makes this Class IV cold laser a truly unique laser. They are pictures and videos on two types of Class IV lasers. One is a typical Class IV laser which most medical professionals are familiar with. The other is the new Class IV cold laser. I did an experiment with two Class IV lasers. The first illustration is the typical Class IV laser. Now the wattage used with this laser is in the 6-watt range. This would probably cause a burn to the skin at this power especially if it were kept in the same spot. On the other hand, the second image is the true Class IV cold laser. Notice the difference in light intensity. I suspect this new Class IV cold laser may be a game changer. The preliminary results in the office are quite impressive. We are truly making use of photonic energy to make a difference. Time will tell, but this seems to be exactly what we asked for. Below is the Class IV hot laser shined into a container having a mixture and saline. We can see the red color from the laser is not vibrant. Realize that when the laser is being used on the body it will need to penetrate a mixture of saline and blood. The next picture and video are of the new Class IV cold laser. Notice how vibrant the color is. The same will happen in your body. Realize that the only difference between these pictures is the lasers. The container is the same container. Thanks,Dr. P

This is an especially fascinating study as far as aging is concerned. I left the article link at the end of my write up. What this study looked at was the ability of long-lived people to repair DNA damage. In this particular case they looked at inherited and naturally occurring genetic changes in older people. They found in the long-lived population two particular genes COA1 and STK17A. These are rather esoteric names but the importance is there! COA1 is involved with energy production and communication between the mitochondria and the cell nucleus. COA1 performed three functions that are part of the blue prints for anti-aging platforms. They directed cell response to DNA damage, they prompted badly damaged cells to die off, and controlled the amounts of Reactive Oxygen Species. I suspect these genes are stimulating the P-53 gene. P -53 is called the tumor suppressor gene. Taking things one step further, remember that NAD+ is a substrate for DNA repair proteins such as PARP1, PARP2 and PARP3 as well as enzymes that can influence DNA repair capacity such as SIRT1 and SIRT6. The PARP enzymes typically get shut off when the body does not have enough NAD+ to go around. Looks like there may be some overlap here. Activate the DNA repair genes and you may live longer. At least you are giving yourself better odds. This is why I feel it is of paramount importance to take NAD supplements both orally and intravenously. Also remember, there is much science out there that shows Ozone therapy can increase the NAD levels in the body in addition to dramatically decreasing damage from Reactive Oxygen Species. The moral of the story here is: MAKE SURE YOU TAKE YOUR NAD TO STAY YOUNG.Here is the article I am talking about:https://bigthink.com/surprising-science/semi-supercentenarians-dna-repairThanks,Dr. P

The more involved I become with stem cells and the field of Regenerative Medicine, the more convinced I become of the importance of the mitochondria. Many of us in clinical medicine seem to brush over mitochondria. We now realize that many diseases are related in some way to deficiencies of the mitochondria. Success in stem cell procedures may depend on the health of the mitochondria. The above illustration shows the structure of the mitochondria. Mitochondria are rod-shaped organelles that can be considered the power generators of the cell, converting oxygen and nutrients into adenosine triphosphate (ATP). ATP is the chemical energy "currency" of the cell that powers the cell's metabolic activities. Mitochondria are often referred to as the powerhouses of the cell. They help turn the energy we take from food into energy that the cell can use. But, there is more to mitochondria than energy production. In fact, only about 3 percent of the genes needed to make a mitochondrion go into its energy production equipment. The vast majority are involved in other jobs that are specific to the cell type where they are found. Here is another illustration of the inner workings of the mitochondria The mitochondria have two membranes, an outer one and an inner one. Each membrane has different functions. The Outer membrane allows small molecules to pass freely through the outer membrane. This outer portion includes proteins called porins, which form channels that allow proteins to cross. Most cellular stress responses converge on the mitochondria. Consequently, the mitochondria must rapidly respond to maintain cellular homeostasis and physiological demands by fine-tuning a plethora of mitochondria-associated processes. The outer mitochondrial membrane proteins are central to mediating mitochondrial dynamics, coupled with continuous fission and fusion. These proteins also have vital roles in controlling mitochondrial quality. When cellular components like mitochondria become damaged or defective, they can be recycled by cells through a process called autophagy, which literally means self-eating. When mitochondria are degraded by autophagy, the process is specifically referred to as mitophagy. Mitophagy often occurs in defective mitochondria following damage or stress. This is actually one of the important aspects of aging. As we age, mitophagy will diminish resulting in increased damaged mitochondria. This has a snowball effect in that it leads to increased reactive oxygen species (ROS), decreased bioenergetics, and many age-related diseases. Mitochondrial damage may be the seminal event in many different diseases. If we increase mitophagy we will slow down aging. The following illustration shows the consequences of accumulated mitochondrial damage. The next structure to discuss is the inner mitochondrial membrane. It is extensively folded and compartmentalized. The numerous invaginations of the membrane are called cristae. Which are separated by crista junctions from the inner boundary membrane juxtaposed to the outer membrane. Cristae significantly increases the total membrane surface area compared to a smooth inner membrane and thereby the available working space. The inner membrane is also loaded with proteins involved in electron transport and ATP synthesis. This membrane surrounds the mitochondrial matrix, where the citric acid cycle produces the electrons that travel from one protein complex to the next in the inner membrane. The crista membranes contain most, if not all, of the fully assembled complexes of the electron transport chain and the ATP synthase. The following illustration demonstrates this concept. We see the two membranes and subsequent ATP production. In review, at the inner mitochondrial membrane a high energy electron is passed along the electron transport chain. The energy released pumps hydrogen out of the matrix space. The gradient created by this drives hydrogen back through the membrane, through ATP synthase. As this happens, the enzymatic activity of ATP synthase synthesizes ATP from ADP. This whole process is called oxidative phosphorylation (OXPHOS), which is the main method and most efficient method the body uses to make ATP. The more efficient this process the better in shape one is. Another structure present is the mitochondrial ribosomes. Mitochondrial ribosomes (mitoribosomes) perform protein synthesis inside mitochondria. Throughout evolution, mitoribosomes have become functionally specialized for synthesizing mitochondrial membrane proteins. Mitochondrial ribosomes resemble bacterial ribosomes and both bacteria and mitochondria ribosomes share a slightly different genetic code from that in the nucleus. Actually, we see that ribosomes have two parts, a large and a small subunit. Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are a trans-kingdom enigma. At the molecular level, the components of Human mitochondria are assembled from viruses, bacteria, and other organisms. As such, the organelle we see in human cells today is called a trans-kingdom mixture that doesn't fully resemble any of its ancestors. The mitochondrial genome is built of 16,569 DNA base pairs, whereas the nuclear genome is made of 3.3 billion DNA base pairs. In keeping with its bacterial ancestry, mtDNA is also circular and multicopy with hundreds to thousands of copies present in every cell. mtDNA is very genetically compact and encodes only 13 proteins, all of which are core subunits of the oxidative phosphorylation (OXPHOS) complexes. These OXPHOS complexes, found only within mitochondria, are unique in human biology as they are the only cellular structures formed of proteins encoded by genes from the two separate genomes. The nuclear DNA provides around 90% of the required proteins for OXPHOS, and the mtDNA provides the remaining 10%. Remember that the OXPHOS complexes are responsible for ATP production. Mitochondria are the only organelle to have their own DNA. Mitochondrial DNA (mtDNA) is more susceptible to damage (including mutations) than nuclear DNA. The reason for this is many folds. Most likely this is due to a lack of histones to protect the DNA from damage. The below diagram gives a brief explanation of histones. Histones package and order the DNA into structural units called nucleosomes. They act as spools around which the DNA gets coiled and thus a very long strand of DNA can be fit into a much smaller space. This is demonstrated in the following: DNA damage is also caused by the proximity of mtDNA to Reactive Oxygen Species (ROS) production. We must remember that the mitochondria are engaged in oxidative phosphorylation which means that they are using oxygen to produce energy. The by-product of the energy production is the ROS. Also, mtDNA has limited DNA repair systems and limited proofreading capacity during replication all of which can lead to accumulated mitochondrial DNA damage. Furthermore, the mitochondrial DNA is ever changing. When a cell divides, its mitochondria are partitioned between the two daughter cells. However, the process of mitochondrial segregation occurs in a random manner and is much less organized than the highly accurate process involved in nuclear DNA division during cell replication commonly called cell mitosis. As a result, daughter cells receive similar, but not identical, copies of their mitochondrial DNA. WHAT REGULATES THE MITOCHONDRIA? THE SIRTUIN FAMILY OF PROTEINS Sirtuins are a family of proteins that regulate cellular health. Sirtuins play a key role in regulating cellular homeostasis. Homeostasis involves keeping the cell in balance. Sirtuins can only function in the presence of NAD+, nicotinamide adenine dinucleotide, a coenzyme found in all living cells. NAD+ is vital to cellular metabolism and hundreds of other biological processes. Humans contain seven sirtuins (SIRT1-7) that modulate distinct metabolic and stress response pathways. Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in the mitochondrion. The others are found in the nucleus and one in the cytoplasm. The basic role of sirtuins, however, is that they remove acetyl groups from other proteins. Acetyl groups control specific reactions. They are physical tags on proteins that other proteins recognize will react with them. Sirtuins work with acetyl groups by doing whats called deacetylation. This means they recognize theres an acetyl group on a molecule then remove the acetyl group, which tees up the molecule for its job. One way that sirtuins work is by removing acetyl groups (deacetylating) biological proteins such as histones. When the histones have an acetyl group, the chromatin is open, or unwound. When the histones are deacetylated by sirtuins, the chromatin is closed, or tightly and neatly wound, meaning gene expression is stopped, or silenced. This is not that common for the Sirtuins in the mitochondria. Mitochondria regulation is where things get interesting. If we start manipulating the regulation of the mitochondria then there are a whole host of conditions from aging to chronic neuro-degenerative conditions which we might be able to impact. Recent findings have shed light on how the mitochondrial Sirtuin functions in the control of basic mitochondrial biology, including energy production, metabolism, apoptosis, intracellular signaling and perhaps most importantly mitochondrial genesis. The following diagram shows some of these aspects: What these Sirtuins do is help in the generation of cellular energy. As high-energy electrons derived from glucose, amino acids or fatty acids fuels are passed through a series of protein complexes (I-IV), their energy is used to pump protons from the mitochondrial matrix through the inner membrane into the inner-membrane space. This is referred to as the electron transport chain. Ultimately, the electrons reduce oxygen to form water, and the protons flow down their gradient through ATP synthase, driving the formation of ATP from ADP. Reactive oxygen species (ROS) are a normal side-product of the respiration process. ROS are essentially free radicals. During cellular stress or damage, mitochondria release a variety of signals to the cytoplasm and the nucleus to alert the cell of changes in mitochondrial function. In response, the nucleus generates transcriptional changes (stimulates certain genes) to activate a stress response or repair the damage. The main function of mitochondria is to metabolize or break down carbohydrates and fatty acids in order to generate energy. In review, ATP generation occurs within the mitochondrial matrix, though the initial steps of carbohydrate (glucose) metabolism occur outside the organelle. Glucose is first converted into pyruvate and then transported into the matrix. Fatty acids on the other hand, enter the mitochondria as is. ATP is produced through the course of three linked steps. First, using enzymes present in the matrix, pyruvate and fatty acids are converted into a molecule known as acetyl-CoA. This then becomes the starting material for a second chemical reaction known as the citric acid cycle or Krebs Cycle. This step produces plenty of carbon dioxide and two additional molecules, NADH and FADH2, which are rich in electrons. The two molecules move to the inner mitochondrial membrane and begin the third step: oxidative phosphorylation. In this last chemical reaction, NADH and FADH2 donate their electrons to oxygen, which leads to conditions suitable for the formation of ATP. As an interesting aside, the optimal ratio of NAD+ /NADH is 700/1. Greater amounts of NADH lead to aging. NADH is considered a marker of aging. A secondary function of mitochondria is to synthesize proteins for their own use. They work independently, and execute the transcription of DNA to RNA, and translation of RNA to amino acids (the building blocks of protein), without using any components of the cell. Another aspect that the Sirtuins control is the control of Apoptosis. Apoptosis is a cellular process of programmed cell death. This occurs when the mitochondrial outer membrane allows much more permeability than normal. This will ultimately commit the cell to death. Mitochondrial sirtuins act in synergistic or antagonistic ways to promote respiratory function, antioxidant defense, insulin response and adipogenesis all of which can protect individuals from aging and aging-related metabolic abnormalities. If these cells are not dealt with they might become senescent cells. A senescent cell is one that should have died but continues to remain alive. The problem with the senescent cells is that they will release a number of inflammatory growth factors which can cause havoc in the body. HOW DO WE KEEP OUR MITOCHONDRIA HEALTHY? We have seen the ins and outs of the mitochondrial structure and function. The question that begs is how do we keep the mitochondria healthy? More and more research articles demonstrate the foundational importance of optimal mitochondrial function for health. There is a growing body of research showing that mitochondrial dysfunction is surprisingly common and associated with most chronic diseases. The above and below illustrations give us an idea of how to keep our mitochondria running smoothly. The first illustration shows some supplements which keep things running smoothly: The second illustration shows not only specific supplements but also classes of supplements such as polyphenols (Polyphenols are micronutrients that we get through certain plant-based foods) and proanthocyanidins (these are chemical compounds that give the fruit or flowers of many plants their red, blue, or purple colors). It also stresses some lifestyle factors that can increase mitochondrial efficiency. The specific supplements that enhance mitochondria function are evident in the list. Let us talk specifically about some of the polyphenols. They are included in many supplements, though they're also easy to get in your diet from foods like fruits, vegetables, teas, and spices. There are more than 8,000 types of polyphenols. A lack of polyphenols isnt associated with specific side effects. However, they are regarded as lifespan essentials'' for their potential to reduce the risk of chronic diseases. This is especially true based on their effects on the mitochondria. Research suggests that supplementation with pyrroloquinoline quinone, also known as PQQ, can improve the number of mitochondria in the body while enhancing their functionality. This research also suggests that effective treatment for many diseases caused by mitochondrial dysfunction may rest at least partly in this coenzyme. PQQ is readily found in the soil, so it makes sense that the best dietary sources are fruits and vegetables grown in that soil. Fermented foods are rich in these molecules. One of the best sources of PQQ is very dark chocolate. MITOCHONDRIAL PEPTIDES The above illustration shows some of the main peptides produced by the mitochondria. Mitochondria derived peptides (MDPs) are a series of peptides encoded by mitochondrial DNA, and have similar functions to mitochondria. They are new metabolic regulators of human body, and play a cytoprotective role in maintaining mitochondrial function and cell viability under pressure. Peptides are biomolecules comprised of amino acids which play an important role in modulating many physiological processes in our body. Peptides are short strings of amino acids, typically comprising 250 amino acids. Amino acids are also the building blocks of proteins, but proteins contain more. Peptides may be easier for the body to absorb than proteins because they are smaller and more broken down than proteins. Mitochondria produce numerous small polypeptides from their short open reading frame (sORF) regions of mtDNA that have significant biological activity. These include humanin, six small-humanin like peptides, and MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c), together termed mitochondrial derived peptides (MDP). MOTS-c is a peptide which is called an exercise mimetic. Exercise Mimetics are novel ways of getting the benefits of exercising, without having to exercise. Multiple studies have demonstrated MOTSc's ability to enhance lipid beta-oxidation, increase thermogenic brown fat, decrease fat gain on a high-fat diet, and improve glucose uptake during glycolysis. Various mitochondrial peptides are produced but their use is not allowed in the USA under the current regulations. Hopefully, this will change with time. As time goes on we are discovering more and more about the importance of the mitochondria and their ramifications to our health lifespan. We see that methods to boost mitochondria efficiency are varied. But when all is said and done. Some of the most important factors are exercise especially intermittent high intensity training, intermittent fasting, a variety of supplements including NAD. Low levels of oxidative stress such as is produced by intravenous ozone therapy are also important in the proper function of the mitochondria. We must remember that mitochondrial decay is inevitable; it cannot be prevented, at least with todays technology. What is not inevitable is the rate of decay. The mitochondrial rate of decay is determined by one thing: oxygen efficiency. Perhaps the following diagram sums it all up: We see many bad things happen when our mitochondria are not working properly. Thanks,Dr. P

Nrf2 is also called the Nuclear factor erythroid 2-related factor 2. NRF2 is a transcription factor that activates over 500 genes. The main reason NRF2 is so highly sought, is because it is a key transcriptional regulator of several antioxidant and anti-inflammatory enzymes. Nrf2 is now recognized to be involved in the cellular response to multiple stressors including foreign substances, excessive nutrient/metabolite supply, inflammation, and the accumulation of misfolded proteins. The Nrf2 protein, known as a transcription factor because of its ability to control genes, is the key component of a pathway (a sequence of biochemical reactions in a cell) that senses and responds to changes in oxidative balance. Nrf2 is one of the body’s major pathways. We need to think of the pathways as the body’s computer software and the cells and organs as the computer hardware. Nrf2, in fact, regulates many hundreds of genes that have nothing to do antioxidant enzymes per se, but rather provide protection from a broader range of stress-related events that are encountered by cells, organs, and organisms, under both normal and pathological circumstances. The Nrf2 pathway is under tight control. When the Nrf2 protein in bound in the cytoplasm it is essentially inactive. The following illustration shows this concept. This illustration is essentially the essence of how the Nrf2 pathway functions. We must remember that Nrf2 is a protein. Proteins, although they are typically confined within the cell or on a cell, have a complicated life cycle. The illustration shows the complicated cycle of the Nrf2 ecosystem. It actually demonstrates its actions in the cell. For example, soon after NRF2 is made by ribosomes in the cytoplasm, it is normally sequestered by KEAP1, which quickly loops the Nrf2 protein with ubiquitin ligase Cullin3 for transport to the proteasome. Here, the ubiquitin is stripped off and NRF2 is degraded and recycled. If all is well in the cell, this process gives NRF2 a half-life of about 20 minutes. Remember, if all is well in the cell Nrf2 is typically not active. Looking at the diagram in a different manner we see that the Nrf2 is held “prisoner” in the cytoplasm. The “prison guard” is called Keap1. If given the opportunity Keap1 will go on and destroy the Nrf2 protein. This is called proteasomal degradation. Given the right conditions (in this case a stress to the body) the Nrf2 protein breaks the stranglehold that the Keap1 proteins maintain. The Nrf2 protein then makes its way to the nucleus where it can eventually react with certain genes and produce certain beneficial compounds. A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway. This explanation is basic but it gives the essentials of how the Nrf2 protein functions. WHAT ARE THE STRESS CONDITIONS THAT STIMULATE THE NRF2 PATHWAY?The Nrf2 pathway senses the need for antioxidant enzymes and regulates their production to maintain metabolic balance. The sensing components of the pathway chemically modify and release Nrf2 so that it may diffuse into the nucleus of the cell where the DNA resides. Once in the nucleus, the Nrf2 will start reacting with a variety of genes found in the DNA of the nucleus. It can then “switch on” or “turn off” the genes it controls (often termed survival genes) to produce the protected state within the cell. Our DNA encodes about 20,000 genes, each representing a “blueprint” for the production of a protein or enzyme necessary for a healthy existence. Each of these “blueprints” requires a regulating control called a “promoter” that determines precisely how much of each product is produced, and under what circumstances. By binding to one specific type of these switch-like promoter regions called the “Antioxidant Response Element (ARE)”, the Nrf2 factor controls the rate of production from hundreds of different genes that allow cells to survive under stressful conditions.NRF2 is part of a group of transcription factors called nuclear receptors. Transcription factors are proteins involved in the process of converting, or transcribing, DNA into RNA. Transcription factors include a wide number of proteins that initiate and regulate the transcription of genes. Once the Nrf2 translocates to the nucleus, it results in the production of Anti-Oxidant Response Elements. There are a number of these elements including Glutathione, Catalase, and a number of other anti-oxidants. We should think of these as endogenous antioxidants. Meaning they are made by the body. These are quite powerful. The next illustration shows more of the whole picture of the Nrf2 pathway. From the Nrtf2 stimulators to the actual response elements to the blocking of the reactive oxygen species (ROS) by the response elements. Ultimately, like many pathways in the body, the Nrf2 pathway targets the mitochondria. The illustration shows certain agents which block the Nrf2 and others which encourage its activation by disabling the stranglehold the Keap1 protein has on the Nrf2 protein. The following is a diagram of transcription factors:The illustration shows how Nrf2 handles the inflammation caused by the ROS. Inflammation is the most common feature of most chronic diseases and complications. Several studies have demonstrated that Nrf2 contributes to the anti-inflammatory process by orchestrating the recruitment of inflammatory cells and regulating gene expression through the antioxidant response elements (ARE). These genes produce a large variety of antioxidant enzymes that create a network of protection by neutralizing primary and secondarily generated oxidants and by cleaning up the toxic byproducts they leave in their wake. Also, they help to repair the damage the oxidants have caused. This is especially important for mitochondrial health. Mitochondria help produce free radicals (Reactive Oxygen Species=ROS) and at the same time are very susceptible to their damage. Oxidants such as the superoxide radical (O2-) and hydrogen peroxide (H2O2) are produced by the process of “burning” the foods that sustain us. The Nrf2 pathway senses the need for these antioxidant enzymes and regulates their production to maintain metabolic balance. Several things can upset this delicate balance, the most significant one is aging. Unfortunately, aging slowly tips the balance toward the oxidative side resulting in “oxidative stress.” Disease processes can also result in overproduction of oxidants. Many major diseases associated with aging, such as heart attacks, stroke, cancer, and neurodegenerative conditions such as Alzheimer’s disease also increase production of oxidants thus creating oxidative stress and inflammation. When our immune cells are stimulated they can produce reactive oxidants (O2-, H2O2, OH, and HOCl) to deal with both bacteria and viruses. This can result in the destruction of the viruses and bacteria. But the problem with these compounds is that our otherwise healthy cells get caught in the cross-fire and sustain collateral damage that we see and feel as inflammation. Unfortunately, we have seen this phenomenon in patients with a Covid 19 infection. They get such a vigorous immune response it is called a cytokine storm. Cytokine storms are one of the contributing factors to the high numbers of Covid deaths.HOW CAN WE HELP STIMULATE NRF2?The above diagram shows many of the moving parts of the Nrf2 pathway and its stimulation and resulting end products. In this illustration we see the arch villain of the Nrf2 pathway. This villain is called the NFkB pathway. This pathway is the opposite of the Nrf2 pathway. It is the thermostat of inflammation. It is a very important pathway. We must remember that some inflammation is essential. It is when the NFkB pathway gets over-stimulated that problems arise. Recent research has identified certain processes to be very effective at stimulating our body’s natural mechanisms for creating antioxidants through NRF2 activation. NRF2 activation can be achieved thru exercise, calorie restriction (including fasting) and ingestion of natural nutrients that are NRF2 activators. In our office we have found that intravenous Ozone is a potent stimulator of the Nrf2 pathway. The intravenous Ozone is part of a protocol called the EBO2 protocol. The intravenous Ozone momentarily produces Hydrogen Peroxide. The Hydrogen Peroxide is quickly converted into compounds called Ozone Messengers. These Ozone Messengers result in the stimulation of the Nrf2 pathway. They ultimately help to reduce inflammation. Other in office Nrf2 stimulants include intravenous Curcumin, Quercetin, and Resveratrol. Intravenously, these are very potent Nrf2 stimulants. Since they are given intravenously they become very bioavailable compared to their oral formulations. The question becomes what else can we do stimulate the Nrf2 pathway without a trip to the doctor’s office? We have already mentioned the usual suspects such as exercise, calorie restriction, modified keto type diet etc. However, we can still help to supplement Nrf2 stimulation with some oral compounds. In an ideal world one would first get some supplements intravenously and then proceed with lifestyle changes and oral compounds. Common NRF2 activators include Curcumin which is a widely studied and potent Nrf2 activator. The problem with Curcumin is its bioavailability. Not all Curcumin compounds are the same. Other stimulators include Pterostilbene and its weaker cousin Resveratrol. The problem with oral Resveratrol is also its bioavailability. Other stimulators include Quercetin (from onions) and sulforaphane (from broccoli) and antioxidants found in green tea, chocolate, and other sources. Different nutrients may activate NRF2 by different mechanisms and, when taken together, may be synergistic. I have taken the bull by the horns and designed a supplement which I feel will be unlike anything out there. The propriety blend of ingredients are:Fumaric AcidBrassicaUltracurAlpha Lipoic AcidQuercetinResveratrolPterostilbeneSome of these are well known while others may be new. One of the common threads with these particular compounds is that by and large they have much better bioavailability then their similar counterparts. Brassica is a broccoli derivative. Ultracur is a Curcumin derivative. They both have much higher bioavailability then competing products. One interesting item in this list is Fumaric acid. Fumaric acid is the “Crown Jewel” of this formula. A derivative of Fumaric acid has been approved by the FDA in the treatment of relapsing forms of Multiple Sclerosis. It is also used in the treatment of psoriasis. Currently I am not aware of any Nrf2 supplement blend that is utilizing Fumaric acid derivative mixed with other supplements to stimulate Nrf2. This product should be available shortly. By raising Nrf2 levels, we are able to tap into one of nature’s most powerful mechanisms for the maintenance of good health. Regular consumption of these Nrf2 stimulating foods and supplements may substantially lower many of the health risks of modern living and increase our resistance to many diseases.IN REVIEW WHAT ARE THE PRACTICAL BENEFITS OF THE NRF2 ACTIVATORS?Recent research has found that “NRF2 activation” is very effective at stimulating our body’s natural protective mechanisms including promoting endogenous (natural) antioxidant production. Activation of NRF2 is believed to provide many health benefits including:REDUCING SYSTEMIC INFLAMMATIONLOWERING OF OXIDATIVE STRESS (REDUCING CELLULAR DNA, RNA AND PROTEIN DAMAGE)IMPROVING MITOCHONDRIAL FUNCTION (CELLULAR ENERGY PRODUCTION) ALL ROADS LEAD TO THE MITOCHONDRIANrf2 activation may have a positive impact on chronic inflammation and oxidative stress and so may be useful in the prevention or treatment of many common chronic disease processes including obesity, high blood pressure, reducing the risk of diabetes, cardiovascular disease, stroke, and the list goes on and on. NRF2 activators have been shown to protect the liver in conditions of chronic hepatitis and fatty liver. Let’s look at some more specific conditions that are directly affected by the Nrf2 pathway. Nrf2 ACTIVATION AND OBESITY AND INSULIN RESISTANCEObesity is now thought to be a systemic disease characterized by increased systemic inflammation and oxidative stress. As a consequence, obesity is clearly understood to be a major contributor to the development of hypertension, heart disease, stroke and some cancers. The importance of Nrf2 in obesity and insulin resistance is clearly evident and the potential use of an Nrf2 activator as a treatment method will continue to be an exciting area to advance. Nrf2 ACTIVATION AND PAINNrf2 activation is thought to reduce pain related to many conditions. The muscle pain and fatigue associated with fibromyalgia is believed to respond to NRF2 activation. Nrf2 activation may reduce the central sensitivity associated with many chronic pain conditions including chronic headaches, chronic back pain, and fibromyalgia etc. Nrf2 ACTIVATION AND ADDICTIONMany of the brain’s neurotransmitters and neurochemical processes are impaired in conditions of chemical and behavioral addiction. NRT2 activation may play a role in facilitating restoration of these neurochemical processes and facilitate addiction recovery. Nrf2 ACTIVATION AND STEM CELLS ACTIVATION AND SURVIVALAs a cellular metabolic and stress sensor, Nrf2 is a pivotal regulator of stem cell self-renewal, proliferation, and differentiation. Nrf2 displays cell type-specific and/or stage-dependent impact on stem cell biology in response to various environmental cues. Nrf2 maintain ASCs self-renewal, quiescence, and regenerative capacity while protecting against ASC depletion in response to stress and aging.I suspect this will take on increasing importance in Regenerative Medicine stem cell procedures. We have seen this concept already in organ transplants and rejection. As time goes on, we may depend more on allogeneic sources of stem cells which exhibit immune evasive rather than privileged responses to the immune system.Thanks,Dr. P

The journey to cultivating and maintaining wellness truly begins inside. For me, wellness began in 2013 when I was just 19 years old. I was a very stressed college student who was eating, breathing, and sleeping nursing studies. Studying at all hours of the day and night came with the development of some unhealthy habits. Most days I would skip exercise in fear of losing study time, and I was definitely not taking the time to cook healthy meals. By the time that I had reached my second year of nursing school, I had enough with feeling helpless to my stressors. That’s when I decided to take things into my own hands.As a new year’s resolution, I went to my first yoga class and it changed my life forever. After just one class I found myself breathing deeper, retaining more information when I studied, and craving healthier foods. During this transitional period, I found myself having more energy and a new zest for life. I found new ways to move my body and making healthy versions of my favorite foods became exciting and delicious. Later, I even went on to become a yoga instructor.I had never really enjoyed eating meat, and actually began a slow transition to a plant-based diet at the age of 10. Contrary to popular belief, vegetarianism is absolutely not synonymous with healthy, and there are many processed unhealthy foods that do not contain animal products. I also don’t believe that there is a “one-size-fits-all” solution when it comes to dietary intake. Just because eating plant-based works for me, does not mean that it will for you.When it comes to cultivating positive habits and longevity, I do not believe that the body benefits from “cold-turkey” methods of diet change. As I stated earlier, I transitioned to a plant-based diet over a number of years beginning with eliminating red meats, then poultry, then seafood. This allowed my body to adjust over time, and now I no longer crave any animal products at all.Here Are My Three Rules of Healthy Living:Find joy in living healthfully, so you don’t fall into old habits.Find your favorite way to move your body and do it daily.It doesn’t have to be long or strenuous, just keep putting one foot in front of the other. Set the tone for the day with your morning routine.I begin my day with 32 ounces of water with lemon, and follow it up with fresh pressed celery juice.Pro tip: you must press the celery fresh each morning or it will lose its benefits.If i’m in a hurry and cannot press the celery fresh, I substitute it with some warm water and apple cider vinegar. A teaspoon of honey helps to tone the bitterness down while you’re getting used to the flavor.Take a moment to breathe.Meditation isn’t for everyone, and I’m not saying that you need to do some sort of extensive breathwork. All I want you to do is wake up, sit on the side of your bed, close your eyes, and take a few deep breaths to acknowledge the start of the day. Use this time for positive affirmations. Tell yourself that it will be a great day!Eat mindfully.This is the best tip that I have ever received. Someone once told me that we must be thankful for our food, enjoy every bite, and be in the moment with it. This may sound a bit odd, but think about how many times we find ourselves in front of the TV or computer mindlessly shoveling food into our mouths.Even if your goal isn’t to eat entirely plant based, we can all benefit from decreasing our intake of red meat. Maybe you try saving it for a “treat” once per week and see how you feel?By eating with intention, I found myself enjoying my food more, and even eating less.At the end of the day, I believe our happiness is of the utmost importance. I’ve found that the degree of health I feel directly affects how happy I feel.Live well, eat well, and be well;Bella Sannasardo, RN, BSN

We are constantly pushing the envelope to come up with methods to improve our results clinically. We think that our new cytokine formula may be such a game changer. Our new formula makes use of Velvet Deer Antler. But the formula is much different from those formulas out there both in strength and the formula itself. It is a proprietary mix. The above illustration represents the growing portion of the antler. Deer Antler Velvet has been used in traditional Chinese medicine for thousands of years but has recently gained popularity in Western medicine. Deer antler can enhance immune system function, improving athletic performance, increasing muscle recovery, enhance sexual function, improve disease recovery, enhance cardiovascular function, and a host of other conditions. Deer Antler Velvet covers the growing bone and cartilage that develops into deer antlers. The growing antler contains a number of necessary cells, including fibroblasts, chondroblasts, chondrocytes and osteocytes. The tips of the antlers begin as undifferentiated mesenchymal stem cells which are transformed into cartilage. Later, the cartilage is turned to bone, due to the effects of testosterone. Deer antler velvet is antler that is still in its cartilaginous stage. One of the problems with Velvet Deer Antler is the purity and concentration of the product. Our antler product is sourced from a very reliable source. Typically, there is a concentration of 1500 mg of velvet extract per bottle. Honestly, that will have some effects but it is not exactly what we are looking for. We have sourced a concentration of 4500 mg of Velvet Deer Antler per bottle. This concentration would not be legal for any professional athlete and thus we would not use it on them. Typically, these higher concentrations will help balance hormones and promote tissue repair. In addition to this we have actually added certain supplements to this very potent formula. These supplements will increase stem cell efficiency and output from the bone marrow. This combination is totally unique to our practice and network and it is proprietary in nature. WHAT ARE THE MAIN COMPONENTS OF VELVET ANTLER? The above diagram gives some idea of the many benefits of deer extract. An important concept that is a common theme of many research papers is that the combination of all components of velvet antler provides a synergistic effect that is greater than the total effect that would be achieved by the separate use of each of its individual constituents. That means that if velvet antler is broken down into its constituents that are used separately, their combined effect is significantly less than the effect realized when the nutrients are provided in the naturally combined form of velvet antler. In summary, the effect of the complete product is greater than the summed effect of all components. Let us take a better look at exactly what is found in the antler products. Most of the antler product consists of protein. The active ingredients include collagen, lipids, glycosaminoglycans, minerals, and various growth factors. We will take a look at the major subgroups of components. The first component to take a look at are the glycosaminoglycans GLYCOSAMINOGLYCANS Glycosaminoglycans are complex carbohydrates. Glycosaminoglycans (GAGs), have widespread functions within the body. GAGs play a critical role in Regenerative Medicine. They play a crucial role in the cell signaling process, including regulation of cell growth, proliferation, promotion of cell adhesion, anticoagulation, and wound repair. They are an integral component of what is called the extracellular matrix. The extracellular matrix (ECM) is the non-cellular component present within all tissues and organs, and provides not only essential physical scaffolding for the cellular constituents but also initiates crucial biochemical and biomechanical cues that are required for tissue morphogenesis, differentiation and homeostasis. Research has shown GAGs exist in velvet antler in several forms including: ● Chondroitin Sulphate a carbohydrate that helps protect and rebuild degenerating cartilage and is regarded as a potent anti-inflammatory agent ● Glycosphingolipids are compounds involved with growth and metabolism of cells and with memory and learning ● Glucosamine Sulphate is a component of Chondroitin Sulphate and is a major component of cartilage and synovial fluid ● Hyaluronic acid a substance that binds cartilage cells together and lubricates joints. It also acts as a signaling molecule in many biological processes. ● Phospholipids the major structural lipid of most cell membranes Here is a good illustration of the ExtraCellular Matrix. It is the substance between the cells. Antlers grow by endochondral ossification, the same way that long bones do. A major non-collagenous protein, proteoglycan, a protein substituted with glycosaminoglycan chains, occurs in the cartilaginous tissue of antler. While its use in the antler is not understood, it has been shown that proteoglycan in cartilage, also called aggrecan, regulates differentiation of chondrocytes and may control calcium concentration in the growth plates where endochondral ossification occurs. This may have important implications when we are treating joints with regenerative medicine. More importantly, the next two illustrations show the ramifications of the ExtraCellular Matrix and repair of various tissues. We can see why enhancing the ExtraCellular Matrix is so important in Regenerative Medicine. We can see that these represent the pillars of regenerative cell therapy. There are few if any other products which have these effects on the extracellular matrix. This is certainly a huge benefit that comes with the Velvet Deer Antler product. The Glycosaminoglycans have a hand in all of the above repair processes. Most products are only addressing the cellular portions of repair while the antler products are more comprehensive in their approach. The next illustration shows how the Glycosaminoglycans are involved in the new field of tissue engineering. In the case of tissue engineering we call the synthetic ECM a scaffold. GROWTH FACTORS: THE CLONES OF WHAT STEM CELLS PRODUCE When we look at velvet antler growth factors, we see a list of whos who in the growth factor universe. Growth factors, which are generally considered as a subset of cytokines, refer to the diffusible signaling proteins that stimulate cell growth, differentiation, survival, inflammation, and tissue repair. The major growth factors which are found in deer antler include Insulin Like growth factors (IGF-1), Bone morphogenetic growth factors (BMPs), Transforming growth factor family (TGF), Fibroblast growth factor (FGF), Platelet derived growth factor (PDGF), Vascular endothelial growth factor (VEGF), Epidermal growth factor (EGF), Interleukins, and a variety of other factors. When looking at the various growth factors we realize that this appears to be similar to what is found in a Platelet Rich Plasma (PRP) product, and for that matter stem cells themselves release. Another aspect of deer antler deals with its Amino acid contents. Remember that amino acids are natures building blocks. Amino acids, often referred to as the building blocks of proteins, are compounds that play many critical roles in your body. They're needed for vital processes like the building of proteins and synthesis of hormones and neurotransmitters. These are broken down to essential and non-essential amino acids. Another type of amino acid is the free form amino acid. These amino acids aren't joined together with any other amino acids in a protein 'string'. This allows the individual amino acids to be instantly absorbed and used by the body without digestion. All of o Of all the growth factors the most consequential might be IGF-1. IGF-1 is a banned substance in the world of professional sports. The precursor of IGF-1 is Human Growth Hormone (HGH). IGF-1 is actually the active form of HGH. It is considered performance enhancing. In the smaller doses this is typically not an issue but in the higher doses we are using this is a problem and across the board we will not give this formula to any athlete in the high school, college, or the professional sports arena. Putting this aside, why do we like IGF-1? We can see some of the benefits below. Perhaps more importantly, we need to look at IGF-1 on the basis of cell biology. IGF-1 has been shown to enhance the migratory response of stem cells. We must realize that the IGF-1 supplied by deer antler is a natural form. It seems to be safer than taking the synthetic anabolic agents which can have disastrous consequences to ones health. The following diagram is somewhat complicated but we see the importance of IGF-1. It will interact with the stem cell and cause the cell to go on to repair tissue or differentiate into that tissue. IGF-1 and the other growth factors can also result in a number of other health benefits. These extra health benefits may include preservation of a persons muscle mass, improving the functioning of the immune system, increasing bone density thus helping to improve Osteoporosis, a valid treatment for fibromyalgia conditions, and lastly it may help in weight loss. The bottom line is that these growth factors are all very important in treating damaged tissue. This tissue could be a tendon, a joint, or muscle. Remember, with the antler we are complimenting the growth factors that are supplied by the stem cells and the Platelet Rich Plasma. Also, by taking these supplements on a daily basis we continue the repair process. The one small caveat that we follow is that in those patients who have a history of certain cancers we will typically recommend a lower dose of the antler product. We should also keep in mind that antler products also contain small amounts of the sex hormones testosterone and estrogen. In the right doses these are also important for regeneration. Another related factor found in the antler is Prostaglandins. They are substances with varying physiologic effects, acting as a vasodepressor, smooth muscle contraction or relaxation, inflammation and uterine stimulation. As components of deer antler velvet, prostaglandins may assist in the capacity of the extract to reduce the swelling associated with arthritis and injury. They also have physiological responses in lipid metabolism, as seen in the cholesterol-lowering effects of deer antler velvet on laboratory animals. AMINO ACIDS Velvet antler contains many different types of amino acids. Amino acids, often referred to as the building blocks of proteins, are compounds that play many critical roles in your body. Amino acids are organic compounds composed of nitrogen, carbon, hydrogen and oxygen, along with a variable side chain group. Your body needs 20 different amino acids to grow and function properly. Though all 20 of these are important for your health, only nine amino acids are classified as essential. These are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Unlike nonessential amino acids, essential amino acids are those that cant be made by your body and must be obtained through your diet. Another type of amino acid is a Free-form amino acid. This refers to single amino acid that is already in a pre-digested form and ready to be used by your body. Some nutritional products, especially amino acid blends, contain whole proteins and large peptides (chains of amino acids), which the body must first break down into smaller peptides and individual amino acids before use. For faster utilization and better bioavailability, look for free-form amino acids. We can see that all the various different types of amino acids work synergistically. They all have their purpose. WHAT SUPPLEMENTS ARE ADDED TO THE FORMULA TO ENHANCE THE EFFECTS? In addition to the Velvet Deer Antler which provides all the aforementioned compounds. There are a host of other compounds which enhance the efficacy of the product. These include a natural matrix of herbs bounded by research and science to help ones stem cells become more active and body supportive. The following compounds highlight these ingredients. FUCOIDAN is found in the cell walls of certain seaweed species that is has been used medicinally for a wide variety of health purposes. Okinawa inhabitants have a diet rich in Wakame seaweed, which contains the highest concentrations of Fucoidan. Okinawa is also known for its high concentration of centenarians (people who are at least a century old), which researchers believe is linked to their fucoidan-rich diet. The anti-aging effects are associated with Fucoidan's remarkable ability to facilitate tissue regeneration, immune function as well as improving cell-to- cell communication. Not only is fucoidan known for its anti-aging effects, it is also believed to combat cancer, metabolic syndrome and other degenerative disorders. With stem cell therapy, there is always the risk that the adult stem cells could migrate to other areas of the body unintentionally. However, the daily use of fucoidan has been proven to increase mobilization of stem cells to the appropriate area/ site of injury. Not only can fucoidan point the stem cells in the proper direction, it has also shown to improve the stem cells' survival during the differentiation process. PTEROSTILBENE is a stilbene molecule and demethylated derivative of resveratrol ( it is more bioavailable than resveratrol) that is found in antioxidant-rich foods like blueberries, cranberries and grapes. These all help to slow down the aging process. It is an antioxidant that helps fight free radical damage. It is known to stimulate a series of pathways in the body called Sirtuin gene pathways. The sirtuin genes have effects on a variety of other pathways in the body. Ultimately, the Sirtuins are involved in the regulation of the mitochondria and subsequent ATP production. Research has shown Pterostilbene protects against memory loss, high cholesterol, high blood pressure levels and even certain types of cancer. CARNOSINE is an important nonessential amino acid that helps support brain, heart, and eye health. It offers antioxidant protection from free radicals and oxidative stress, boosts endurance, aids in the recovery process, and offers electrolyte support. BLACK RASPBERRY EXTRACT, one of the least known, but yet strongest anti-oxidants that insures chromosomes retain their health and rebuild themselves to optimum health. RHODIOLA an adaptogenic herb that can elevate your mood and mental stamina, reduce the stress hormone, cortisol and fight depression due to its protective effects on key mood neurotransmitters. Rhodiola rosea extracts have recently demonstrated its anti-aging, anti-inflammation, immuno-stimulating, DNA repair and anti-cancer effects in different model systems. An adaptogenic herb helps the body adapt to and resist physical, chemical, and environmental stress. ASTRAGIN is a 100% natural compound which is patented and promotes a healthy gut lining reducing inflammation in the intestinal lining and increasing absorption of nutrients. AstraGin has the ability to increase the assimilation of important amino acids which increase nitric oxide levels in the human body, making it the perfect performance enhancer when taken pre-workout. Higher levels of nitric oxide result in enhanced blood flow to the muscle which leads to better pumps, muscular contraction, and improved nutrient transportation. AstraGin also aids in glucose absorption so having this pre-workout ensures that you have sufficient energy levels whilst you train. THE FINAL QUESTION HOW DOES THE ANTLER PRODUCT GET TO WHERE IT IS NEEDED? One could have the absolute best formula on paper but the question is will it work? When we evaluate medications and supplements a very important aspect to consider is what we call the pharmacokinetics of the product. This concerns the science of how the drug moves around in the body. Unfortunately, on paper many compounds seem very promising but in real life are a failure. The main reason for this is that they cannot be absorbed by the body. The mode of absorption of the antler product is what is referred to as sublingual. This means it is absorbed under the tongue. This is many times a very effective mode of absorption. It bypasses the gut and goes directly into the bloodstream where it is needed. The components are not broken down. Also, in the saliva are very small particles called exosomes which can be considered a rising star in drug delivery. Saliva is a very rich source of exosomes. Thus, we have a very efficient method of delivering the velvet components in a safe and reliable manner. If we were to undertake the task of trying to design a complete supplement to utilize in Regenerative Medicine and Stem Cell therapy, Velvet Deer Antler would be at the top of our list. It has most of the ingredients needed for success. Furthermore, there is a very efficient way to deliver the goods to the cell where they are needed. Deer antler will not be the only modality we will use, but it certainly has an important place on our mantle. We are constantly working to push the envelope and I suspect more advances will come. Thanks, -JP

NQO1 is a gene which controls the production of the enzyme NAD(P)H dehydrogenase, quinone 1. The above diagram shows some of the many functions of the NQO1 pathway. We can see that there are three major pillars of health that NQO1 directly influences. These pillars include detoxification which entails the ratio of NAD to NADH, its ability as an antioxidant, and lastly how it helps to stabilize the P-53 gene. Detoxification and antioxidant activity go hand and hand. They are intertwined with each other. Each of these pillars have extreme importance for our health and well-being. The detoxification pillar is a very important aspect of NQO1 functions. Much of the detoxification deals with compounds called Quinones. Quinonoid compounds generate reactive oxygen species (ROS). Quinones are ubiquitous in nature and constitute an important class of naturally occurring compounds found in plants, fungi and bacteria. Human exposure to quinones therefore occurs via the diet, but also clinically or via airborne pollutants. For example, the quinones of hydrocarbons are prevalent as environmental contaminants and provide a major source of current human exposure to quinones. The inevitable human exposure to quinones, and the inherent reactivity of quinones, has stimulated substantial research on the chemistry and toxicology of these compounds. NQO1 is employed in the removal of a quinone from biological systems as a detoxification reaction: NAD(P)H + a quinone → NAD(P)+ + a hydroquinone. The hydroquinone is excreted. This reaction ensures complete oxidation of the substrate without the formation of semiquinones and reactive oxygen radicals that are deleterious to cells. The localization of NQO1 in epithelial and endothelial tissues of mice, rats and humans indicates their importance as detoxifying agents, since their location facilitates exposure to compounds entering the body. In addition to the detoxification, NQO1 helps produce NAD+ which in its own right is very important. The ratio of NAD+/NADH is of extreme importance. We are well aware of the importance of NAD+ for our body. NAD+ is instrumental in the production of ATP which is the body’s energy currency. However, NAD+ is also used in a variety of biological processes in the body. Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD+depletion may occur in response to excessive DNA damage due to free radicals. This damage results in significant poly (ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD+. PARP is instrumental in DNA repair. Also, chronic immune activation and inflammatory cytokine production results in accelerated CD38 activity and subsequent decline in NAD+ levels. We now think that the NAD+/NADH ratio may be as important if not more important than the levels of NAD+. One of the insights arising from the scientific studies of calorie restriction is that the ratio of NAD+ to NADH (NAD+/NADH ratio) might be important for the lifespan extension benefits. This ratio has been reported to decline with age, with NAD+ being decreased and NADH increased in older individuals. While boosting the amount of NAD+ has been getting a lot of attention, improving the ratio between NAD+ and NADH might be more significant than the amount of cellular NAD+ in isolation. In yeast experiments, calorie restriction decreases NADH much more dramatically than it affects NAD+. This decrease in NADH is important for enhancing lifespan, because, on its own, it increases activity of the NAD+ consuming enzymes that boost longevity processes (e.g., Sirtuins) and DNA repair (e.g. PARPs) in yeast. This is thought to occur because NADH is an inhibitor of these enzymes, so lowering it releases the inhibition. As an example, inducing the enzyme NQO1—an enzyme that uses NADH as an electron donor increases intracellular NAD+ levels because it shifts the NAD+/NADH redox ratio in favor of oxidation (NAD+). A side effect of this reaction is that intracellular NAD+ levels increase. Upregulation of the pathway that induces NQO1 occurs in calorie restriction and appears to be an important component of producing the benefits. We must remember that cellular levels of NAD+ are more important than the serum levels. In review, what NQO1 does is convert NADH to NAD+ while at the same time it maintains a very delicate ratio of NAD/NADH. This ratio is not affected by dietary or IV intake. One important fact is that NQO1 will oxidize NADH to NAD+ and thus it increases NAD+ in the cell. HOW IS THE NQO1 PATHWAY REGULATED? Another name for the NQO1 gene is the longevity gene. NQO1, regulates the NAD+/NADH ratio in cells. NQO1 does this by oxidizing NADH to NAD+. During aging the ratio of NAD+ to NADH changes in part to a reduced level of the expression of NQO1. As we age the cells accumulate a type of protein called BET proteins. The BET proteins are Bromodomain and Extraterminal Proteins. They are referred to as epigenetic readers. The following diagram shows the various components involved in epigenetics, namely the writers, erasers, and readers all of which effect gene behavior. In this case, the BET proteins will suppress the induction of the NQO1 gene. There is now much research looking for inhibitors of BET proteins for a variety of conditions including cancer. Lowered levels of NQO1 will affect the amounts of a compound called Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha). PGC-1a is a member of a family of transcription coactivators that plays a central role in the regulation of cellular energy metabolism. It is strongly induced by cold exposure, linking this environmental stimulus to adaptive thermogenesis. PGC-1alpha stimulates mitochondrial biogenesis and promotes the remodeling of muscle tissue to a fiber-type composition that is metabolically more oxidative and less glycolytic in nature, and it participates in the regulation of both carbohydrate and lipid metabolism. Oxidative metabolism produces far more ATP than the glycolytic type. It is highly likely that PGC-1alpha is intimately involved in disorders such as obesity, diabetes, and cardiomyopathy. In particular, its regulatory function in lipid metabolism makes it an inviting target for pharmacological intervention in the treatment of obesity and Type 2 diabetes. PGC-1a is regulated by the oxidative state of the cell. NQO1 will regulate the PGC-1a levels by controlling the rate of PGC-1a degradation not its synthesis. Like many regulatory factors, PGC-1a has an extremely short half-life. All of these extremely short-lived proteins are regulated by degradation rates, not synthesis rates. Higher levels of NQO1 shift the ratio of NAD+/NADH and protect proteins from being oxidized. PGC-1 plays an important role in regulating mitochondrial function. Higher levels of PGC-1a help prevent age related mitochondrial dysfunction. Thus, it appears that under conditions of oxidative stress, such as with aging, NQO1 may be a major factor that controls the concentration of PGC-1a in the cell. PGC-1a is not some esoteric co factor, it is extremely important in many different functions as can be seen from the following diagram. PGC-1α is a transcriptional coactivator that is a central inducer of mitochondrial biogenesis in cells. Thus, it appears that under conditions of oxidative stress, such as with aging, NQO1 may be a major factor that controls the concentration of PGC-1a in the cell. WHAT ELSE DOES NQO1 STIMULATE? NQO1 seems to have a significant effect on the P-53 gene. It helps to stabilize the P-53 gene. P-53 is many times referred to an the “Tumor Suppressor Gene”. It is a potent sentinel in the body looking for and destroying cells which may go on to tumor lines. It has the ability to fix DNA damage if it is not too severe or if too severe it will destroy the cell. The following diagram shows P-53 in action: It is now thought that many cancers arise from a defect in the P-53 gene. It appears that the NQO1-dependent (ubiquitin-independent) pathway is the most important pathway for regulating p53 levels within the cell. Ubiquitin is a small protein that is found in almost all cellular tissues in humans and other organisms. It helps to regulate the processes of other proteins in the body. Through a process known as ubiquitination or ubiquitylation, a ubiquitin molecule can bind to a substrate protein, changing the way it functions. This can lead to a number of different outcomes. It is most widely recognized for its role in apoptosis of proteins, earning it the title of the molecular “kiss of death” for proteins, although it also plays a major part in several other cellular processes related to the regulation of proteins. If P-53 is working properly hopefully the chances of a cancer arising are significantly diminished. Treatment with curcumin augments the levels of P53 in tumor cell lines through incrementing its half-life in a NQO1 dependent manner. Curcumin treatment promotes the interaction between NQO1-p53. HOW CAN WE INCREASE THE PRESENCE OF NQO1? One statement that can be made across the board is that anything which increases the NRf2 pathway will increase the NQO1 gene action. The NRf2 pathway has a profound effect on the NQO1 gene. One can read my previous blogs concerning the NRf2 pathway. I call this pathway the thermostat of anti-inflammation. One of the important stimulators of the NRf2 pathway are ozone messengers which are produced by intravenous ozone such as is delivered by the EBO2 protocol. These messengers will allow the NRf2 to enter the nucleus and activate certain genes. Another offshoot of the EBO2 protocol is the use of photodynamic therapy which stimulated the NQO1 gene. Phototherapy also includes the stimulation of heat shock proteins which are encouraged by the exposure of UVA light. Again, for those people unaware of the EBO2 protocol, it is a protocol which uses a dialysis filter, intravenous Ozone gas, and photo modulation. The following is a picture of the set up used in the EBO2 protocol: Other compounds which seem to have stimulating influences on NQO1 include resveratrol, Pterostilbene, Taxifolin (also called dihydroquercetin), sulforaphane (broccoli), curcumin, and Fumaric acid derivatives. Another important supplement perhaps the most important, to stimulate the NQO1 gene is Beta-lapachone, a compound found in the bark of the South American Lapacho tree. It is a potent activator of the NQO1 gene and produces ROS in cancer cells, but reduces ROS in non-cancer cells. Beta-Lapachone is a NQO1 activator. In addition to stimulating the NQO1 gene it stimulates the NRf2 pathway which helps to lower inflammation. Beta-lapacho was very popular a number of years ago. It then seemed to lose it way. Now there is a resurgence in the use of Beta-lapachone on multiple fronts including clinical studies in a variety of universities. A few final thoughts, if a clinic is utilizing NAD+ but not stimulating the NQO1 pathway then they are behind the times. There are a number of clinics which like to dabble in utilizing NAD on their patients. Unfortunately, they are not aware of the basic science of NAD, its effect on senescent cells, methods allowing the body to handle NAD better, and the importance of the NQO1 gene. If you encounter a clinic which is “just” utilizing NAD without addressing these related matters, your best bet is to seek treatment elsewhere!! This will ensure you the best chance of success. It is all a matter of knowing the basic science of the various pathways and how these can be manipulated to the benefit of the patient. The following illustration gives all the salient points about the NQO1 gene. There is a reason why this is called the Longevity Gene. The answers lie in the illustration. When all is said and done this seems to represent the essence of aging. Thanks, Dr. P

There now seems to be intense interest in EBO2 techniques. Copious volumes of research have provided evidence that Ozone’s dynamic resonance structures facilitate physiological interactions useful in treating a myriad of pathologies. The comment of Ozone opponents is that ozone therapy looks like a panacea for all diseases. Indeed, it seems so, but in reality, this is due to the multitude of compounds originated at first from the reaction of ozone with body fluids, and eventually able to display pleiotropic effects delivered by different organs. Ozone can be considered a “PRODRUG”. What exactly is a Prodrug? A prodrug is a medication or compound that, after administration, is metabolized into a pharmacologically active drug. Instead of administering a drug directly. The following illustration shows how a prodrug works: One of the issues raised by the scientific community is: how does Ozone really acts on Humans? Ozone is quite different from a drug and its action is not a consequence of a binding reaction between one molecule (drug) and one receptor (cellular membrane protein). For this reason, we cannot look at Ozone in the classical terms of pharmacology. Ozone like other agents, and unlike the common drugs that act on a specific receptor, induces small stress to the whole cell when used at adequate doses. This, in turn, triggers a series of intracellular metabolic processes and promotes a myriad of intracellular activities. Because of these reactions, the defense mechanisms of the cell are alarmed and pushed to improve cell activity, explaining in part the surprising therapeutic actions of Ozone. By the same token Ozone is not truly a prodrug since it can have direct effects on phospholipids, lipoproteins, the cell membrane envelopes of bacteria and viruses. These bioactivities can eradicate bacteria and viruses. In order to fully understand the biochemical basis underlying the pharmacological effects of ozone, it is important to illustrate its effects on various coenzymes. These coenzymes are responsible for ozone cell metabolism regulation. These effects on metabolism have profound effects on many aspects in the body. One of the significant effects of ozone is the acceleration of glycolysis. Glycolysis results in breaking glucose into pyruvate and getting a very valuable H+ hydrogen ion. The free energy released in this process is used to form the high-energy molecules ATP (adenosine triphosphate) and NADH (reduced nicotinamide adenine dinucleotide). ATP is cellular energy that all cells depend upon. Ozone will allow the ratio of NAD/NADH to be about 700/1. A fundamental condition for guaranteeing the continuity of this process is the reoxidation of NADH as it occurs following ozone exposure. The NADH is converted to NAD+. The above diagram shows some important relationships. The ratio of NAD/NADH should be about 700/1. Ozone will stimulate the NQO1 gene which has profound effects on this ratio. NQO1 also stimulates the Sirtuin genes which are very significant in anti-aging and general well-being. As far as protein metabolism, ozone intervenes mainly due to its remarkable affinity towards sulfhydryl groups. A sulfhydryl is a functional group consisting of a sulfur bonded to a hydrogen atom. The sulfhydryl group is one of the most reactive and ubiquitous binding molecules in biological systems. It is found in most proteins and also in a few low molecular-weight substances such as glutathione, CoA (Coenzyme A, notable for its role in the synthesis and oxidation of fatty acids), lipoate, thioglycolate, and free cysteine. It is the most studied of chemical groups, particularly in relation to its role in enzymatic activity and properties of proteins. Similarly, ozone reacts with essential amino acids such as methionine, tryptophan, and other amino acids containing sulfur (i.e., cysteine). In this case, the amino acids are protected from ozone inactivation by two reactions that prevent their degradation: first the oxidation of glutathione and then the oxidation of the coenzymes NADH and NADPH, which are key reactions in the biochemical mechanism of ozone. Nicotinamide adenine dinucleotide, or NAD, is in all living cells, where it functions as a coenzyme. It exists in either an oxidized form, NAD+, which can accept a hydrogen atom (i.e., a proton), or a reduced form, NADH, which can donate a hydrogen atom. Note that "donate a proton" and "accept a pair of electrons" translates to the same thing in biochemistry. Nicotinamide adenine dinucleotide phosphate, or NADP+, is a similar molecule with a similar function, differing from NAD+ in that it contains an additional phosphate group. The oxidized form is NADP+, while the reduced form is NADPH. Finally, ozone reacts directly with unsaturated fatty acids, which have a double carbon bond and are therefore available for an oxidative reaction, leading to the formation of peroxides following cleavage of the lipid chains. In addition to the direct contributions to cellular metabolism described above, both NADH and NADPH may take part in other important physiological processes, including mitochondrial functions, calcium regulation, antioxidation and its counterpart (the generation of oxidative stress), gene expression, immune functions, the aging process and cell death. As a result, some biochemistry researchers have proposed that further investigation Ozone dissolved in the plasma reacts immediately with a number of biomolecules producing two compounds. There are two compounds Reactive Oxygen Species (ROS) and Lipid Oxidative Products (LOPS). They represent the “ozone messengers” and are responsible for many of the biological and therapeutic effects attributed to ozone. ROS are produced immediately in the early phase (mainly Hydrogen peroxide or H2O2) and are responsible for the early biological effects on blood (erythrocytes, leucocytes, platelets). Hydrogen peroxide, now universally recognized as one of the main intracellular signaling molecules, acts on the different blood cells. Hydrogen peroxide is one of the most significant cytokine inducers in white blood cells. The mass of erythrocytes mops up the bulk of hydrogen peroxide. H2O2 diffuses easily from the plasma into the cells and its sudden appearance in the cytoplasm represents a triggering stimulus. This stimulus depends upon the cell types. Different biochemical pathways can be concurrently activated in erythrocytes, leukocytes and platelets resulting in numerous biological effects. On the other hand, Lipid Oxidative Products (LOPS), which are simultaneously produced at the same time as ROS have a far longer half-life. They reach the vascular system and interact with several organs, where they trigger late effects. Some of these real targets are liver, vascular system, while other organs are probably involved in restoring normal homeostasis including the central nervous system, gastrointestinal tract, mucosal associated lymphoid tissue. The LOPS molecules can elicit the upregulation of antioxidant enzymes such as superoxide dismutase (SOD), GSH-peroxidases (GSH-Px), GSH-reductase (GSH-Rd) and catalase (CAT). Moreover, LOPS exert a neuroimmunomodulatory effect highlighted by a feeling of well-being reported by patients during ozone therapy. OZONE THE WONDER DRUG Ozone is a wonder drug because it can produce four extraordinary phenomena: 1) the induction of Oxidative Shock Proteins (OSP) 2) the upregulation of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) 3) the reduction and/or normalization of oxidative stress; and 4) the release of bone marrow stem cells. Ozone mobilizes bone marrow stem cells (BMSC) and produces LOPS, which induce Nitric Oxide synthase (NOs). This produces inhibition of platelet-leukocyte aggregation.NO is responsible for producing neovascularization and neoangiogenisis. Also, NO activates MMP-9 (matrix metalloproteinase 9) which is indispensable for stem cell mobilization. MMP-9 actually releases the bond that holds stem cells in the bone marrow and releases them to the circulation. The production of Nitric Oxide is one of the main mechanisms by which hyperbaric oxygen will increase stem cell output from the bone marrow. These numbers will include a wide variety of the stem cells that are released from the marrow including Hematopoietic and Mesenchymal Stem cells. Ozone forms lipid oxidative products which in turn produce nitric oxide which makes proteases which release stem cells from the bone marrow into the circulation. The release of stem cells from the marrow is a multi-step process dependent on many different factors. We can see from the following diagram the very process of how Ozone affects stem cell release: The above diagram shows release of stem cells (HSC) from the bone marrow to the circulation. This is very dependent upon the production of MMP-9. This stimulation releases the stem cells from the bone marrow and allows them to go into circulation. The fact that Ozone releases stem cells from the bone marrow is very important. It should be mentioned that this concept is similar to the mechanism of hyperbaric oxygen. In the above diagram it is demonstrates that LOPS, throughout the treatments, act as acute oxidative stressors in the bone marrow microenvironments activate the release of metalloproteinases, of which MP-9 particularly may favor the detachment of stem cells. These cells, once in the blood circulation, may be attracted and home at sites where a previous injury (a trauma or an ischemic-degenerative event) has taken place. The potential relevance of such an event would have a huge practical importance and will avoid the unnatural, costly and scarcely effective practice of the bone marrow collection with the need of the successive and uncertain re-infusion. OZONE AND OXIDATIVE STRESS One of the most important aspects of Ozone therapy is activation the Nuclear Factor Erythroid 2 Related Factor 2 commonly known as NrF2. NrF2 is like the body’s “missile defense system”. It helps keep oxidative stress under control. Oxidative stress arises from free radicals. Free radicals are compounds which have free electrons. These rogue molecules can cause havoc by “stealing” electrons from other molecules. Some free radicals are capable of damaging the DNA or crippling the proteins and lipids that make up various tissues. As a result, these crucial molecules become damaged, weak, dysfunctional, or otherwise incapable of fulfilling their roles. Produced deep within cells as a byproduct of ordinary energy-producing processes, free radicals are thought to be responsible for aging and disease, including even cancer. How does NrF2 protect us from free radicals? NrF2 is basically like a thermostat. But instead of regulating temperature, it regulates stress levels known as oxidative stress. It responds by binding with the DNA, signaling the cells to make thousands of molecules to shield the cells. They will later activate a new response to form a new barrier. This “barrier” will protect the cells from future stress. Furthermore, Nrf2 will remove the toxins that cause cell damage and boost the normal function. Both of these functions will return the stress levels to normal, minimizing the negative effects. We must realize that we do not want to constantly have NrF2 activated. Ozone is a selective NrF2 activator. How does this work? Ozone produces Antioxidant Responsive Elements (ARE). Antioxidant responsive elements (AREs) mediate the transcriptional induction of a battery of genes which comprise much of this chemoprotective response system and ultimately the NrF2 pathway. Under normal conditions, Nrf2 is expressed at very low levels, and is mainly sequestered in the cytoplasm by its specific inhibitor called Kelch-like ECH associated protein-1 (Keap-1) that also promotes its rapid degradation. The effectiveness of this mechanism allows a rapid turnover of Nrf2, which displays a half-life of a few minutes. Under specific stimuli, Nrf2 dissociates from Keap1 and translocates into the nucleus and transactivates the ARE-driven genes. These genes encode for proteins involved in a multitude of vital biological functions which include protein homeostasis, oxidative stress response, detoxication, DNA repair, proliferation, autophagy (body's way of cleaning out damaged cells), mitochondrial biogenesis and function, inflammation, and the metabolism of lipids, carbohydrates and amino acids. When you stimulate NrF2 you have a healthier patient. The following illustration shows these concepts: NrF2 goes on to control a wide variety of processes in the body including proper formation of proteins, control of inflammation, healthy mitochondrial function, and healthy adipose tissue. WHAT ARE SOME OF THE OTHER EFFECTS OF OZONE THERAPY The oxidation chemistry of ozone is known to produce Hydrogen Peroxide (H2O2) that enters cells where it has various effects. In red blood cells (RBCs), it shifts the hemoglobin dissociation curve to the right and facilitates release of oxygen, while in leukocytes (WBCs) and endothelial cells it can stimulate the production of interleukins, interferons, growth factors and nitric oxide production. In platelets it favors release of growth factors. As a further aspect of the therapeutic action of ozone, there is the capacity to regulate the cell antioxidant network positively. This aspect is of key relevance in all those conditions in which an imbalance between production and neutralization of ROS (Reactive Oxygen Species) may develop, resulting in oxidative stress. Again, this relates to the implications of the NrF2 pathway and its activation or inactivation. These events may turn into a self-feeding cycle in which oxidative stress is sustained by micro- and macro-inflammatory reactions that lead to cell and tissue degeneration and necrosis. This scenario features the pathogenetic role of oxidative stress in several chronic, degenerative disease states such as chronic viral infections, atherosclerosis, tumor growth, neurodegenerative diseases and accelerated aging. Ozone can help stop these problems in their tracks. HEAT SHOCK PROTEINS Another aspect of Ozone therapy is the production of HEAT SHOCK PROTEINS (HSPS). Shock proteins are a family of proteins that are produced by cells in response to exposure to stressful conditions. They were first described in relation to actual heat shock, but are now known to also be expressed during other stresses including exposure to cold, UV light (this is one of the reasons we are utilizing a UVA light to stress the blood cells) and during wound healing or tissue remodeling. We can also stimulate Heat Shock Proteins by using a sauna or by subjecting our body to very cold temperatures. Many members of the Heat Shock Protein group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. This increase in expression is genetically regulated. In the packed, busy confines of a living cell, hundreds of chaperone proteins vigilantly monitor and control protein folding. From the moment proteins are generated in and then exit the ribosome until their demise by degradation, chaperones act like helicopter parents, jumping in at the first signs of bad behavior to nip misfolding in the bud or to sequester problematically folded proteins before their aggregation causes disease. People often mistakenly think that proteins are free to live out their lives in a cell. As it becomes increasingly clear that folding is not a once-in-a-lifetime event for proteins but instead a part of day-to-day life in the cell. Scientists are discovering that problems in this sophisticated system of protein folding are implicated in diseases as diverse as cancer, diabetes, and Alzheimer’s. As time goes on we are finding more and more diseases associated with misfolded proteins. This will open up a new realm in medicine in which Ozone therapy and Photo modulation may be integral players on taking the science of Heat Shock Proteins to the next level. Not only is Heat Shock Proteins important in disease control but it seems to have a place in improving athletic performance. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). The following illustrations demonstrate the very important work of the Heat Shock proteins: HSPs are found in virtually all living organisms, from bacteria to humans. HSPs are known to modulate the effects of inflammation cascades leading to the generation of ROS and intrinsic apoptosis through inhibition of pro-inflammatory factors, thereby playing crucial roles in the pathogenesis of human inflammatory diseases and cancer. There is a scientific push for studying the HSPs for the treatment of various inflammatory diseases and cancer. Also, it appears that a safe and effective method of stimulating HSPs is by the use of Ozone in blood. Heat shock proteins may play a critical role in reducing recovery time and boosting muscle development. The following illustration shows the mechanism of HSPs: We can see that the HSPs can have profound implications for a person’s well-being. This is a field where more research will certainly be needed. We can see that when we have an altered expression of Heat Shock proteins many bad things happen. It appears that many autoimmune diseases are related to altered Heat Shock proteins. The following diagram is a good illustration of this. Chronic inflammatory conditions are accompanied by a partial or sometimes large resetting of the immune system to a pro-inflammatory and pro-oxidant state. This response has gross implications also in the integrity of vascular components and may represent a sensitive therapeutic target of chronic, degenerative conditions. On the basis of these theoretical foundations, reported therapeutic applications for ozone therapy were the activation of the immune system in infectious diseases and cancer, and an improved oxygen utilization and release of growth factors that can reduce the extent of ischemic lesions in vascular diseases. - Dr. P

The above diagram represents the FOXO gene pathways. FOX proteins are named for a gene found in fruit flies that cause the insects to have forked structures on their heads (supplying the “F”) and a particular group, known as “box”, of specialized genes (supplying the “OX”). They’re named alphabetically, from FOXA to FOXS. There are over 100 subclasses of FOX proteins in humans, such as FOXA, FOXR, FOXE, etc. and they have many functions. An important group of FOX proteins is the class “O”. This class is regulated by the insulin/Akt/mTOR signaling pathway. Invertebrates have a single FOXO gene, whereas mammals have four: FOXO1, FOXO3, FOXO4, and FOXO6. FOXO proteins regulate stress resistance, cellular turnover, apoptosis, glucose and lipid metabolism, and inflammation. FOXO factors are evolutionarily conserved mediators of insulin and growth factor signaling. FOXO proteins act as transcription factors by binding to specific regions on DNA, thereby controlling the transmission of genetic information and influencing the chemical "blueprint" for proteins. Of all the different groups the FOXO group may be the most important. The following is a summary of these ideas: As stated, there is accumulating evidence that FOXO factors play an important role in stem cell biology and tissue homeostasis. There is also a great deal of research on the FOXO pathway and its relationship with osteoarthritis and osteoporosis both of which consume a large portion of our health care dollars. During aging, the balance of removal and regeneration of cells in tissues becomes disturbed mainly due to a decrease in the regenerative potential of adult stem cells. The FOXO family of transcription factors (proteins that can bind to DNA and “switch on” other genes) regulate the expression of genes in cellular physiological events including apoptosis (cellular programmed death), cell-cycle control, glucose metabolism, oxidative stress resistance, and longevity. These six pillars can be the blueprint for significant anti-aging strategies in addition to allowing for greater stem cell success in both the lab and the real world. Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype (the physical appearance from the expression of one or more genes). Transcription factors are regulated by phosphorylation, ubiquitination, acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. The regulation of these various processes typically involves the addition or removal of certain chemical compounds to a protein. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The forkhead transcription factors have four members: FOXO1, FOXO3, FOXO4, and FOXO6. FOXO1 and FOXO3 are expressed in nearly all tissues. FOXO4 is highly expressed in muscle, kidney, and colorectal tissue while FOXO6 is primarily expressed in the brain and liver. The following illustration shows the various Forkhead transcription factors. It shows the far-ranging influences that these transcription factors have: Over the last decade, studies have demonstrated that FOXOs play critical roles in a wide variety of cellular processes. FOXOs transcriptionally activate or inhibit downstream target genes, thereby playing an important role in proliferation, apoptosis, autophagy, metabolism, inflammation, differentiation, and stress resistance. Remember when we are dealing with anti-aging we want to influence downstream events from an upstream process. Deletion of FOXOs has given insight into their function. For instance, deletion of FOXO1 is lethal; it causes embryonic cell death due to incomplete vascular development. Deletion of FOXO3 is not lethal but affects lymph proliferation, widespread organ inflammation, age-dependent infertility, and decline in the neural stem cell pool. Deletion of FOXO4 exacerbates colitis in response to inflammatory stimuli. Deletion of FOXO6 displays normal learning but impaired memory consolidation. The process of aging is accompanied by a decline in physiological function and cellular maintenance. It is known that aging dramatically alters gene expression and transcription factor activity. FOXO functions downstream of insulin/insulin-like growth factor (insulin/IGF). Studies have found that lifespan extension effects of insulin/IGF deficiency depend on FOXO activity, probably through the transcriptional regulation of key longevity assurance pathways. However, how FOXO elicits this response remains to be fully elucidated. FOXO proteins are tightly regulated to ensure that transcription (first step in protein synthesis) of specific target genes is responsive to environmental conditions. A major form of regulation is Akt-mediated phosphorylation of FOXO in response to insulin or growth factors. This can be seen on the following diagram: In the absence of insulin or growth factors, FOXO transcription factors are located in the nucleus, where they specify target gene expression. We are able to see the various tasks accomplished by the FOXO genes including DNA repair, Cell Cycle arrest, help eliminate reactive oxygen species, and have some effects on glucose metabolism. When insulin and other growth factors are present they result in phosphorylation which subsequently results in the export of the FOXO proteins from the nucleus to the cytoplasm thereby decreasing expression of FOXO target genes. This is regulated by the Akt-pathway. The opposite happens when the FOXO genes are stimulated. FOXO proteins are phosphorylated by other protein kinases which phosphorylate FOXO under conditions of oxidative stress. This phosphorylation causes the movement of FOXO from the cytoplasm to the nucleus, thus opposing Akt’s action. Once in the nucleus the FOXO genes can do their work. WHAT ABOUT THE DIFFERENT CELLULAR PROCESSES? AUTOPHAGY is a key player in the aging process. Autophagy involves the disassembly and recycling of unnecessary or dysfunctional cellular components. It allows the orderly degradation and recycling of cellular components. Premature aging and age-related disorders have been related to defects in autophagy. FOXO proteins regulate many genes responsible for autophagy. Autophagy has important effects that occur both within the cell and outside of the cell. Within the cell, autophagy helps to decrease oxidative stress, increase genomic stability (which aids in the prevention of cancer), increase bioenergetic metabolism, and increase the elimination of waste. Outside of the cell, autophagy helps to decrease inflammatory responses, increase neuroendocrine homeostasis, increase surveillance of cancer by the immune system, and increase the elimination of aging cells. CELL CYCLE ARREST Cells constantly monitor their cell cycle status at various checkpoints. These checkpoints help ensure the accuracy of DNA replication and division and provide time for DNA repair. In some scenarios, FOXO blocks the cell cycle by either switching on cell cycle inhibitors or by switching off cell cycle activators. But FOXO is highly sensitive to physiological context and needs, and under conditions of cellular stress, it mediates cell cycle arrest to allow time for repair of damaged DNA and cellular detoxification. When dealing with the cell cycle it might appear strange that FOXO could induce both stress resistance and cell death? The regulation of stress-resistance genes and pro-apoptotic genes by FOXO is not necessarily a paradox. FOXO factors may orchestrate different patterns of gene expression based on the intensity of the stimulus, perhaps activating stress-resistance genes under mild conditions but pro-apoptotic genes when the intensity of stress stimuli increases beyond a certain threshold. It is also possible that FOXO factors regulate different genes in different cell types, causing apoptosis in some cells (e.g. neurons, lymphocytes) while promoting survival in others. Importantly, the induction of apoptosis by FOXO may cause the death of damaged or abnormal cells, therefore benefiting the longevity of the entire organism. FOXO PATHWAYS AND ENERGY HOMEOSTASIS The FOXO pathway has been called the Transcriptional Chief of Staff of Energy Metabolism. FoxO1 is highly expressed in insulin-responsive tissues, including pancreas, liver, skeletal muscle and adipose tissue, as well as in the skeleton. In all these tissues FoxO1 orchestrates the transcriptional cascades regulating glucose metabolism. Indeed, FoxO1 is a major target of insulin which inhibits its transcriptional activity via nuclear exclusion. In skeletal muscle FoxO1 maintains energy homeostasis during fasting and provides energy supply through breakdown of carbohydrates, a process that leads to atrophy and underlies glycemic control in insulin resistance. In a dual function, FoxO1 regulates energy and nutrient homeostasis through energy storage in white adipose tissue, but promotes energy expenditure in brown adipose tissue. In its most recently discovered novel role, FoxO1 acts as a transcriptional link between the skeleton and pancreas as well as other insulin target tissues to regulate energy homeostasis. We can see the importance of these concepts in the following: FoxO1 is a unifying regulator of energy metabolism through the skeleton and peripheral organs FOXO PATHWAYS AND OSTEOARTHRITIS FoxO transcription factors protect against cellular and organismal aging, and FoxO expression in cartilage is reduced with aging and in OA. Observations suggest that FoxO transcription factors play a key role in cartilage development, maturation, and homeostasis and protect against OA-associated cartilage damage. FoxO transcription factors control the expression of genes that are essential for maintaining joint health. The following illustration shows what the lack of FOXO protein transcription and subsequent oxidative stress contribute to in the joint: The next illustration shows this more succinctly: FOXO PATHWAYS AND OSTEOPOROSIS Just like in the joint, FOXO pathways have significant effects on osteoporosis. The effects can sometimes be confusing. How the FOXO proteins function in bone metabolism is a bit more complicated than in the joint. The proper stimulation of the FOXO pathways will encourage the formation of new bone. The cells which make new bone, namely the osteoblasts will have increased survival by FOXO stimulation. At the same time the FOXO pathway will diminish activity of cells which cause bone resorption. Aging increases oxidative stress and osteoblast apoptosis and decreases bone mass, whereas FoxO transcription factors defend against oxidative stress by activating genes involved in free radical scavenging and apoptosis. Conditional deletion of FoxO1, 3 and 4 in three-month-old mice resulted in an increase in oxidative stress in bone and osteoblast apoptosis and a decrease in the number of osteoblasts, the rate of bone formation, and bone mass at cancellous and cortical sites. The effect of the deletion on osteoblast apoptosis was cell autonomous and resulted from oxidative stress. Conversely, overexpression of a FoxO3 gene in mature osteoblasts decreased oxidative stress and osteoblast apoptosis, and increased osteoblast number, bone formation rate and vertebral bone mass. FoxO-dependent oxidative defense provides a mechanism to handle the oxygen free radicals constantly generated by the aerobic metabolism of osteoblasts and is thereby indispensable for bone mass homeostasis. In the future, research will become devoted to the study of supplements and medication which stimulate the FOXO pathway which may become a viable alternation for Osteoporosis treatment. The following diagram shows some of the relationships between the FOXO proteins and the various cells in bone metabolism. There is still much we need to learn concerning this topic. How to Increase FOXO Proteins The enzyme SIRT1 increases FOXO DNA binding by deacetylating FOXO in response to oxidative stress. So, what happens is that the FOXO leaves the cytoplasm and enters the nucleus ultimately affecting the DNA. FOXO proteins get increased in response to cellular stress and increased energy depletion. Taking it one step further we find that many things which stimulate the Sirtuin genes will stimulate the FOXO genes. Calorie restriction increases sirtuins as well as FOXO factors. For instance, fasting for forty-eight hours elevates FOXO1,3, and 4 by 1.5-fold and but when one eats it will drop back to baseline. FOXO1 is also critical for adapting to fasting by activating gluconeogenesis in the liver, which can make the liver produce glucose whether from amino acids or fatty acids. This can be important in someone who is following a Keto diet. Another method of increasing FOXO is high intensity exercise. FOXO factors are important for regulating muscle energy homeostasis. In response to heat stress, FOXO contributes to increased heat shock protein levels. Heat shock proteins will protect DNA from damage and maintains cellular resistance. One way they do this is to make sure that proteins fold properly in the cell. Taking this to a more practical level, taking a sauna or exercising and sweating can promote FOXO activation and subsequent heat shock protein. Exposure to cold stress production. Hypoxia will also activate FOXO3. The general trend for increasing FOXO follows the same pattern as the other longevity pathways such as AMPK and Sirtuins. Energy deprivation and adaptation to stress can lead to more resilient and longer life. It forces the body to continue producing energy and survive in situations of low nutrients and thus become really efficient at its own metabolic processes. FOXO3 is activated by dietary components, such as EGCG, which is found in green tea, and by quercetin, which is found in onions and apples. WHY STIMULATE THE FOXO PROTEINS? Why would you want to activate FOXO proteins? FOXO proteins activate genes that maintain healthy joints and bone structure. People with osteoarthritis have significantly lower FOXO proteins. FOXO transcription factors modulate autophagy, which promotes cellular turnover and maintenance. Defects in autophagy are associated with age-related diseases. FOXO factors are important for stem cell production and DNA repair. FOXO1 and FOXO3 promote mitophagy which is mitochondrial autophagy FOXO proteins suppress tumorigenesis in cancer. FOXO factors increase the antioxidant capacity of cells, which influence aging and promote longevity. Reactive oxygen species and oxidative stress activate FOXO pathway to adapt to the stress. Inactivity of FOXO factors accelerates atherosclerosis and compromises stem cell proliferation. HOW ABOUT THE FUTURE OF FOXO PROTEINS? Is there a connection between FOXO and cancer? FOXO proteins were originally identified in human tumors. They play an important role in cell-cycle arrest, DNA repair, and apoptosis cell functions that go awry in cancer the FOXO family is thought to coordinate the balance between longevity and tumor suppression. An example of this is found in certain breast cancers. In these cancers, FOXO3 is sequestered in the cytoplasm and inactivated. Expression of active forms of FOXO in tumor cells prevents tumor growth in vivo. Additionally, protein partners of FOXO, such as p53 and SMAD transcription factors, are tumor suppressors. Investigating the ensemble of FOXO protein partners will provide insight into the connection between aging and cancer. The following illustration best defines this relationship: The above entities show the far-reaching hands of the FOXO proteins. These hands all have a direct effect on aging and disease prevention. Thanks, Dr. P

The above diagram shows just a portion of the symptoms that some patients who are recovering from Covid-19 infection are manifesting. They present with these symptoms long after they have tested negative for the covid-19 virus. These are a group of patients that are now given the name Covid Long Haulers. I have written a few articles on some methods that may help prevent patients from becoming infected with the Covid-19 virus. These recommendations include a number of supplements such as Zinc, vitamins C, D, and melatonin . Also, lifestyle changes such as weight loss and exercise may also help. These recommendations are based on science. BUT WE MUST REALIZE THAT THESE ARE JUST RECOMMENDATIONS AND NOT TO BE TAKEN AS THE GOSPEL TRUTH. THEY HAVE NOT BEEN BASED ON RIGOROUS SCEINTIFIC STUDIES. They are based on clinical hunches and observations. The new question is what might we offer those patients who have had a Covid infection and they continue to be symptomatic. We see some of the manifestations below. These seem to be the most common post Covid symptoms. Patients having long lasting symptoms after a viral infection are not new. This has been seen in the past with Ebola, and the first SARS virus in the early 2000s. Both viruses gave rise to long-lasting symptoms after some people recovered. A 2009 study in Hong Kong found that psychiatric problems and chronic fatigue still plagued SARS-1 survivors up to four years later. People who completely recover from an Ebola infection can still suffer from fatigue, headaches, muscle, joint and stomach pain, eye problems, memory and hearing loss, and mental health issues. The Ebola virus can persist in their bodies, including in the eyes and the central nervous system, even after being cleared from the rest of the body. Covid Long Haulers, recovering patients whose symptoms persist after their coronavirus infections disappear, are a mix of younger people who never needed hospital care and older people with chronic conditions that predate Covid. Their symptoms trail the infection’s path through their lungs, hearts, muscles, nerves, and brains. Deadening fatigue can dog them for weeks or months. Sometimes their problems wane, then resurface in a stuttering pattern that leaves them wondering if they’ll ever get over the condition. Long-haulers include two groups of people affected by the virus. Those who experience some permanent damage to their lungs, heart, kidneys, or brain that may affect their ability to function. While the second group continue to experience debilitating symptoms despite no detectable damage to these organs. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, has speculated that many in the second group will develop a condition called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS can be triggered by other infectious illnesses such as mononucleosis, Lyme disease, and severe acute respiratory syndrome (SARS), another coronavirus disease. WHAT MAY BE THE ETIOLOGY OF THE LONG HAULER SET OF SYMPTOMS? This may be due to an immune-inflammatory response gone amok, or perhaps to ongoing viral activity that might not be clinically detectable. The etiologies are almost certainly multifactorial, but may involve overzealous immune responses, cardiopulmonary or systemic inflammation, vascular inflammation or clotting disorders, and direct damage from viral replication during acute illness. COVID-19 often strikes the lungs first, but it is not simply a respiratory disease, and in many people, the lungs are not the worst-affected organ. In part, that’s because cells in many different locations harbor the ACE2 receptor which is the virus’s major target. However, the infection can harm the immune system, which pervades the whole body. ACE2 is a protein on the surface of many cell types. It is an enzyme that generates small proteins by cutting up the larger protein angiotensinogen that then go on to regulate functions in the cell. The following diagram gives an idea of the ACE 2 receptors and their relationship to Covid 19. Some people who have recovered from COVID-19 could be left with a weakened immune system. Many other viruses are thought to do this. It has been suggested that people who have been infected with measles are immunosuppressed for an extended period and are vulnerable to other infections. This may or may not be case for COVID-19. SARS, for instance, is known to decrease immune-system activity by reducing the production of signaling molecules called interferons. The real problem most long haulers are facing is what is stated earlier by the concept from Dr. Fauci. Many post Covid patients may develop a chronic fatigue syndrome (CFS). CFS, is considered an immune-mediated disorder. It has long been considered a "mystery illness," but that viewpoint is becoming dated. Now it is becoming evident that in CFS there are roles of both of inflammation and autoimmunity. Inflammation is part of a healthy response to problems in the body. When inflammation becomes chronic due to ongoing damage or a misfiring immune system, then you've got a problem. Autoimmunity is when the immune system mistakenly identifies a part of your body as a foreign invader, treating it much like a virus, it needs to get rid of. Your own body triggers its inflammatory process and sends specialized cells to destroy the target and begin the healing process. Only with autoimmunity, the healing process creates more of whatever body part your immune system doesn't like, so it continues to attack and heal and attack in a vicious fashion. The process continues indefinitely. Autoimmunity is a specific type of immune-system dysfunction, but it's important to note that not all immune-system dysfunction is autoimmunity. If we look at the diagram below we see that the symptoms of the Covid Long Haulers and those patients with CFS very much overlap I could substitute the name Covid Long Haulers for CFS. Thus, one big clue in treating patients with Post Covid syndrome is treat them as we would treat Chronic Fatigue Patients. It seems that patients with the Post Covid syndrome and those who have CFS have many similarities. Both conditions seem to have increased levels of cytokine growth factors such as Interleukin 1 and Tumor Necrosis Factor which cause inflammation. This diagram gives a better picture of the relationship to inflammatory growth factors and the Covid Long Haulers. Thus, it seems that the evidence is overwhelming as far as inflammatory growth factors being associated with post Covid symptoms. It would seem logical if we diminish inflammation we can diminish many of the symptoms of the Post Covid Long Haulers. WHAT IS THE ANECDOTAL EVIDENCE WE LOOKED AT FOR COVID LONG HAULERS? When we looked at the clinical results of some of our post Covid patients it seemed that when attempts were made at reducing inflammation the patients’ health improved. Again, these are anecdotal observations but they are what we observed nevertheless. When we look at the playbook for treating CFS it seems that it might be adaptable to treating the Post Covid Syndrome Long Haulers. We are trying to reduce inflammation in the body WHAT MIGHT BE OF BENEFIT IN TREATING THESE PATIENTS AND WHAT SEEMED TO WORK? First off, we think intravenous NAD would be a be a great help. NAD will improve the health of the mitochondria. NAD provides the mitochondria with the necessary tools to produce more ATP which is the cells energy currency. NAD has a significant effect on the Sirtuin pathways in the body. These pathways are intimately involved with longevity and health. There are a number of reports that the body is somewhat depleted of NAD levels after dealing with an infection. The diagram below gives good idea of the importance of the Sirtuin pathway. Influencing the Sirtuin pathway in a positive manner is certainly a step in the right direction in improving the health of the Long Haulers. NAD certainly has its value but we must remember one important fact. NAD will make senescent cells flourish which is not something we want in a patient who is trying to recover. Remember senescent cells are those cells that should have died but did not. They unfortunately can cause multiple problems in the body such as secreting the inflammatory growth factors. Senescent cells are one of the reasons why Covid-19 seems to be more unforgiving in the elderly. As we age, we accumulate more and more senescent cells. None the less, in the Post Covid long haulers we want to eliminate a portion of the senescent cells. For our general health we still need some senescent cells but we wish to diminish their numbers. This is accomplished by the use of what are called senolytic agents. One of these agents is Quercetin. There are also some other ones which will be of benefit. INFLAMMATION IN LONG HAULERS We still have the problem of post infection inflammation. There is no simple solution for turning off inflammation. However, by utilizing and taking advantage of the pathways in the body we are aware of methods to reduce inflammation. The body and its cells are like the hardware of a computer and the pathways are the computer software. In this case we are interested in stimulating the NRF2 pathway software. The Nrf2 pathway is the thermostat of anti-inflammation. Get this pathway activated and inflammation is diminished. The NRF2 is the software which stimulates the computer hardware namely the genes in the cells which than produce compounds. The above diagram shows the NRF2 pathway in action. What the NRF2 pathway does is produce reduce inflammation in the body. One very good method of doing this is thru the EBO2 protocol. This is a protocol which uses a dialysis filter and blood ozonation at the same time. By using the blood ozonation certain “Ozone Messengers” are created in the body and they appear to have a direct positive effect on the NRF2 pathway. The NRF2 pathway will help stimulate various compounds which will reduce inflammation. Remember that the NRF2 pathway is the computer software, it causes certain genes to turn on and produce certain compounds which dramatically reduce inflammation. We will also be utilizing a supplement that we specifically designed to stimulate the NRF2 pathway. Another medication that may be of benefit in reducing inflammation in long haulers is a medication called Low Dose Naltrexone (LDN). Naltrexone was approved by the FDA in the USA for the treatment of opioid addiction. For our purposes the dosage we will utilize in long haulers will be much smaller than that used for addiction problems. Naltrexone is an antagonist for the opiate/endorphin receptors. Endorphins are polypeptides made by the pituitary gland and central nervous system to moderate the production of neurotransmitters, such as serotonin and dopamine. Endorphins primarily help to reduce pain and inflammation, promote autophagy, and cellular clean up. For instance, when one gets a high after exercising it is typically from the release of endorphins. In individuals with diagnoses such as depression, fibromyalgia, cognitive degeneration, and autoimmunity we are consistently finding chronically low levels of endorphins. Specifically, low levels of an endorphin called Opioid Growth Factor (OGF). OGF is an endorphin produced in most cells in the body to both influence and regulate cell growth, as well as immunity. When low levels of OGF endorphins exist, it is likely for individuals to develop immune system disorders. Low Dose Naltrexone (LDN) has been shown to increase OGF levels in the body, resulting in positive outcomes for those suffering from a variety of diagnoses. The following diagram gives an idea of how Naltrexone can accomplish its goals. The diagram shows that reducing certain cytokine growth factors will reduce inflammation. We must be cognizant of the fact that these effects of Naltrexone only occur with the low doses. The lower doses are blocking the activation of certain immune cells. This is accomplished by blocking receptors on the cell surface with low doses. How does LDN work? LDN first binds to opioid receptors which are found on the surface of the cell. In doing so, it helps to displace the body’s naturally produced OGF. As LDN displaces OGF receptors, affected cells become OGF-deficient and, as a result, three vital processes occur. The first is an increased receptor trying to capture more OGF. Secondly, receptor sensitivity is increased to capture more OGF. Lastly, production of OGF is increased to compensate for the perceived shortage of OGF. Since LDN will only block OGF receptors for three to five hours, the body experiences a rebound effect which greatly increases the production and utilization of OGF. Once the LDN has fallen off the OGF receptors and excreted, the increased number of endorphins bind to the now more-sensitive and more-plentiful receptors. As a result, these new and improved receptors assist in regulating cell growth, promoting healing, reducing inflammation, and increasing immunity and autophagy. This is accomplished by utilizing a low dose of Naltrexone per day. This is exactly what we are looking for in treating Chronic Inflammation syndrome and Post Covid Syndrome. This is accomplished by utilizing a low dose of Naltrexone per day. We must realize that the Naltrexone must be used only in a low dose. A higher dose will have will not work and will cause the Naltrexone not to work. One other treatment protocol that seems to have efficacy is the use of a very small embryonic like stem cell, many times referred to as a V cell. V cells are found in each of us. There are some propriety methods of stimulating their numbers and activation. They seem to have some far-ranging effects on various systems in the body. We have utilized these cells for years with great results. I looked at some of the Post Covid patients that we have treated in our clinic and analyzed what worked well for them. The bottom line is what is our approach in treating Covid Long Hauler patients? THE ANSWER IS REDUCING INFLAMMATION!! We feel that NAD will be instrumental in treating these patients. This will initially be done with a loading intravenous dose followed by oral doses. We will employ some propriety methods to increase NAD efficiency. The NAD will stimulate the Sirtuin pathways which have multiple desirous effects. We will also treat the patients with senolytic agents to keep senescent cells at bay. We will also incorporate some other intravenous formulas which will help boost immunity and at the same time help fight inflammation. The EBO2 protocol will help to stimulate the NRF2 pathway and hopefully diminish inflammation. Use of some supplements which will help stimulate the NRF2 pathway, the immune system, and well-being. Utilize low dose Naltrexone. We will utilize a low dose as has been described in the literature. The idea is to again reduce inflammation. Finally, we will utilize some growth factor transdermal patches. These patches have some potent cytokine growth factors. One is called Interleukin 10 and the other is called Interleukin 1 antagonist. I call Interleukin 10 “cortisone with no baggage”. V-cell from the patient which will be beneficial on multiple levels. RIGHT OFF THE BAT, HOWEVER, LET ME GIVE THE DISCLAIMER THAT THIS ARTICLE DOES NOT CONSTITUTE MEDICAL ADVICE -- ONLY MEDICAL HYPOTHESIS. THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FDA. They are based on some of our observations and a review of science that is found in the literature. Before embarking on any treatments, one must consult a physician. Thanks, Dr. P