The above diagram shows the difference between normal bone and osteoporotic bone. We can see that the osteoporotic bone has much bigger holes and in general is much weaker bone. When we talk about Osteoporosis I can wear both of my hats. The hat of an orthopedic surgeon and that of a Regenerative Medicine stem cell doctor. For 35 years I have seen first hand the ravages of osteoporosis. I have operated on thousands of fractures that were caused by osteoporosis. Many of these fractures were quite challenging. The fixation of the fractures required different surgical solutions including plates, rods, and screws and different combinations. These fractures were the precursor of many other serious problems such as blood clots, strokes, pneumonia and other serious medical problems. The next slide shows the incidence of osteoporosis in the USA. There is not any widely accepted treatment for osteoporosis. In the above diagram we can see some of the methods that are used to treat osteoporosis. Unfortunately, these treatments are at best band aid approaches. Last year a meta-analysis of no fewer than 33 studies was published in the prestigious BMJ (the former British Medical Journal). This study confirms what had been suspected. Namely, that bisphosphonates are totally ineffective at preventing fractures. Bisphosphonates are a class of osteoporosis drugs such as Boniva (ibandronate), Fosamax (alendronate), Actonel (risedronate) and Reclast (zoledronic acid). Their mode of action is to disrupt normal bone remodeling, which is ultimately detrimental to bone integrity and fracture resistance. They do not increase bone density but slow down bone loss. Teriparatide also called Forteo is the only osteoporosis medicine which has been shown to have the potential to rebuild bone. It has to be given as a daily injection and one of its risks is that it can cause a bone cancer called osteosarcoma. As can be seen none of these medicines are a bargain. Either they do not work or have a significant risk. The interesting new aspect concerning Osteoporosis is the use of stem cells to treat osteoporosis. The following slides give a good idea of what the stem cells are doing. From this slide we get a better idea of the concept of how stem cells can treat osteoporosis. The cell we are talking about is not any stem cells but what we call an Adult Pluripotent Embryonic-Like Stem Cell. Also called a VSEL stem cell. These cells are revolutionary. We are fortunate in that we are one of the few facilities that are utilizing these cells. I describe these cells as an emergency stem cell supply. They are found in everyone but typically they are not activated. One of the common threads on the studies with these cells is that they seem to be activated by cold temperatures. The propriety information here includes the methods to dramatically increase the number of cells released, how to activate them and finally how to keep them going. We are fortunate to be able to utilize this technology. The technique is relatively non-invasive. It requires an injection or two of some propriety compounds and then a harvesting of some blood. We have utilized these cells for a few years. They work exceptionally well with auto-immune diseases (a type of condition where the body can attack itself) such as Rheumatoid Arthritis and Ankylosing Spondylitis. We also use them for anti-aging as well as for musculoskeletal conditions with good success. When we talk about osteoporosis we think osteoporosis is somewhat like an autoimmune disease. We have seen some of our preliminary results with using these cells for osteoporosis. The results are astounding. The slide below shows one of the patients we have treated. We have had similar results in other patients we have treated for osteoporosis. As can be seen this patient has received two injections of the pluripotent cells. They were spaced about one year apart. Our recommendations are to perform two of these treatments a year, spaced approximately 6 months apart. We are also placing the patients on some propriety growth factors and supplement mixes. To make things somewhat easier I have included the patient's most recent bone density report below. I think that this is easier to follow. This report shows the patient's bone density INCREASED 14% IN LESS THAN 6 MONTHS!! This increase is exceptional. There is currently no treatment for osteoporosis that I am aware of that would even approach this amount of improvement. Unlike many things in regenerative medicine we see very specific improvement in results in a test (bone density) that is completely objective. The implications of this treatment are profound. If we are able to turn the tide of osteoporosis it will save our health care system billions of dollars. The amount of money spent on a fractured hip is astounding. More importantly this treatment can dramatically improve the quality of life of the patient. Fractures take a toll on the patient and their families. The problem with osteoporosis is that it is a silent problem. Most of the time you have osteoporosis or its less severe counterpart which is called osteopenia there are initially no symptoms. The symptoms occur when fractures start happening. Other manifestations include some wedging of the vertebral bodies (back bones) which can cause spinal deformities. As far as other manifestations of the VSELs we have seen significant improvements in the treatment of auto-immune diseases. We have had a number of patients go off their medications for these diseases. Some of the side effects for these medications include developing a lymphoma. There also seems to be some manifestations of some anti-aging properties but I will leave this for another blog. We are very high on these cells. I will be attending and lecturing at a meeting in Kuala Lumpur on Dec. 17 and 18. This meeting will present some of the newest information on VSELs by those experts in the world involved with these cells. Some of the topics will include infertility, treatment of various inflammatory diseases including COPD, addiction problems. We are quite excited about these cells and have a published paper coming out about these cells. We will now be offering an osteoporosis program that will include two of these VSEL treatments a year. Incorporated into these treatments we will utilize a proprietary blend of cytokine growth factors and a supplement program. Both the growth factors and the supplements will also target osteoporosis. Also we will pay for one bone density so that we can track our results. So the warning should go out to Osteoporosis and Osteopenia. We have targeted them in our gun sites and we are going to assassinate them. More to come Thanks Dr. P

There are four main longevity pathways identified in organisms including humans: 1. AMP-activated protein kinase (AMPK) pathway 2. mTOR Pathway 3. Sirtuin Pathway 4. Nuclear factor-kappa B (NF-kB) pathway. In this blog we would like first like to address the AMPK pathway. AMPK is an important aspect of the new field of bioenergetics. Although the above picture looks to be modern art it is actually a picture of molecular structure of AMPK which is an enzyme. An enzyme is a protein that performs chemical reactions. AMPK’s full name is 5’-AMP-activated protein Kinase. A kinase is an enzyme that transfers a phosphate ion to another protein, a reaction known as phosphorylation that acts as a biomolecular “on/off switch”, turning the activity of that protein either on or off. We should think of enzymes as traffic lights. They can slow, speed up, or stop metabolic processes. A metabolic pathway is a series of chemical reactions in a cell that build and breakdown molecules for cellular processes. Anabolic pathways synthesize molecules and require energy. Catabolic pathways break down molecules and produce energy. AMPK is more of a catabolic pathway. The following illustration shows this well: AMPK IS CONSIDERED A CATABOLIC PATHWAY Typically, most diseases in the body result when there are malfunctions related to a pathway. This is the reason that in order to truly address Anti-Aging one must address these four pillars of the pathways of aging. Malfunction of these pathways are what is called the upstream causes of aging. The AMPK pathway is one of the major players that can have a dramatic effect in slowing down aging. What affects the AMPK pathway will have many effects downstream from it. WHAT EXACTLY IS AMPK? The above diagram represents the cycle of how the body produces ATP from the assistance of AMPK. The metabolic protein AMPK has been described as a kind of magic bullet for health. Studies in animal models have shown that compounds that activate the protein have health-promoting effects to reverse diabetes, improve cardiovascular health, treat mitochondrial disease and even extend life span. AMP-activated protein kinase, or AMPK, is known as a master regulator of metabolism. It is a fuel sensing enzyme found in all mammalian cells. The science of bioenergetics is producing paradigm-shifting discoveries, including the role of AMPK in regulating the ways our bodies use and transform energy. Cells activate AMPK when they are running low on energy, and AMPK is activated in tissues throughout the body following exercise or during calorie restriction. In response, AMPK alters the activity of many other genes and proteins, helping keep cells alive and functioning even when they're running low on fuel. AMPK is the “switch” that is the link between metabolic disease, inflammation, and longevity. This “switch” tells our cells when to store and generate energy-containing molecules such as fat, and when to “hunker down” and use existing energy stores. For our survival, AMPK needs to maintain cellular homeostasis that requires efficient regulation of energy metabolism during rest and especially when under greater stress. AMPK controls energy metabolism in cells and helps to maintain an energetic balance by mobilizing the body’s fuel sources. AMPK gets activated by increased concentrations of AMP and ADP due to ATP depletion. AMP or adenosine monophosphate is a nucleotide that gets interconverted into ADP or ATP. This process helps to produce energy. AMPK uses AMP for maintaining homeostasis during high energy expenditure such as exercise. ADP or adenosine diphosphate is an organic compound found in cells that helps energy currents. ATP or adenosine triphosphate is an organic chemical that provides energy for all cellular processes, such as muscle contractions, nerve impulses, and chemical syntheses. It’s often called the energy currency of the cells. AMPK detects the number of ATP in cells and then regulates it when it gets too high or too low. In different tissues throughout the body and at different time points in development, AMPK likely has varying effects. Remember that ATP is intimately related to the mitochondria. AMPK is a kinase enzyme that transfers a phosphate ion to another protein. This is a reaction known as phosphorylation that acts as a biomolecular “on/off switch”, turning the of that protein either on or off. Many steps of phosphorylation occur between different proteins communicating to one another in a “cell-signaling cascade”. These signals take an input (such as a hormone, drug or exercise) and can induce any number of outcomes including cell growth, cell death, energy breakdown, energy storage or turning on specific genes for expression. Ultimately, cell signaling is required for all of the physiological processes that we perform as organisms and is key to how we adapt in training to become stronger, faster and fitter. WHAT PROBLEMS ARISE WHEN AMPK PATHWAY IS NOT FUNCTIONING PROPERLY The following illustration shows the various avenues of damage caused by the malfunction of the AMPK pathway. These malfunctions involve three of the cardinal areas where problems arise. Metabolic dysfunction is probably the biggest while loss of proteostasis (protein homeostasis) and the loss of genetic instability are not far behind: We can see that AMPK problems lead to multiple problems and as we get older they seem to be compounded. Also important are the effects AMPK may have on the other pathways of aging. Like many things in life as we age the pathway becomes less active you will notice that AMPK effects all the other major pathways of aging. We can see essentially most of the major pathways the are directly affected by the AMPK pathway. These include NFkB, Sirt1, and mTOR. In more practical terms the next illustration shows the “deadly effects” of an AMPK deficit. These are all aspects of an unhealthy individual who is rapidly aging and is showing the aspects of “inflammaging”. We can see very well the far-ranging effects that a deficiency of AMPK will have upon the body. In some way shape or form all of these problems lead to increasing inflammation in the body. This inflammation which is associated with aging is now called “Inflammaging”. It seems that if we can get a handle on AMPK and prevent it deficits, we might just get a better handle on aging. There are a number of methods that we can improve how our body deals with the AMPK pathway. The next section discusses this in greater detail. Remember AMPK deficiency is not just genetic in nature. One other significant finding in the AMPK pathway is the effect AMPK has upon the health of our gut bacteria. Many medical problems arise when our gut bacteria is not in a healthy state. Accumulating studies have demonstrated that AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine, indicating an essential role of AMPK in intestinal health. Gut health and the mitochondria are intimately related. The flowing diagram show how AMPK and gut health affect metabolism, inflammation, and oxidative stress. We are aware that a number of diabetes medicines target AMPK and ultimately have their effects on the gut bacteria. Metformin is one such medicine. Although it is mainly used for diabetic control Metformin is used by many non-diabetics for its anti-aging, anti-cancer, and potential performance enhancing properties due to its effects on the AMPK pathway. We can extrapolate this further on athletic performance. There seems to be a crosstalk between the gut microbiota and mitochondria during Exercise. This can be seen in the following illustration. Ultimately we need to remember that we are only as healthy as our mitochondria. What we see is that endurance performance is increased by the relationship between the gut, AMPK, and mitochondria functions. We can see that it is very important to maintain our gut bacteria in the best of condition. This is why probiotics are very important in maintaining the AMPK pathway. Remember that a healthy gut is a healthy and typically a happy patient. WHAT ARE BEST WAYS TO CONTROL AMPK PATHWAY There are a number of methods to control and stimulate the AMPK pathway. Some involve medications and supplements. Diet seems to play a large role in managing the AMPK pathway. That is rather evident in the above diagram. Exercise, we now know, is one of the most powerful AMPK-activating strategies. Activated AMPK promotes all the processes we look for to maintain a youthful profile: rapid, efficient release of energy, with little energy storage as fat or new sugar molecules. Thus, activated AMPK keeps us lean and active, with a steady renewal of cellular components. AMPK activity fades with age. Just as importantly, when excessive calories are available, the result is accelerated tissue aging. You can boost AMPK activity through exercise and/or calorie restriction, but should also make use of natural supplements that support AMPK activity. Boosting AMPK activity will keep your tissues young and slow aging throughout your body. It is now clear that, when caloric intake remains much higher than needed to sustain energy expenditure AMPK activation is markedly decreased. With reduced AMPK activity, cells decrease their energy-releasing ATP-generating activities, and instead shift to energy-storing processes that generate new fat deposits and glucose molecules leading to premature aging and diseases. The above picture shows Barberries which are the red berries from the Berberis vulgaris plant. These compounds contain the compound called Berberine. Berberine acts similar to the common diabetes medicine called metformin. Berberine seems to be a potent activator of the AMPK pathway. It has minimal side effects. Also as stated earlier, it is crucial to maintain the health of one’s gut bacteria. What else seems to affect AMPK pathway in a positive way? What other supplements also are beneficial when dealing with the AMPK pathway. These supplements include Resveratrol, Alpha Lipoic Acid, Gynostemma (a form of Ginseng), Curcumin and Quercetin. They all seem to act as potent stimulators of the AMPK pathway. The good news is that our clinic now has the ability to deliver Quercetin and Curcumin via an intravenous route. The bottom line is that we can now take AMPK stimulation to the next level. Thanks, JP

I am a huge fan of NAD+ supplementation. My family and I take an NAD supplement on a daily basis. In addition to that, we will occasionally take an Intravenous dose of NAD+. It is indisputable that as we age we absolutely need more NAD+ or we basically face an increasing assault by the ravages of aging. Can NAD+ be like a Trojan Horse and on the outside look promising but at the same time cause danger from the inside? Well if you go to an ill prepared clinic the answer is yes! Like most things in life there is no free lunch. Indeed, we are well aware that NAD+ and its precursors will have significant effects on a number of pathways in the body. The following diagram shows what happens with low NAD levels: One of the Anti-Aging Pathways that NAD affects is the Sirtuin gene pathway. There are seven different components to the Sirtuin genes. The Sirtuins are a family of proteins that play a huge role in aging by regulating cellular health, especially the health of the mitochondria. They're responsible for critical biological functions like DNA expression and other aspects of aging. However, sirtuins can only function in the presence of NAD+, nicotinamide adenine dinucleotide, a coenzyme found in all living cells. NAD is an essential building block during energy production. The energy in this case is ATP. We lose up to 50% of our NAD levels between the ages of 40 and 60 as can be seen in the following illustration: We must also remember that NAD+ is not just used for energy production but also is utilized by enzymes (PARP) that repair DNA damage. These enzymes are also huge consumers of NAD. The Sirtuin genes seems to have significance over the health of our mitochondria. Ultimately, the decline in mitochondrial function causes us to age. A prominent theory of aging holds that decaying of mitochondria is a key driver of aging. To slow down aging one needs to increase NAD+ and its precursors. This is absolutely the case and is practiced by many well-informed people and clinics. Unfortunately, most people and clinics for that matter seem to stop here. The premise is that NAD+ will slow aging and everyone goes on their merry way. What we need to realize that NAD+ alone may in some ways act as a Trojan horse. On the outside it seems to be a gift to our health which in many ways it is. But there are also some aspects of NAD+ therapy that might not be conducive to our health UNLESS WE ADDRESS THESE PROBLEMS AT THE TIME OF THE NAD TREATMENT. I have previously mentioned one detrimental aspect of NAD+ treatment is its effect on Senescent cells. Remember a Senescent cell is a cell that should have died but continues to survive causing a variety of problems. I wrote an extensive blog on this subject some time ago. Please go to my website and check the blog I wrote entitled “NAD and Senescent Cells on a Collision Course”. Unfortunately, most clinics are not aware of the potential problems NAD+ may cause with Senescent cells. It can actually make these cells thrive. So low and behold you actually may not make a patient healthier if he is given NAD+ without addressing Senescent cells. You may be going in the opposite direction and possibly cause a decline in their overall health. We have addressed the Senescent cell problem with Senolytic agents for some time now. The Senolytic agents that will directly attack the Senescent cells and aid in their elimination. We have done this for years and will continue to do so. METHYLATION OR LACK OF IT: A MAJOR HIDDEN DANGER OF NAD THERAPY Senescent cells can cause havoc by their inflammatory secretions but they are only one problem that can be increased by NAD+ therapy. The other major concern unleashed by NAD+ therapy concerns a process called methylation. Methylation is the transfer of a methyl group (one carbon and three hydrogens) from one molecule to another in the body and is a fundamental element of our biochemistry. Methylation is accomplished by enzymes. Methylation can modify heavy metals, regulate gene expression, RNA processing and protein function. It is recognized as a key process underlying Epigenetics. Epigenetics involves essentially turning on and off switches of different genes. The above diagram illustrates the intersection between methylation and control of our genes. As noted above, methylation generally acts as a suppressor for many of the gene regulatory elements such as insulators, promoters, enhancers and repressors. These regulatory elements play a significant role in maintaining the integrity of chromosomes and homeostasis of organisms. Epigenetics ensures that only a single allele (different forms of the same gene) should be expressed for that specific gene. This process is known as imprinting. In the case of failed imprinting, it can result in a spectrum of diseases. In simplistic terms, epigenetics involves putting a methyl group on a DNA strand. Methyl groups are organic molecules. What we are really dealing with is called DNA methylation. DNA methylation occurs when a methyl group is added to a DNA strand. DNA methylation is a tool to typically lock genes into their off position. Aberrant DNA methylation, which is a nearly universal finding in cancer results in disturbed gene expression. DNA methylation is modified by environmental factors such as diet that may modify cancer risk and tumor behavior. Abnormal DNA methylation has been observed in several cancers. These alterations in DNA methylation may play a critical role in cancer development and progression. Dietary nutrient intake and bioactive food components are essential environmental factors that may influence DNA methylation. In recent years, researchers have learned a great deal about DNA methylation, including how it occurs and where it occurs, and they have also discovered that methylation is an important component in numerous cellular processes. So, we can see that DNA methylation is crucial to our well-being and healthspan. HOW DO DNA METHYLATION AND NAD THERAPY INTERSECT WITH EACH OTHER? We are able to see the importance methyl groups play in our health and well-being. Below we see a diagram of the metabolism of NAD+. The problem develops when we start to metabolize the byproducts of NAD+. Although NAD+ is used by the body to create ATP, NAD+ is also metabolized to a methylated nicotinamide molecule called MeNAM. The process of metabolizing NAD+ stresses the body’s “methyl pool,” the molecules that donate methyl groups. The methyl pool is crucial to maintain one’s health. A methyl group needs to be added to NAD+ to create MeNAM, which uses up methyl groups that are needed for other biochemical reactions. If adequate amounts of methyl groups are not available than methylation is diminished allowing genes to either be kept on or off sometimes resulting in significant problems. Also, when NAD+ treatments are given, as the NAD+ is metabolized it is converted into a compound called Methionine which is ultimately converted into a compound called Homocysteine. Homocysteine is a byproduct of methionine metabolism. It is a powerful pro-oxidant and free-radical generator known to be a leading cause of heart disease and other problems as the following illustration shows. A clinical study of niacinamide supplementation showed not only an increase in MeNAM, but also an increase in homocysteine levels, which is an independent risk factor for heart disease. There appears to be a relationship between high levels of homocysteine and artery damage. That can lead to atherosclerosis (hardening of the arteries) and blood clots. We must also realize many individuals in the United States – some estimates are as high as 60% have a genetic defect in a critical enzyme involved in methylation – MTHFR. This makes methylation even more difficult. Here is a good illustration of the damage homocysteine causes to the vessels: The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving the vitamin folate (also called vitamin B9). Specifically, this enzyme converts a form of folate called 5,10-methylenetetrahydrofolate to a different form of folate called 5-methyltetrahydrofolate. This is the primary form of folate found in blood, and is necessary for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds. When dealing with homocysteine, if one gets adequate amounts of vitamin B6, either from foods or supplements, a portion of the body’s homocysteine is converted into cystathionine, an antioxidant and free-radical deactivator. About half of our homocysteine is detoxified by this process. The other half is detoxified by the addition of a methyl group. With the addition of methyl groups, homocysteine is converted to methionine by the transfer of the methyl group from a methyl donating compound such as Trimethylglycine (TMG). We have been using TMG for some time now in our clinics. In brief, TMG detoxifies homocysteine, recycles methionine and supplies B15. Thus, we are able to see that NAD+ treatment will worsen the ongoing shortage of methyl groups in the body. Unless methyl donating compounds are utilized with NAD+ treatment we will exacerbate the methyl group shortage which could adversely affect the patients’ health and well-being on a few different levels. When we are giving a patient intravenous NAD+ we have found that Trimethylglycine (TMG) dramatically enables to patient to receive intravenous doses of NAD at a much faster rate. Typically, if the rate is too fast, patients will develop a variety of symptoms including flushing, chest tightness etc. Although these symptoms sound serious they are benign and cause the patient no problems other than some anxiety. One of the big reasons for eliminating these symptoms is the fact that Trimethylglycine is a potent and rich methyl donor. The propriety trick is to know when and how much TMG to use. By utilizing TMG as methyl donor, we are eliminating unpleasant symptoms and at the same time improving the patient’s health on many levels. So again, make sure the if you receive any type of NAD treatment that Senescent cells and the methyl group problem be addressed. Your health and well-being depend upon it. Thanks, Dr. P

The three above supplements are extremely important for optimal health but unfortunately, we have problems with their absorption. We may diligently take them orally on a daily basis which certainly helps but many times that may not be sufficient. However, if we are able to supplement our daily oral doses with Intravenous applications then we are talking about something special. We have been searching for Intravenous or injectable forms of these compounds for some time now and have finally found reliable sources. When something is delivered via an Intravenous route (IV) there is instant and significant absorption. Many times, the same can be said for an intra-muscular (IM) route as far as absorption is concerned. We are happy to report that these three compounds will now be an integral portion of our repertoire. The centers that have access to all these compounds are few and far between. The main problem with most of these compounds is their bio-availability. We can take them by mouth but how much of them will we absorb is a different story. This is the situation with many supplements and for that matter medications. The science of how compounds are absorbed is called pharmacokinetics. Pharmacokinetics involves the absorption, distribution, metabolism, and excretion of a compound. Co Q10: A CRUCIAL FACTOR FOR THE BODY Coenzyme Q10 is a member of the ubiquinone family of compounds. All animals, including humans can to some degree synthesize ubiquinones, hence, Coenzyme Q10 is not considered a vitamin. The name ubiquinone refers to the ubiquitous presence of these compounds in living organisms and their chemical structure, which contains a functional group known as a benzoquinone. Coenzyme Q10 is soluble in lipids (fats) and is found in virtually all cell membranes including the mitochondrial membrane. Remember that the cell membrane represents the eyes and ears of the cell. It interacts with the environment. Co Q10 is present in every cell of your body. However, the highest concentrations are found in organs with the greatest energy demands, such as the heart, kidneys, lungs and liver. Co Q10 is a fat-soluble, vitamin-like compound that seems to have many health benefits. As we can see from the following diagram it is vital for the production of energy in the body while at the same time serving as an anti-oxidant. It does this crucial work by its effects on the electron transport chain. The ability of Coenzyme Q 10 to accept and donate electrons is a critical feature to its function. These properties make it helpful in the preservation of cells and the prevention and treatment of some chronic diseases. It's critical to add Co Q10 supplements as you age. After the age of 30, your natural levels of Co Q10 begin to diminish. By the age of 50, this depletion of Co Q10 continues to accelerate. By age 70, your natural Co Q10 levels may be 50% lower than they were when you were a young adult. It is widely known that statins severely deplete your body's natural levels of CoQ10, which can be very dangerous. A Columbia University study found that within 30 days, your levels of Co Q10 can be decreased by half. However, statin drugs aren't the only culprit. In fact, there is a long list of pharmaceuticals that rob your body of Co Q10. Nearly 50% of American adults take at least one prescription daily, it's more important than ever to supplement with Co Q10 so you can be sure your body has the necessary levels needed for proper cellular energy function and a strong cardiovascular system. Co Q10’s health benefits are far reaching. We now have an injectable form of Co Q10 that will dramatically increase the amount of Co Q10 the body will absorb. This will pay the patient many health dividends including better health, more energy and less sickness. Remember that mitochondrial dysfunction is the basis of many diseases. Co Q10 fights mitochondrial problems making the mitochondria healthier enabling them to ward off diseases. QUERCETIN group Quercetin-type Flavonols, the most abundant of the flavonoid molecules, are widely distributed in plants. Remember that a flavonoid is a group of plant chemicals found in fruits and vegetables. They give fruits and plants their color and smell. Flavonoids are powerful antioxidant agents that help regulate cellular activity. They are found in a variety of foods including apples, berries, Brassica vegetables, capers, grapes, onions, shallots, tea, and tomatoes, as well as many seeds, nuts, flowers, barks, and leaves. Quercetin is also found in medicinal botanicals, including Ginkgo biloba, Hypericum perforatum, and Sambucus canadensis. In red onions, higher concentrations of quercetin occur in the outermost rings and in the part closest to the root, the latter being the part of the plant with the highest concentration. Quercetin in the pharmaceutical field is limited due to its poor solubility, low bioavailability, poor permeability and instability. Quercetin possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, anti-cancer, anti-anaphylaxis effects and Anti-aging. These aspects are evident in the following diagram: QUERCETIN The above diagram shows the main mechanism of Quercetin’s actions namely reducing oxidative stress. Oxidative stress is what I call an upstream cause of aging. If we control oxidative stress than we can eliminate or significantly alter the course of many degenerative diseases while at the same time slow down the clock of aging. As we can see, Quercetin is attacking some of the upstream pathways of aging. Although Quercetin is very powerful, the problem is delivering it to the places where it is needed. To improve the bioavailability of Quercetin, numerous approaches have been undertaken. These involve the use of promising drug delivery systems such as inclusion complexes, liposomes, nanoparticles also called micelles, which appear to provide higher solubility and bioavailability. If we can enhance bioavailability of Quercetin in the future, then it is likely to bring this product to the forefront of therapeutic agents for treatment of human disease. The fact that we can now deliver it via an intravenous route makes these other drug delivery systems not be as important. Certainly, they can be convenient, but at present they cannot compete with the intravenous route as far as absorption and efficacy are concerned. This is a monumental step. In addition to the beneficial aspects already mentioned for Quercetin there is one other huge benefit. This benefit concerns the aspect that Quercetin has on Senescent cells. A Senescent cell is essentially a cell that should have died but continues to live. It has lost its ability to reproduce. It secretes a number of undesirable growth factors which encourage a variety of degenerative conditions and other health problems. Quercetin will act as a Senolytic agent. A Senolytic agent helps to clear out the Senescent cells. If we eliminate Senescent cells than we eliminate their growth factors which can cause havoc. In our office when we are utilizing NAD+ we make it standard practice to give the patient some Quercetin to help keep the Senescent cells at bay rather than encourage their health. We do need some Senescent cells but only in small numbers. Quercetin is a good protector from Senescent Cells. CURCUMIN ALSO CALLED TUMERIC Turmeric is a spice that has long been recognized for its medicinal properties. It has received interest from both the medical/scientific world as it is the major source of the curcumin. Turmeric is a spice derived from the rhizomes of the tropical plant Curcuma longa Linn, which is a member of the ginger family (Zingiberaceae). The bright yellow-orange color of turmeric comes mainly from fat-soluble pigments known as curcuminoids. Curcumin, the principal curcuminoid found in turmeric, is generally considered its most active constituent. It aids in the management of oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, and hyperlipidemia. It may also help in the management of exercise-induced inflammation and muscle soreness, thus enhancing recovery and performance in active people and athletes. In addition, a relatively low dose of the complex can provide health benefits for people that do not have diagnosed health conditions. Most of these benefits can be attributed to its antioxidant and anti-inflammatory effects. Ingesting curcumin by itself does not lead to the associated health benefits due to its poor bioavailability which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. There are several components that can increase bioavailability. For example, Piperine is the major active component of black pepper and, when combined in a complex with curcumin, has been shown to increase bioavailability by 2000%. Personally, I have found the best form of oral form of Curcumin come from a product called Ultra Cur. The uniqueness of Ultra Cur comes from the whey protein scaffold on which Ultra Cur is delivered into the body. This scaffold dramatically increases the bioavailability. But we still must realize that an intravenous form will far surpass the bio absorption of any oral forms. The diagram below shows the far-reaching medical benefits from Curcumin: When discussing Curcumin from scientific point we need to address what pathways of aging it seems to address. The following diagram shows some of these pathways: In some of the pathways above we are able to see some significant pathways related to aging. One important pathway mentioned above is the NFkB pathway. This pathway is a master regulator of inflammation in the body. If it is stimulated it causes inflammation to get a foothold possibly resulting in many degenerative diseases and conditions. The Th-1 response results from our immune system. This portion of our immune system can result in autoimmune conditions. We need to remember many diseases may have their roots in an auto immune condition. The blocking of the COX-2 pathway is the mechanism of how many anti-inflammatories work. Increasing the amount of BDNF has many profound implications. BDNF plays a critical role in preventing cerebral atrophy and cognitive decline. We also know that BDNF has profound effects on muscle tissue. It helps muscles repair themselves, preserve their integrity, and prevent the typical decline we see with advanced age. We see Curcumin increases antioxidative enzymes which will help eliminate free radicals and the damage they cause. Lastly, there are many studies underway looking at the inhibition of cancer growth. The next diagram shows some other aspects of Curcumin: What is of great significance in this diagram is the fact that Curcumin acts as a transcription agent. A transcription agent will typically turn on genes that have become silenced due to a variety of reasons. In this case Curcumin will activate the P-53 gene. This gene is called the Tumor Suppressor Gene. This gene is on patrol to analyze cells as far as DNA damage is concerned. The diagram below explains the P-53 gene in simple terms. If the P-53 is not working properly than it allows cells with accumulated DNA damage to persist and possibly go on to cause degenerative diseases and cancers. When it is working properly than it eliminates the bad cells and repairs those cells worth repairing. We can see the far-reaching effects that Curcumin has upon our health and well-being. Thus, we can see the multiple benefits that we can offer from the use of Intravenous Quercetin and Curcumin and injectable Co Q10. They would seem to be especially helpful as an adjunct to NAD+ and other treatments. I still believe in taking oral forms of these compounds but there is no doubt that we occasionaly need to supplement them with Intravenous or Injectable forms. Your life, health, and well being many depend upon it. Thanks, Dr. P

Oxidative stress is an imbalance between free radicals and antioxidants in your body. Free radicals are oxygen-containing molecules with an uneven number of electrons. The uneven number allows them to easily react with other molecules. Free radicals can cause large chain chemical reactions in your body because they react so readily with other molecules. These reactions are called oxidation. They can be beneficial or harmful depending the amount and circumstances. Here is a diagram of a free radical: We can see that the free radical has an unpaired electron. Oxidative stress occurs when an oxygen molecule splits into single atoms with unpaired electrons, which are called free radicals. The body is under constant attack from oxidative stress. Oxygen in the body splits into single atoms with unpaired electrons. The “unpaired” electrons become unstable free radicals that seek other atoms or molecules to bond to. If this continues to happen, it begins a process called oxidative stress. How the body deals with this oxidative stress can determine if one is healthy or one is prone to a variety of degenerative medical conditions. FREE RADICALS: SOMETIMES AN ENEMY AND SOMETIMES A FRIEND OF THE BODY Free radicals damage the growth, development and survival of cells in the body. Their reactive nature allows them to engage in unnecessary side reactions causing cellular impairment and eventually injury when they are present in disproportionate amounts. They directly impair cell membranes and DNA. The next diagram shows various other causes of free radicals but utilization of oxygen is the most common cause. We can see that Free radicals and other ROS (Reactive Oxygen Species) are derived either from normal essential metabolic processes in the human body or from external sources such as exposure to X-rays, cigarette smoking, air pollutants, and industrial chemicals. The bottom line is that even if you live in a pristine area with no pollution your body will still be bombarded by free radicals since you must BREATHE OXYGEN which produces free radicals. Disease processes can also result in overproduction of oxidants. Infections, allergies, and autoimmune diseases activate our immune cells, which produce reactive oxidants in order to kill germs that the immune system assumes to be present, but our otherwise healthy cells get caught in the cross-fire and sustain collateral damage that we see and feel as inflammation. Other major diseases associated with aging, such as heart attacks, stroke, cancer, and neurodegenerative conditions such as Alzheimer’s disease also increase production of oxidants, creating oxidative stress, and inflammation. One further free radical body that needs mentioning is a Reactive Nitrogen Species. Actually, both Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS) can have duel effects especially the RNS. Recent evidence has suggested that intracellular RNS are an important component of intracellular signaling cascades. ROS can have similar effects in that they can affect a wide variety of metabolic functions in the body. RNS can also be very beneficial in fighting certain bacterial and viral infections in the body. Further elevation of RNS leads to fatigue. RNS can induce mitochondrial biogenesis, influence the levels of SIRT1 which controls vital metabolic processes, and is involved in hypertrophy of skeletal muscle. Massive elevation of RNS can lead to increased oxidative stress and alteration of lipids, proteins, and DNA. It is suggested that a moderate level of oxidative damage of lipids can be important to membrane remodeling. A moderate level of protein modification by RNS could be an important control of protein synthesis. Moreover, moderate level of oxidative DNA modification could be important to increased gene expression and cellular signaling. In skeletal muscle the age-associated decline in muscle mass and function is also related to RNS level and inflammation. Regular exercise has a powerful effect on RNS production, antioxidant, and oxidative damage repair systems. Moreover, regular exercise can attenuate the age-associated function deteriorations. ANTIOXIDANTS Before we move on, when discussing oxidative stress, we must also mention ANTIOXIDANTS. Antioxidants are substances that can prevent or slow damage to cells caused by free radicals. They are sometimes called “free-radical scavengers”. Unfortunately, the human body is not so cut and dry when it comes to dealing with free radical generation. Oxidants are produced by the process of “burning” the foods that sustain us, just as the internal combustion engines in our cars produce similar reactive chemicals. Cars have catalytic converters to neutralize and detoxify these reactive chemicals; our bodies have antioxidant enzymes to accomplish the same result. Realize that we can supply our bodies with anti-oxidants from a dietary source and at the same time the body is able to produce powerful anti-oxidant compounds on its own. The following diagram shows anti-oxidants at work. WHAT IS THE TRUE SCIENCE OF OXIDATIVE STRESS? Remember that we said ROS and RNS can act as signaling molecules in the body. This is where the true science comes into the play. As was mentioned, these two free radicals can act as signaling molecules. Although it may seem hard to fathom, some oxidative stress is actually a “good” thing. There are two main pathways in the body that control inflammation. These two pathways are called the NrF2 (nuclear factor erythroid 2–related factor 2) pathway and the NFkB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) pathway. These pathways are at the extremes of the spectrum. These pathways are actually transcription factors. Transcription factors are proteins that help turn specific genes "on" or "off" by binding to nearby DNA. Transcription factors that are activators boost a gene's transcription such as the case with Nrf2. While repressors decrease transcription as is the case with NFkB. The amount of oxidative stress will determine which pathway will be activated. This can mean the difference between health and disease. Think of Nrf2 as a thermostat of inflammation. Nrf2 has traditionally been regarded as the cell's main defense mechanism and a major regulator of cell survival. Activation of the Nrf2 defense response has been shown to protect against neuro-degenerative diseases, aging, diabetes, photo-oxidative stress, cardiovascular disease, inflammation, pulmonary fibrosis, acute pulmonary injury, and cancer. Mild stress will activate this pathway. Nrf2 will initially be found in the cytoplasm of the cell. When in the cytoplasm it is tightly bound to Keap 1. Under quiescent conditions, Nrf2is anchored in the cytoplasm to Keap1. Keap 1 is a protein which binds the Nrf2 which is also a protein. Keap 1 keeps the Nrf2 molecule under wraps until a stimulus is received (for instance high levels of free radicals) and Nrf2 breaks its chains and goes into the cell nucleus where it stimulates certain genes to produce biochemical compounds. These compounds are called ARE which stands for Antioxidant Response Elements. These are very potent anti-oxidants that the body produces. There are a number of them. The following diagram shows the Nrf2 pathway at work: We are able to see the Nrf2 is held in the cytoplasm by the KEAP1 protein. Subsequently, with activation the Nrf2 makes its way into the nucleus and subsequently affecting the nuclear DNA thus acting as a transcription factor turning on certain genes and subsequently producing the ARE products. 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, and simply growing older is one of them. We produce less Nrf2 as we age, and the balance slowly tips toward the oxidative side—a condition known as “oxidative stress.” Disease processes can also result in overproduction of oxidants. Infections, allergies, and autoimmune diseases activate our immune cells, which produce reactive oxidants (O2-., H2O2, OH. and HOCl) in order to kill germs that the immune system assumes to be present, but our otherwise healthy cells get caught in the cross-fire and sustain collateral damage that we see and feel as inflammation. Other major diseases associated with aging, such as heart attacks, stroke, cancer, and neurodegenerative conditions such as Alzheimer’s disease also increase production of oxidants, creating oxidative stress, and inflammation. The bottom line for the Nrf2 pathway is that some oxidative stress is good for activating this pathway, while too much will turn it off. Some final thoughts on the Nrf2 pathway. Nrf2 has a crucial role in maintaining cellular redox homeostasis. Nrf2 affects the mitochondrial membrane potential and ATP synthesis. Nrf2 influences mitochondrial fatty acid oxidation. Nrf2 supports the structural and functional integrity of the mitochondria. Nrf2 activators have beneficial effects when mitochondrial function is compromised. Anything that increases mitochondrial health will increase our health. The next diagram shows some other methods of stimulating this pathway: OZONE THERAPY One very effective method of stimulating the Nrf2 pathway is thru the use of Medical Ozone gas. The method is called EBO2 which stands for Extra Corporeal Blood and Ozone therapy. This is a cutting-edge technique where blood is both filtered and subsequently Ozonated after removing a number of offending agents. The Medical Ozone gas when delivered in this manner is a potent stimulator of the Nrf2 pathway as can be seen I the following illustration: THE NFkB PATHWAY: THE ANTITHESIS OF THE Nrf2 PATHWAY Whenever we discuss oxidative stress we must also address the “elephant in the room” namely the NFkB pathway. NF-kB is a short name of Nuclear Factor kappa-light-chain-enhancer of activated B cells. It is not a single protein, but a small family of inducible transcription factors that play an important role in almost all mammalian cells. NF-kB acts as a central mediator of immune and inflammatory responses, and is involved in stress responses and regulation of cell proliferation and apoptosis. The respective NF-kB target genes allow the organism to respond effectively to these environmental changes. The classical NF-kB pathway is activated by a variety of inflammatory signals, resulting in coordinate expression of multiple inflammatory and innate immune genes. Nuclear factor-κB is essential for inflammatory responses. It is one of the most important molecules linking chronic inflammation to cancer while its activity is tightly regulated by several mechanisms. As we can see from the following diagrams there are a number of methods in which the NFkB pathway gets stimulated: We can see from the two proceeding diagrams that NFkB pathway is stimulated either by external or internal factors. NF-κB is a master switch that sets in motion a chain of events that is specific to a cell type and its environment. Some auto-immune diseases (e.g., arthritis, type 1 diabetes, asthma, Crohn’s disease and irritable bowel) are associated with an excess of NF-κB. Its activation generally rises with age, but it is necessary at all ages, particularly for its contribution to the regulation of apoptosis (the selective elimination of cells that are potentially damaging). It will probably be necessary to strongly but selectively inhibit NF-κB, beginning in middle age. Inflammatory responses are complex and focused on the immediate threat at hand. We must remember that NFkB is not always a culprit. It can actually save our lives. The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines. It also participates in inflammasome regulation. An inflammasome is a multiprotein intracellular complex that detects pathogenic microorganisms and sterile stressors. It subsequently activates the highly pro-inflammatory cytokines interleukin-1 and interleukin 18. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. This can be instrumental in dealing with a bacteria or virus. However, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory and autoimmune diseases. It can also be responsible for some of the complications we are seeing with Covid-19 such as a cytokine storm. In a cytokine storm in the body’s attempt to eliminate the pathogen there is much collateral damage to surround tissue. WHAT ARE THE BEST METHODS THAT WE CAN USE TO STIMULATE THESE PATHWAYS IN ORDER TO ASSIST THE BODY WITH OXIDATIVE STRESS. The real key is to activate the Nrf2 pathway and quite down the NFkB pathway. Nrf2 contributes to the anti-inflammatory process by orchestrating the recruitment of inflammatory cells and regulating gene expression through the antioxidant response elements (ARE). It regulates anti-inflammatory gene expression and inhibits the progression of inflammation. There is a regulatory loop of Nrf2 and NFĸB. In other words when Nrf2 is stimulated then stimulation of NFkB diminishes. OF ALL METHODS TO INCREASE THE STIMULATION OF THE NRF2 PATHWAY, WE FEEL THAT MEDICAL OZONE DELIVERED VIA THE EBO2 PROTOCOL TO BE ONE OF THE MOST EFFECTIVE METHODS. In addition to the EBO2 technique, a number of supplements seem to be noteworthy. These include trans-pterostilbene, TrueBroc broccoli extract, Turmeric extract (curcumin) “Ultra-cur”, Green Tea Extract, Resveratrol, Fumaric acid compounds= potent stimulator of nrf2, Quercetin, Genistein (soy isoflavones), NAD, Neo-40 a nitric oxide stimulator. A Fumaric acid derivative was just recently approved by the FDA for the treatment of certain forms of Multiple Sclerosis. One final note, there is a company called Clearwater Nutrition Lab which will soon launch a product to address the Nrf2 pathway. This product has many of the above compounds. The reason I know this is that I helped to design it for them. -JP

BIOCHEMICAL REACTIONS THAT OCCUR IN LIVING CELLS IN RESPONSE TO LIGHT THERAPY The chamber uses the principles of Photo Bio Modulation to enhance, stimulate, and activate stem cells, platelets, Red Blood Cells, Leukocytes, Fibroblasts, fat grafts and other cells found in autologous biologics. It can help increase the efficiency of essentially any autogenous biologic. The PBM chamber is an interventional medical therapy providing physical stimulus on a biologic typically found in either a ten or twenty CC syringe. It gives the physician the ability to induce biological changes inside, or outside of cells, by using the radiation and the scattering properties inherent in light of differing wave lengths. This is accomplished by the propagating light stream interacting with the aggregate tissue target resonating at the same wave length front. This has been and will continue to be a Regenerative Medicine game changer. The following is a picture of the inner chamber in action: It is a picture of the interior showing Red and Green LED light strips, mirrors etc. The syringe is placed into opening and subjected to the various light wavelengths. The Photonic Chamber excites photo receptors within the cell body or the cell surface. It can accomplish this on an atomic or molecular basis affecting the molecules which compose living tissue. It will create a dependent sensory and biochemical alteration in the radiated tissues. It is recommended that all autologous biologics should be subjected to PBM for 10-20 minutes before injection to realize maximum benefit. Typically, the exposure time is 10 minutes for a PRP product and 20 minutes for a nucleated cell product such as bone marrow aspirate, fat graft, SVF, and Very Small Embryonic Like Stem Cells etc. The following photograph shows the chamber with both a 10 CC and 20 CC syringe undergoing Photo Bio Modulation: The chamber has primary Red and Green colors but will also have Blue, Orange, and Yellow spectrums adding additional benefits. A SUMMATION OF THE MECHANISM OF PBM CHAMBER THERAPY The precise biochemical mechanism underlying the therapeutic effects of photo modulation are not well known but the effects are found to be quite beneficial on multiple levels. One of the most distinctive features of LED light therapy relative to other modalities is that the effects are mediated not through induction of thermal effects but rather through a photobiostimulation. At the most basic level, light therapy acts by inducing a photochemical reaction in the cell, a process referred to as bio stimulation or Photobiomodulation. This process involves intracellular photoreceptors. The photons must be absorbed by electronic absorption bands belonging to some molecular chromophores or photoreceptors. A chromophore or photoreceptor is a molecule (or part of a molecule) where the energy difference between electrons in two different molecular orbitals falls within the energy possessed by photons in the visible spectrum. What we do know is that it appears that photo modulation therapy has a wide range of effects at the molecular, cellular, and tissue levels. There are several pieces of evidence that point to a chromophore within mitochondria being one of the initial targets of light therapy. Within the cell, there is strong evidence to suggest that Red light therapy acts on the mitochondria to increase adenosine triphosphate (ATP) production, modulation of reactive oxygen species (ROS), and the induction of transcription factors. A transcription factor (TF), also called a sequence-specific DNA-binding factor, is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA by binding to a specific DNA sequence. These transcription factors have significant importance in Regenerative Medicine. The transcription factors are regulated by changes in cellular redox state. Some of these redox factors include nuclear factor kappa B (NF-κB), p53, hypoxia-inducible factor (HIF)-1, and HIF-like factor. These transcription factors then cause protein synthesis that triggers further effects down-stream. These effects include increased cell proliferation and migration, modulation in the levels of cytokines, growth factors and inflammatory mediators, and increased tissue oxygenation. There are three major intracellular photoreceptors. These include Cytochrome c Oxidase, Porphyrins, and Flavoproteins. Flavoproteins are group of protein complexes containing a riboflavin group. Flavoproteins are involved in a wide array of biological processes, including removal of radicals contributing to oxidative stress, and DNA repair. Realize that NADH which is involved in the NAD/NADH cycle ATP production is a flavoprotein. There are also a number of other compounds that also act as photoreceptors such as Vitamins B6 and K. There are other compounds that are photo sensitive but that id for another discussion. Evidence indicates that cytochrome c oxidase (CCO), also known as complex 4, is a very crucial chromophore in the cellular response to light therapy. It is most stimulated around 650Nm wavelength (red light). CCO is a component of the respiratory electron transport chain. The precise manner in which light affects CCO is not yet known. The observation that Nitric Oxide (NO) is released from cells during light therapy has led to speculation that CCO and NO release are linked by two possible pathways. It is possible that light therapy may cause photodissociation of NO from CCO. Nitric Oxide is an extremely important signaling molecule preforming multiple tasks. The influence of light therapy on the electron transport chain extends far beyond simply increasing the levels of ATP produced by a cell. Oxygen acts as the final electron acceptor in the electron transport chain and is, in the process, converted to water. Part of the oxygen that is metabolized produces reactive oxygen species (ROS) as a natural by-product. ROS are chemically active molecules that play an important role in cell signaling, regulation of cell cycle progression, enzyme activation, and nucleic acid and protein synthesis. Because PBM promotes the metabolism of oxygen, it also acts to increase ROS production (remember that mild oxidative stress is beneficial). In turn, ROS activates transcription factors, which leads to the upregulation of various stimulatory and protective genes. These genes are most likely related to cellular proliferation, migration, and the production of cytokines and growth factors, which have all been shown to be stimulated by light therapy. Immune cells, in particular, appear to be strongly affected by Photo Modulation. Mast cells, which play a crucial role in the movement of leukocytes, are of considerable importance in inflammation. Specific wavelengths of light are able to trigger mast cell degranulation, which results in the release of the pro-inflammatory cytokine TNF-a from the cells. This leads to increased infiltration of the tissues by leukocytes. However, in the long run this will help stimulate anti-inflammatory pathways. Photo modulation also enhances the proliferation, maturation, and motility of fibroblasts, and increases the production of basic fibroblast growth factor. Fibroblast growth factors (FGFs) that signal through FGF receptors (FGFRs) regulate a broad spectrum of biological functions, including cellular proliferation, survival, migration, and differentiation. Lymphocytes become activated and proliferate more rapidly, and epithelial cells become more motile, allowing wound sites to close more quickly. The ability of macrophages to act as phagocytes is also enhanced under the application of light therapy. Remember, that phagocytosis of MSCs will result in the production of T-reg cells which have a long-term effect on tissue repair and decreased auto found in the autologous biologics that are injected. SPECIFIC ACTIONS OF THE VARIOUS WAVELENGTHS The above illustration shows the various wavelengths (Red, Blue, and Green) and their actions on the cells. The above diagram is an excellent illustration of the aspects of the Photonic Chamber as related to various wavelengths of light. We must realize that the Optical chamber does have two main colors, Red and Green, yet realize that there is a bleeding of colors. For instance, the Red Led light also has some Orange and Yellow that will “bleed out”. Thus, we are getting wavelengths of mainly Red in the vicinity of about 650 Nano meters but at the same time getting some wavelengths of Orange and even a bit of Yellow. The Green Led strip has a wavelength of 540Nm and it bleeds into the Blue and Yellow spectrum. One interesting bit of information is that chemicals appear a particular color to our eyes based on the wavelengths of light they reflect. Hemoglobin bound to oxygen absorbs blue-green light, which means that it reflects red-orange light into our eyes thus appearing red. That's why blood turns bright cherry red when oxygen binds to its iron. Let us talk about the specific colors. The Red LED and the bleeding of Yellow and Orange from the Red LED. One of the most general benefits of light therapy in these wavelengths is the production of ATP. Perhaps the most well-known aspects of the Red light concern its effects on the mitochondria of cells. It has been observed that mitochondria are changed to so called “giant mitochondria” after irradiation resulting in activation of various metabolic pathways and increased production of ATP. As stated earlier, ATP production comes from the actual stimulation of the Cytochrome C Oxidase. ATP production is observed in all cells. BECAUSE THERE IS MORE ATP PRODUCTION BY THE EFFECTS OF RED LIGHT, THE SECONDARY EFFECT IS TO PROMOTING STEM CELL DIFFERENTIATION. This occurs due to shifting the metabolic profile from glycolysis to oxidative phosphorylation due to the increased mitochondrial number and activity induced by the light exposure. It is known that this metabolic switch, glycolysis to oxidative phosphorylation, is a key factor in stem cell differentiation. Remember when these biologics are injected into the joint ATP may be at a premium given the harsh conditions of the joint. Although lacking nucleus, platelets also contain functional mitochondria thus subjected to PBM. On PBM activation, platelets produce extracellular vesicles known as microparticles. Platelet microparticles are very similar to exosomes except they appear to be more plentiful. The microparticles contain little snippets of RNA which give direction to cells. It is hypothesized that activated platelets also release their mitochondria with the microparticles. Both the mitochondria and microparticles can have significant effects on various cells. Photo Bio Modulation also increases the generation of platelets from precursor cells called megakaryocytes (MKs). It appears that Red light is instrumental in in helping to release the platelet micro particles. Red light energy irradiation helps bone marrow mesenchymal stem cell migration and proliferation, inhibits bone marrow mesenchymal stem cell apoptosis, which contributes to bone marrow mesenchymal stem cell migration to targeted tissue. Another important aspect of PBM is pronounced anti-inflammatory effects. While the exact cellular signaling pathways responsible for this anti-inflammatory action are not yet completely understood, it is becoming clear that both local and systemic mechanisms are operating. Reductions in markers of oxidative stress and proinflammatory cytokines are well established after PBM. It has been noted by some studies that after photo bio modulation there has been increases in Interleukin-10 and Interleukin-1 antagonist. These increases will dramatically affect the clinical outcomes by reducing pain, inflammation and swelling. It appears that both Red and especially Green light will be helpful in the polarization of Macrophages M-1 and M-2 types. The light therapy will increase polarization of the Macrophages to the M-2 type which are instrumental in tissue healing. M-1 macrophages are more important in dealing with bacterial infections. The M-2 macrophages help in the production of collagen formation. Several parameters showed that green light was even more potent to stimulate proliferation and migration of endothelial cells than clinically well-established red-light therapy. Other effects attributed to the green light include decreases in lactic acid, reduced blood viscosity and improved oxygen affinity by the effects green light has on the hemoglobin molecule. Green light seems to stimulate the Flavoproteins which mediate a wide array of biological processes such as quenching of oxidative stress-induced radicals, DNA repair, and apoptosis. When the Green color bleeds into the Blue light spectrum range there are some studies which hint that Blue light may have a therapeutic effect on exosomes. It can be beneficial in the release of exosomes from cells. THE SUMMATION THE EFFECTS OF PHOTONICS CHAMBER ON REGENERATIVE MEDICINE DIRECT EFFECT ON THE VIABILITY OF STEM CELLS BY INCREASING MITOCHONDRIAL EFFICIENCY AND SIZE ULTIMATELY PRODUCING MORE ATP AND GREATER CELL SURVIVAL. HELPING IN THE STABILIZATION OF STEM CELL AND OTHER CELL MEMBRANES. DIRECT EFFECT ON THE LEUKOCYTES ULTIMATELY PRODUCING INCREASED AMOUNTS ON IL-10 AND IL-1 A MAKING FOR AN ANTI-INFLAMMATORY NICHE. THE PRACTICAL CLINICAL RESULT IS THAT TYPICALLY THE PATIENT HAS MUCH LESS POST INJECTION PAIN. DIRECT EFFECT ON MACROPHAGE POLORIZATION DIRECTING THE POLORIZATION TO M-2 MACROPHAGES WHICH CONTRIBUTE TO TISSUE REGENERATION. POSSIBLE INCREASED PRODUCTION AND RELEASE OF EXOSOMES INCLUDING INCREASED RELEASE OF PLATELET MICROPARTICLES. NITRIC OXIDE IS RELEASED BY THE CELLS AND MAY HAVE A BENEFIT ON THE CELLUAR ENVIRONMENT. FORMATION OF TRANSCRIPTION FACTORS WHICH HAVE IMPLICATIONS ON MULTIPLE LEVELS DOWNSTREAM. ENHANCES BONE MARROW MESENCHYMAL STEM CELL MIGRATION AND PROLIFERATION, INHIBITS BONE MARROW MESENCHYMAL STEM CELL APOPTOSIS SUPPRESSES INFLAMMATORY RESPONSE OF HUMAN ADIPOSE-DERIVED STEM CELLS BY MODULATING INTRACELLULAR CYCLIC AMP LEVEL AND NF-ΚB ACTIVITY BY INCREASEING THE AMOUNT OF ATP AVAILABLE, A METABOLIC SWITCH (GLYCOLYSIS TO OXIDATIVE PHOSPHORYLATION) IS TURNED ON WHICH IS A KEY FACTOR INDUCING STEM CELL DIFFERENTIATION. The chamber will make a significant difference in the success one will have using a variety of autologous cell products. Pain, swelling and inflammation will be diminished. Across the board the cells will typically be healthier and have a better chance of longevity in their perilous journey in the joint, tendon, or other area into which they are injected. I have used the Photo Bio Modulation techniques for many years. We have now made the technology available to numerous Regenerative Medicine doctors at a very reasonable price.

Light therapy has been used by humans since before the time of the ancient Egyptians. There have been various names placed on light therapy but it now seems that the preferred name is Photobiomodulation (PBM). PBM does not imply that a laser is necessary for the therapeutic benefits to occur. If we break down the word Photobiomodulation we get a sense of its meaning. Photo refers to light. Bio refers to living organisms. Modulation means to change or improve. Photobiomodulation is a treatment method based on therapy research findings showing that irradiation with certain wavelengths of red, or near-infrared light, or ultraviolet can have profound effects on cells in many ways. The above shows the various properties of light and terms that we use when discussing light therapy. Typically, the wavelength is the most important aspect of light therapy we are concerned with. While the diagram below shows the various color lights and their wavelengths. The wavelength is what causes the bio-stimulation When discussing photonic therapy, it is important to discuss the science of light therapy. Distinct wavelengths of light have been known to have various biological effects on humans. Of all the variables the wavelength seems to be most important. Specific wavelengths have specific effects on cells. The two above diagrams are the essence of the mechanics of photo therapy. Many people use the term low level laser therapy to be synonymous with photo biomodulation. In no uncertain terms photo modulation does not require a laser. It requires a light source of which laser is one type and the other main type of light source is LED (light emitting diode) lights. Laser is an acronym for “light amplification by stimulated emission of radiation”. The light beam produced by LED and LASER also creates a key difference between LED and LASER. The light emitted by LED source and consists of various colors while the light beam produced by LASER consists of a single color. The working principle of LED and LASER also created major differences. LED works entirely on the principle of electro-luminance which means lumination by means of electrons. On the other hand, LASER works on the principle of stimulated emission which use photons. Laser light is unique, in that it is monochromatic (one color), coherent (occurs when the light beam will not spread out and diffuse). These traits make it well-suited to many medical applications. The monochromatic, or single wavelength, beam is ideal for stimulating chromophores (an atom or group whose presence is responsible for the color of a compound) in biological tissue that only respond to very specific wavelengths. Coherent photons are organized where non-coherent photons are not. This property is important to minimize photon scatter as light interacts with tissue. Lastly, since injured tissue is normally deep in the body, laser’s columned beam helps focus energy in a narrow, direct path which is ideal for treating tissues at depth. LEDs usually emit light in a small band of wavelengths but usually cannot emit a single specified wavelength. This bandwidth impacts their ability to dial in the wavelength to optimally target desired tissues. Additionally, LEDs produce neither a collimated nor coherent beam, which is less ideal when treating deeper tissues. Lastly, LED’s operate at significantly lower power (wattage) than most lasers, which impacts their ability to reach deeper tissues in smaller windows of time. REALIZE ONE IMPORTANT FACT: WITH OUR PHOTOTONIC SLEEVES WE ARE NOT INTERESTED IN THE DEPTH OF TISSUE PENETRATION. WE ARE ONLY SUBJECTING THE BLOOD CARRYING LINES TO PHOTOMODULATION THUS TISSUE PENETRATION IS A NON-ISSUE. IF ANYTHING, LED LIGHTS ARE BETTER SUITED FOR OUR PURPOSES. Hopefully the information presented gives a window into the world of lasers and LED lights. In our treatments, extracorporeal photo modulation depends upon LED light therapy. We like the LED light concept for a variety of reasons including safely and efficacy in treatment goals. The LED gives us a wider range of possible benefits to the cells. We have two sleeves which we will initially introduce. One is the ultraviolet A LED sleeve and the other is the Red LED sleeve. ULTRAVIOLET EXTRACORPOREAL PHOTOTHERAPY Photo therapy is also known by many names such as Photoluminescence, Ultraviolet Blood Irradiation, or Extracorporeal Phototherapy. In this particular case the stimulation to the blood is performed outside the body (extracorporeal). Ultraviolet Blood Irradiation (UBI) is one of the most commonly performed blood phototherapy procedure. It is a procedure that exposes the blood to ultraviolet light to heighten the body’s immune response and to kill infections. Dr. Michael Hamblin, a professor at Harvard Univ., is a principle investigator at the Wellman Center for Photomedicine at Mass General Hospital. He has written extensively about UV blood irradiation. He calls UV Blood irradiation the “cure that time forget”. With exposure to UV light, bacteria and viruses in the bloodstream absorb five times as much photonic energy as do the red and white blood cells. When we are discussing UV radiation we must be aware that there are three different types of UV radiation. The above diagram shows the penetration of the various forms of UV light. The longest wavelength (UVA) penetrates the deepest. Realize the UVB and UVC can cause significant tissue damage and must be used with caution. These are called UVA, UVB, and UVC. UVA rays have the longest wavelengths, followed by UVB, and UVC rays which have the shortest wavelengths. The above diagram shows the depth of penetration. Our unit depends mainly upon the UVA wavelength. Most ultraviolet rays are invisible to most humans. The lens of the human eye blocks most radiation in the wavelength range of 300–400 nm. Typically, the wavelength of UVA in our UV photonic unit has a wavelength is about 395nm. We have chosen this wavelength for a variety of reasons but one important reason is that this wavelength easily penetrates thru plastic lines such as the ones that carry the blood in our processes. UVA PHOTONIC SLEEVE Ultraviolet A LED therapy has been shown to produce a range of physiological effects in cells, tissues, animals and humans. Our unit depends mainly upon the UVA wavelength. Typically, the wavelength of UVA is commonly used in a process called Ultraviolet Blood Irradiation (UBI). UBI is a procedure that exposes the blood to light to heighten the body’s immune response, to kill infections and a host of other benefits. With exposure to UV light, bacteria and viruses in your bloodstream absorb five times as much photonic energy as do your red and white blood cells so there are obviously significant antibacterial and anti-viral effects. Other benefits from UV light is that it heightens the body’s immune response while increasing oxygenation of the tissue. UV treatments also include anti-hypoxic, vasodilatory effects, and improvements of the rheological (flow, structure, etc.) of the blood and the microcirculation. Other benefits include increasing the activation of circulating IgM antibodies by 2-16 times, IgG antibodies by 2-4 times and complement by 2-4 times, i.e. it rapidly activates these factors of nonspecific immune defense. These components are extremely important factors of the immune system. UBI boosts the antioxidative capacity of the blood by activating peroxidase. This activation has reached 40-50% above normal levels. Also, UBI provides some oxidative stress that also stimulates a powerful adaptive response in the blood. This response triggers the up-regulation of many antioxidant defenses that lead to decreased systemic inflammation. Our sleeve utilizes UVA light which is very safe. Ultraviolet light can be absorbed directly by cellular macromolecules, leading to photochemical modification of DNA and proteins. There is another added benefit of using UVA light. Ultraviolet light leads to an increase in the cellular levels of the tumor suppressor protein p53, followed by a biological response of either growth arrest or programmed cell death. It is believed the many cancers are a failure of P-53. P53 Is also called guardian of the genome. Again, oxidative stress is a causative agent in the ultraviolet light activation of the p53 pathway. The diagram below shows the mechanism of P53. Another aspect the UVA sleeve is the effect it has on the energy production of the cells. UVA will emit the primary wavelength that stimulate NADH AND NAD+. The ratio of NAD/NADH is a very important one in the body. In healthy mammalian tissues, estimates of the ratio between free NAD+ and NADH in the cytoplasm typically lie around 700:1; the ratio is thus favorable for oxidative reactions. The ratio of total NAD+/NADH is much lower, with estimates ranging from 3–10 in mammals. This is because the ratio dictates how effectively the cell can produce ATP, adenosine triphosphate, which is the energy currency of the cell as noted below. Production of NAD and subsequently ATP has profound implications for cellular health. The following diagram illustrates the NAD/NADH concept. Another of the mechanisms of medical activity of extracorporeal UBI is that UV irradiation has positive influence on morpho- functional properties of erythrocytes (Red blood cells). For those special cases where there is a concern about a virus or bacterial infection we will have a special UVB sleeve. This is designed to achieve a more potent eradication of viruses and bacteria in the blood. We feel we can achieve a good level of eradication with the standard UVA sleeve. The UVB sleeve is more powerful and specific for infections. But it does cause some cellular damage and we feel it is not necessary for routine use. The UVB light works by damaging the lipid envelope of the virus or bacteria resulting in its death. RED LED PHOTONIC LIGHT SLEEVE The Red LED light is similar to the UVA light yet is it is also very different. NASA scientists first used red light therapy to stimulate plant growth on space stations in the 1990s, and then began wondering “what can light therapy do for astronauts?” shortly after. In a nutshell the 660nm Red LED wavelength has a multitude of effects on the body. It activates different enzymes and decomposes redundant fat in the bloodstream. It increases the oxygen amount in the blood, boosts metabolism and enhances the process of lipid peroxidation to reduce cholesterol in the vessels. It is also important in the energy production for the cell namely NAD. If we look at the 660 wavelength we see that it is the red-light spectrum. But we must remember that the LED light source we are using will stray into the yellow and orange spectrum. We are purposely using this impurity of the LED light to exploit the biological properties of the yellow and orange spectrums. We feel the Red LED Sleeve is very valuable for purposes of Regenerative Medicine including general well-being, immune boosting, energy production and a host of other benefits. We feel the best possible benefits will by utilizing the UVA and the Red sleeves. We now know that Photobiomodulation (PBM) seems to have effects on three specific areas of the cell. Among these, three discrete PBM mechanisms have been described—namely, inside the cell (cytochrome C oxidase within mitochondria), at the cell membrane (photosensitive receptors and ion transporters like Opsins, TRPV1), and extracellular (activation of latent TGF-ß1) matrix. While there may be a predominant mechanism operative in a given PBM application, research is showing that there are typically several mechanisms at work creating specific biological responses noted during clinical therapy. One cellular area impacted by PBM is the mitochondria. The mitochondria are the cell power houses that produce ATP. It appears that many of the effects of light therapy deal with dysfunctional mitochondria. Dysfunctional mitochondria are thought to be the cause of many degenerative diseases. Within the mitochondria are found cytochromes. Cytochromes can be defined as electron or proton-transfer proteins that act as energy producers for human biological functions at the cellular level. Both of the cytochrome enzymes, Cytochrome c Oxidase and Nitric Oxide Synthase (NOS) have been found to be particularly reactive to light photon stimulation. Perhaps a good concept to consider is that a mitochondrion is like a chloroplast in a plant. A chloroplast converts sunlight to energy. Mitochondria are very similar. Another area is that is photosensitive is the cell membrane. The cell membrane contains certain photo sensitive receptors. The final area involves areas around the cell called the extra cellular matrix. PBM treatment can instead be used as a minimally invasive tool to activate an endogenous latent growth factor complex, transforming growth factor-β1 (TGF-β1), that subsequently differentiates host stem cells to promote tissue regeneration. TGF-β1 is a very important growth factor in the stem cell field. The production of these enzyme-signaling molecules has been shown to induce growth factor production, to increase cell proliferation and motility, and to promote extracellular matrix deposition and pro-survival pathways. The following diagram shows these concepts of the three effects light therapy has on and about cell. Outside the cell, nitric oxide signaling drives vasodilation which improves microcirculation in the damaged tissue, delivering oxygen, vital sugars, proteins, and salts while removing wastes. The 620-670 waveband directly influences the parameters of all cells in the blood, blood plasma, the coagulation process and all the structural components of the vascular wall. Red transport function of blood due to modification of the affinity of hemoglobin for oxygen. There is another excellent diagram of the mechanism of LED red light stimulation is found in the following diagram. It is a review of what has been presented but the importance of this concept cannot be dismissed thus the repetition. The science is complicated but necessary. MECHANISM OF LED LIGHT THERAPY IN TISSUE Red light stimulates the mitochondria within the cell increasing the production of ATP causing damaged cells to accept nutrients and eliminate toxins more efficiently. Red light activates the last enzyme of the mitochondrial respiratory chain, the cytochrome c oxidase and as can be seen ATP is produced. It increases the oxygen amount in the blood, boosts metabolism and enhances the process of lipid peroxidation to reduce cholesterol in the vessels. It has been shown that many cellular molecules are able to absorb various wavelengths of light. In Photobiomodulation with visible red light and near-infrared radiation, evidence suggests that the primary cellular photo acceptors are the copper centers of cytochrome c oxidase (CCO), a complex protein functioning as unit IV in the mitochondrial electron transport chain. The initial interaction between light and cellular photo acceptors (called a “primary photoreceptor mechanism”) is followed by the activation of multiple secondary mediators. These eventually lead to broad shifts in gene expression, cell signaling, cellular metabolism and cytokine secretion. These effects been described in numerous review articles in the literature. This brings up a fascinating new field called Optogenetics, which uses proteins that change their function in response to light. In this case, the researchers have adapted the light-sensitive proteins to either stimulate or suppress the expression of a specific target gene almost immediately after the light comes on. However, this is still a new experimental field but more to come. Getting back to reality in less futuristic terms how does red light work? What is one of its most important features? The main short answer is: by breaking up the major roadblock to ATP and water production, which is harmful excess nitric oxide. During the creation of ATP synthase, nitric oxide competes with oxygen, which stops the eventual production of ATP. Once more ATP is present everything else falls into place. The photons in red light excite electrons, which helps break up nitric oxide bonds so H+ ions can move through the process more effectively, resulting in more ATP energy that powers your cells and your entire body. Specific wavelengths of light help to create a better oxidative environment in the cells. This results in the activation of numerous intracellular signaling pathways, increased protein synthesis, enzyme activation, and enhanced cell cycle progression. Now realize this stimulation involves the entire circulatory system. Other benefits of Red sleeve therapy include improved blood flow, lower blood pressure, reduced cholesterol, increased the ability of oxygen binding in Hemoglobin and more stabilized cell membranes. Also, like UVA light the red light will also have beneficial effects on the immune system. Numerous studies have revealed the stimulating influence of laser irradiation on the indices of humoral (antibody) and cellular immunity. The counts of a large number of related cells types, including macrophages, T-helpers, T-suppressors, and B-lymphocytes increase under the influence of Red LED therapy. Last but not least the Photonic Sleeve system is a closed system which dramatically reduces the possibility of contamination of the blood. When combined with other dynamic cutting-edge therapies, the Photonic Sleeves are in a world of their own. .

The above is the title to a new article published by Dr. Sinclair and his group from Harvard. I had the good fortune of being sent this paper by an associate of mine. The paper is still not officially published but it drives home some significant points. David A. Sinclair, Ph.D., A.O. is a Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School. I hold Dr. Sinclair in great esteem for his work on understanding why we age and how to slow its effects. Dr. Sinclair has taught us about Resveratrol and more recently NAD and its supplements. The paper contains an excellent synopsis of the relationship between Covid-19 and the aging immune system, namely immunosenescence. It gives a comprehensive breakdown on the failures of the innate and acquired immune systems. These are the two major components of our immune system. The paper itself is a rather technical one and I will try to discuss it in layman terms. First off, let’s take a quick look at some of the benefits of the NAD to our bodies. We can see the effects are wide ranging. Among other things we see in the above diagram that NAD affects both immunity and inflammation. Many of the other effects indirectly affect immunity and inflammation. We now know that as we age there is steady increase in the abundance and activity of NLRP3 protein. NLRP3 which is a major protein component of an inflammasome. Inflammasomes are a group of protein complexes found in the cytoplasm of the cell. They are formed to mediate host immune responses to microbial infection and cellular damage. NLRP3 is responsible for a host of problems including auto immune diseases, metabolic disorders, and severe damages from infections such as a cytokines storm. You will definitely be hearing more about NLRP3 as time goes on. It is on the cusp of major scientific research. Now just how does NAD come into the picture when dealing with the NLRP3 inflammasome? The real crux of the matter is that the NLRP3 activation is under the control of SIRT2 gene. Sirtuins are a family of proteins that regulate cellular health. SIRT2 is a member of the NAD+ dependent sirturn family of deacetylases enzymes. If NLRP3 is activated and at the same time one is exposed to Covid-19 virus the combination may cause quite a few problems to the patient. However, it one maintains NAD levels and there is a good chance of alleviating Covid 19 symptoms by the Sirtuin suppression of the NLRP3 inflammasome. In 2013, Sinclair further reported scientific studies that demonstrated NAD fuels the activity of a group of proteins called the sirtuin proteins, including SIRT2. Sirtuins are a fascinating family of enzyme-genes. It is now clear that sirtuins are involved in the regulation of many fundamental biological processes throughout the body. The following is a diagram of the various Sirtuin genes and where they are found in the cell. If we look in the above diagram we see the SIRT2 gene which is located in the cell cytoplasm. The cell cytoplasm also contains the NLRP3 inflammasome. The bottom line is if the SIRT2 gene is activated it will squash the actions of the NLRP3 and the Covid-19 virus will have a harder time getting established. What has been a common thread in many patients infected with the Covid-19 virus is that co-morbidities seem to dramatically affect the symptoms of the patient. One of the biggest co-morbidities seems to be obesity. It is well known that obesity will increase the complications of the Covid-19. Obesity will dramatically increase the activity of the NLRP3 inflammasome. Thus, anyone who is obese should absolutely be taking NAD supplements and possibly even take it intravenously. NLRP3 inflammasome is found in the cytoplasm of the cell while many times when we are dealing with infections it is the cell receptors on the cell surface membrane that detects the infection and elicit a response. Multiple studies show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of NLRP3 as well as with decreased inflammation and improved insulin sensitivity. Remember the control of NLRP3 activity is under the direct control of SIRT2, which is dependent upon NAD and its derivatives. Studies have shown old mice, especially those deficient in SIRT2, have accelerated inflammaging, along with decreased glucose tolerance and increased insulin resistance. So, the bottom line is take your NAD!! THE BIOLOGIC CLOCKS OF AGING The second part of the article talks about BIOLOGICAL CLOCKS. We have developed a number of biological clocks that have been shown to predict human health and longevity more accurately that chronological age. These biological clocks are based on various aspects of aging. There are at present any number of approaches to measuring biological age, the burden of cell and tissue damage that leads to dysfunction. THE EPIGENIC CLOCK OF AGING The first clock to discuss is the EPIGENETIC CLOCK. Epigenetic age seems like a concept pulled from a futuristic science-fiction movie where a drop of blood is fed into a machine, in which an algorithm churns through an accumulation of chemical groups coating a strand of DNA and spits out an individual's true age reflecting a lifetime of experiences and exposures. In simplistic terms, epigenetics involves putting a methyl group on a DNA strand. Methyl groups are organic molecules. What we are really dealing with is called DNA methylation. DNA methylation occurs when a methyl group is added to a DNA strand. DNA methylation is a tool to typically lock genes into their off position. Aberrant DNA methylation, which is a nearly universal finding in cancer results in disturbed gene expression. DNA methylation is modified by environmental factors such as diet that may modify cancer risk and tumor behavior. Abnormal DNA methylation has been observed in several cancers. These alterations in DNA methylation may play a critical role in cancer development and progression. Dietary nutrient intake and bioactive food components are essential environmental factors that may influence DNA methylation. In recent decades, researchers have learned a great deal about DNA methylation, including how it occurs and where it occurs, and they have also discovered that methylation is an important component in numerous cellular processes. The following diagrams illustrate some of these concepts: We are able to see from the above diagram that healthy lifestyles cause age deceleration. While the opposite is true with unhealthy lifestyles. Another way of looking at things is found in the diagram below. The blue arrows represent anti-aging while the red arrows represent pro-aging effects on blood chemistry. Pictorial summary of our main findings. The blue and red arrows depict anti‐ aging and pro‐aging effects in blood respectively. The two clocks symbolize the extrinsic epigenetic clock (enhanced version of the Hannum estimate) and the intrinsic epigenetic clock (Horvath 2013) which are dependent and independent of blood cell counts, respectively. What does this boil down to? Age-associated changes to the epigenome, essentially our DNA, have profound effects on the immune system, including T cell function, cytokine production and macrophage (white blood cell) pattern recognition. DNA methylation is believed to set the pace of the aging clock in several of our tissues, including hematopoietic (Red and White Blood) cells of the immune system. Recently there was a study that restoration of the thymus gland using a drug cocktail of metformin, growth hormone and DHEA (dehydroepiandrosterone) led to the reversal of features of immunosenescence which is the decline in the immune system that comes with aging. This is actually a monumental study that may have profound implications on our health. Most of the existing research suggests that DNA methylation relies at least in part on folate, vitamin B-12, vitamin B-6, and choline, in addition to other vitamins and minerals. Increasing your intake of these nutrients may help to support DNA methylation, preventing certain genes from being expressed. One parting thought is that the pattern of methylation in DNA has been shown to be an even better predictor of not just biological age, but also lifespan and healthspan. THE GLYCOSYLATION CLOCK The above diagram is a very real biological clock. One method of measuring the glycosylation clock can be measured be a simple blood test which is called the A1C hemoglobin blood test. This is a common blood test performed in diabetic patients. It gives a snapshot of blood glucose levels over a period of time. It gives a picture of the amount of glucose that is binding to the hemoglobin protein molecule. The higher the number of the A1C the greater the number of glucose molecules attached to the hemoglobin protein and thus the worst the control of the diabetes. The glycosylation clock is clearer than most biological clocks. It is a very direct assessment of the chronic inflammation associated with aging. In more technical terms, Glycosylation is the enzymatic process by which carbohydrates called glycans are attached to proteins or lipids, typically on the cell surface or in the bloodstream. An individual's repertoire of glycans, a notable example being the type of N-glycans attached to immunoglobulins, changes with age and environmental factors such as such as smoking and poor diet. The type of glycans attached to IgGs affects their pro- and anti-inflammatory properties. IgGs are a type of antibody representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. It is instrumental in fighting most infections. The real problem with glycosylation is the production of what are called “advanced glycation end products” (AGEs). This occurs when the sugars bind to proteins causing a host of problems as can be seen in the following diagram. Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney disease, and Alzheimer's disease. Animal-derived foods that are high in fat and protein are generally AGE-rich and prone to new AGE formation during cooking. In particular, grilling, broiling, roasting, searing, and frying propagate and accelerate new AGE formation. The following diagram shows the variety of the clinical manifestations of glycosylation. GLYCOSYLATION’S MANY DEADLY SINS As we can see these are very damaging to various systems in the body. Remember, glucose is one of the main driving forces in the production of AGE products! Another great diagram of the effects of AGEs is found in the following diagram. Realize that AGEs and glycosylation can lead to significant musculoskeletal symptoms. THE IMMUNE CLOCK The last clock to mention is the IMMUNE CLOCK. There is an old saying that we are as old as our immune system. There is some good scientific literature that the immune system may be made “younger” by among other things a type of cell found in the body called a V cell. Here is the study from a research journal which explains this concept. What the V cells do is extend the Telomere length of the cells of the immune system. Telomeres are the ends of the DNA of the cells. When cells reproduce they lose a snippet of DNA which is called the telomere. The smaller the DNA length typically the less effective the cell becomes. Well the V cells restore the length of the DNA telomere and thus increase the effectiveness of the cell. They are literally making the cell take on younger characteristics. V cells are found in each and every one of us. The trick is to activate them (which we have mastered) to than let them perform their good deeds. When all is said and done what effect will this article have upon myself? The answer quite a bit. I am already a big believer in NAD and I am becoming more to cognizant of Nature’s Biological Clocks and how we can manipulate them. I practice what I preach. V cells have been on my horizon and will continue to remain there. Hopefully this article has opened your eyes on the “Biological” clocks in the body and how we can influence them with certain life style changes, procedures, and medications such as NAD which I consider one of nature’s elixirs. Remember time always moves forward but there is no reason why we cannot slow down its progression. ONE FINAL THOUGHT IS THAT I AM PROUD TO SAY IS THAT OUR OFFICE WILL BE ONE OF THE FIRST TO OFFER A BLOOD TEST FOR DNA METHYLATION. IT IS THE MOST ACCURATE, REVOLUTIONARY, BIOLOGICAL AGE PREDICTOR. THE TEST UTILIZES STATE-OF-THE-ART TECHNOLOGY AND A POWERFUL ALGORITHM WHICH LOOKS AT SPECIFIC LOCATIONS ON YOUR DNA, ALLOWING US TO PREDICT YOUR BIOLOGICAL AGE! ONCE WE HAVE THAT INFORMATION THAN WE CAN START MAKING RECOMMENDATIONS. Thanks, -Dr. P

The above was a recent headline. I know what my political persuasions are, and they should obviously never get in the way of science or the health of a patient. Furthermore, I always try to be non-political in my posts. I see that some members of the press have tried to ridicule President Trump for an idea of “getting light inside the body.” Here are the quotes attributed to the President: "Suppose that we hit the body with a tremendous, whether it's ultraviolet or just very powerful light," Trump said at the White House coronavirus press briefing, adding: "Supposing you brought the light inside the body, which you can do either through the skin or in some other way." Well, low and behold, if reporters find this a ridiculous statement, then they need to do their homework and learn some science, and have a more analytical mind. I would like to mention a paper that was published a few years ago by Dr. Michael Hamblin. Michael Hamblin is a Principal Investigator at the Wellman Center for Photomedicine (see below) at Massachusetts General Hospital, an Associate Professor of Dermatology at Harvard Medical School and a member of the Affiliated Faculty of Harvard-MIT Division of Health Science and Technology. The next insert is a copy of the title page of a paper written and published by Dr. Hamblin in 2017. We can see that the title of the article is Ultraviolet Irradiation of Blood: “The Cure that Time Forget”. As one can see we have a PHD from Harvard and MIT who is a main principle investigator at Harvard’s photomedicine center state that ultraviolet light to the blood is a cure that time forget. So, it seems that that President was not off the mark at all. I think he is owed an apology by those in the media and in the medical community who ridiculed him. I have been fortunate to meet Dr. Hamblin when we were both lecturing at a regenerative medicine meeting. I consider him one of the world’s experts on photo-therapy. I read the above article a few years ago and found it intriguing. There are many similar articles. In this article there is a discussion of the potential of Ultraviolet Blood Irradiation (UBI) as an alternative approach to current methods used to treat infections. It goes on to say that this therapy can also be an immune-modulating therapy and also as a method for normalizing blood parameters. The article states there is no resistance of microorganisms to UV irradiation. Low and mild doses of UV kill microorganisms by damaging the DNA, while any DNA damage in host cells can be rapidly repaired by DNA repair enzymes. Ultraviolet light when used for sterilization purposes causes the direct destruction of pathogens. Many people believe that this is also the mechanism of action for UBI which is absolutely not the case. It is the stimulation of the immune system and its various components that gives ultraviolet light therapy is effectiveness in addition to destroying the micro-organisms. The following diagram is from the article by Dr. Hamblin. It shows some of the various aspects of UBI on the immune system. This may be a complicated picture but when all is said and done it is stimulating the immune system in many different ways. It is somewhat complicated to the lay person. UBI appears to have three broadly different classes of effects on different blood components. In the case of various white blood cells which are called neutrophils, monocytes, macrophages, and dendritic cells. UBI can activate phagocytosis. Phagocytosis is a process wherein a cell, in this case a type of white blood cell, binds to a microbe such as a bacteria or virus and engulfs it. UBI also increases the secretion of Nitric Oxide which stimulates the production of cells which can calm down an inflammatory reaction. By reducing the inflammatory response, we are lessening the effects of a “cytokine storm” as is often found in infections and seems to be the crux of many Covid-19 complications. The oxidative nature of UBI may have mechanisms in common with ozone therapy and other oxygen therapies. Namely, we are reducing the oxidative stress on the immune system. Oxidative stress is an imbalance between free radicals and antioxidants in your body. Free radicals are oxygen-containing molecules with an uneven number of electrons. The uneven number allows them to easily react with other molecules. Free radicals can cause large chain chemical reactions in your body because they react so easily with other molecules. These reactions are called oxidation. They can be beneficial or harmful Think of oxidative stress as synonymous with inflammation and inflammation is the root of most medical problems. Dr. Hamblin’s article is but one article concerning the use of light therapy. I think there is little doubt there is strong science behind the use of ultraviolet blood irradiation and for that matter phototherapy to treat a number of medical conditions. Although this seems like cutting edge therapy it is actually old. Ultraviolet blood irradiation (UBI) was extensively used in the 1940s and 1950s to treat many diseases including septicemia, pneumonia, tuberculosis, arthritis, asthma and even poliomyelitis. The early studies were carried out by several physicians in USA and published in the American Journal of Surgery. However, with the development of antibiotics, UBI use declined and it has now been called “the cure that time forgot”. Hopefully more research on various types of blood irradiation will be performed. I would also like to include a few slides from my lectures. These slides concern the use of phototherapy. The first slide is a summary of phototherapy. As we can see there are a myriad of beneficial aspect to light therapy. I will draw your attention to sentence six, “Whatever cells are designed to do will be improved by light therapy”. The next slide shows some of the many benefits of phototherapy in pictorial form. The takeaways from the above slide is that light therapy is intimately involved in cell energy production, positively impacts cellular repair and healing, stimulates the immune system. As President Trump said “GET THE LIGHT INSIDE THE BODY” and hopefully control the covid-19 virus. Certainly, no guarantees or cures but it might be a step in the right direction. Actually, we can take things to the next level by giving the patient certain medications which are called photosensitizers. Photosensitizers make light therapy work even better. However, this is a discussion for a different day. I will end this quick blog with a rather somber thought. Covid -19 is certainly a serious problem for our planet and I believe we will conquer it. I would like to present some information by the Rand Europe Think Tank. Unfortunately, there are much greater biological time bombs that may be facing us. One ticking time bomb we are facing is that of antibiotic resistance. Here is the chart of what we are facing, namely approximately 10,000,000 deaths per year caused by antibiotic resistance. It might just be that blood irradiation may save the day. Meantime, stay safe and get some sunshine which is a primitive form of blood irradiation. Thanks, Dr. P DEATHS PER YEAR SECONDARY TO ANTIBIOTIC RESISTANCE 2050 2050

The above was a recent headline. I know what my political persuasions are, and they should obviously never get in the way of science or the health of a patient. Furthermore, I always try to be non-political in my posts. I see that some members of the press have tried to ridicule President Trump for an idea of “getting light inside the body.” Here are the quotes attributed to the President: “Suppose that we hit the body with a tremendous, whether it’s ultraviolet or just very powerful light,” Trump said at the White House coronavirus press briefing, adding: “Supposing you brought the light inside the body, which you can do either through the skin or in some other way.” Well, low and behold, if reporters find this a ridiculous statement, then they need to do their homework and learn some science, and have a more analytical mind.I would like to mention a paper that was published a few years ago by Dr. Michael Hamblin. Michael Hamblin is a Principal Investigator at the Wellman Center for Photomedicine (see below) at Massachusetts General Hospital, an Associate Professor of Dermatology at Harvard Medical School and a member of the Affiliated Faculty of Harvard-MIT Division of Health Science and Technology.The next insert is a copy of the title page of a paper written and published by Dr. Hamblin in 2017.We can see that the title of the article is Ultraviolet Irradiation of Blood: “The Cure that Time Forget”. As one can see we have a PHD from Harvard and MIT who is a main principle investigator at Harvard’s photomedicine center state that ultraviolet light to the blood is a cure that time forget. So, it seems that that President was not off the mark at all. I think he is owed an apology by those in the media and in the medical community who ridiculed him. I have been fortunate to meet Dr. Hamblin when we were both lecturing at a regenerative medicine meeting. I consider him one of the world’s experts on photo-therapy. I read the above article a few years ago and found it intriguing. There are many similar articles. In this article there is a discussion of the potential of Ultraviolet Blood Irradiation (UBI) as an alternative approach to current methods used to treat infections. It goes on to say that this therapy can also be an immune-modulating therapy and also as a method for normalizing blood parameters. The article states there is no resistance of microorganisms to UV irradiation. Low and mild doses of UV kill microorganisms by damaging the DNA, while any DNA damage in host cells can be rapidly repaired by DNA repair enzymes. Ultraviolet light when used for sterilization purposes causes the direct destruction of pathogens. Many people believe that this is also the mechanism of action for UBI which is absolutely not the case. It is the stimulation of the immune system and its various components that gives ultraviolet light therapy is effectiveness in addition to destroying the micro-organisms.The following diagram is from the article by Dr. Hamblin. It shows some of the various aspects of UBI on the immune system. This may be a complicated picture but when all is said and done it is stimulating the immune system in many different ways. It is somewhat complicated to the lay person.UBI appears to have three broadly different classes of effects on different blood components. In the case of various white blood cells which are called neutrophils, monocytes, macrophages, and dendritic cells. UBI can activate phagocytosis. Phagocytosis is a process wherein a cell, in this case a type of white blood cell, binds to a microbe such as a bacteria or virus and engulfs it. UBI also increases the secretion of Nitric Oxide which stimulates the production of cells which can calm down an inflammatory reaction. By reducing the inflammatory response, we are lessening the effects of a “cytokine storm” as is often found in infections and seems to be the crux of many Covid-19 complications. The oxidative nature of UBI may have mechanisms in common with ozone therapy and other oxygen therapies. Namely, we are reducing the oxidative stress on the immune system. Oxidative stress is an imbalance between free radicals and antioxidants in your body. Free radicals are oxygen-containing molecules with an uneven number of electrons. The uneven number allows them to easily react with other molecules. Free radicals can cause large chain chemical reactions in your body because they react so easily with other molecules. These reactions are called oxidation. They can be beneficial or harmfulThink of oxidative stress as synonymous with inflammation and inflammation is the root of most medical problems.Dr. Hamblin’s article is but one article concerning the use of light therapy. I think there is little doubt there is strong science behind the use of ultraviolet blood irradiation and for that matter phototherapy to treat a number of medical conditions. Although this seems like cutting edge therapy it is actually old. Ultraviolet blood irradiation (UBI) was extensively used in the 1940s and 1950s to treat many diseases including septicemia, pneumonia, tuberculosis, arthritis, asthma and even poliomyelitis. The early studies were carried out by several physicians in USA and published in the American Journal of Surgery. However, with the development of antibiotics, UBI use declined and it has now been called “the cure that time forgot”. Hopefully more research on various types of blood irradiation will be performed. I would also like to include a few slides from my lectures. These slides concern the use of phototherapy. The first slide is a summary of phototherapy.As we can see there are a myriad of beneficial aspect to light therapy. I will draw your attention to sentence six, “Whatever cells are designed to do will be improved by light therapy”. The next slide shows some of the many benefits of phototherapy in pictorial form.The takeaways from the above slide is that light therapy is intimately involved in cell energy production, positively impacts cellular repair and healing, stimulates the immune system. As President Trump said “GET THE LIGHT INSIDE THE BODY” and hopefully control the covid-19 virus. Certainly, no guarantees or cures but it might be a step in the right direction. Actually, we can take things to the next level by giving the patient certain medications which are called photosensitizers. Photosensitizers make light therapy work even better. However, this is a discussion for a different day. I will end this quick blog with a rather somber thought. Covid -19 is certainly a serious problem for our planet and I believe we will conquer it. I would like to present some information by the Rand Europe Think Tank. Unfortunately, there are much greater biological time bombs that may be facing us. One ticking time bomb we are facing is that of antibiotic resistance. Here is the chart of what we are facing, namely approximately 10,000,000 deaths per year caused by antibiotic resistance. It might just be that blood irradiation may save the day. Meantime, stay safe and get some sunshine which is a primitive form of blood irradiation.Thanks,Dr. P DEATHS PER YEAR SECONDARY TO ANTIBIOTIC RESISTANCE 2050 2050Thanks,- Dr. P