Tourniquet training? Yes, you read that right. An exciting form of advanced physical therapy called Blood Flow Restriction Therapy (BFR) has proven to be especially useful after a regenerative cell procedure to strengthen the muscles around an affected joint. The way it works is quite simple: after partially restricting blood flow using a series of well-calibrated, inflatable Velcro bands (tourniquets), patients perform muscle contractions to increase the size, strength and endurance of healing muscles. Its like lifting weights, but with tight cuffs on your arms or legs. Heres what you need to know: ● BFR training can be performed 2-3 times a week for three weeks OR 1-2 times a day for less than three weeks ● A good ratio for upper body and lower body is 40% arms to 50% legs (or even 50/50) ● BFR is best used with four reps per set, in the following sequence: 30-15-15-15 ● Maximum wear time for the cuffs is 20 minutes ● The ideal loads will be 20% to 50% of a patients one rep maximum lift ● Repetitions should be slow, up to two full seconds for each positive and negative movement ● Rest should be anywhere from 30 to 60 seconds between sets. BLOOD FLOW RESTRICTION THERAPY (BFRT) IS AN INNOVATIVE TRAINING METHOD FOR THE DEVELOPMENT OF MUSCLE STRENGTH AND HYPERTROPHY Our Institute is always on the prowl to find new regenerative technologies. More importantly, we are looking to combine these new technologies to add to our uniqueness. One newer technique that we are looking at is Blood Flow Restriction Therapy (BFRT). Blood flow restriction is becoming a new modality in the world of Regenerative Medicine, Sports Medicine, and performance enhancement. It is one of the hottest trends in this years Tokyo Olympics. Actually, it has been around for a while. In professional sports circles, BFRT is becoming more and more accepted. The initial appeal for BFRT training was driven by studies demonstrating rapid increases in muscle size, strength, and endurance capacity, even when notably low intensities and resistances, which would typically be incapable of stimulating change in healthy populations, were used. The incorporation of BFRT exercise into the training of strength- and endurance-trained athletes has recently been shown to provide additive training effects that augment skeletal muscle and cardiovascular adaptations. The above illustration shows the main tools for blood flow restriction, namely a series of tourniquets that are used during exercises. As we can see, the equipment is not extremely expensive or complicated. Blood flow restriction is a training method partially restricting arterial inflow and fully restricting venous outflow in working musculature during exercise. This technique seems to have originated in Japan by Dr. Sato in 1966. This technique is called Kaatsu training which translates to training with pressure. The manipulation of blood flow in conjunction with skeletal muscle contraction has helped us with the physiological understanding of muscle fatigue, blood pressure reflexes, and metabolism in humans. BFRT and KAATSU training differ by only modifying blood flow rather than stopping it. KAATSU training uses expensive pneumatic tubes, cuffs and electronic monitors and requires a certified specialist to monitor you during your workout. Blood flow restriction solutions, such on the other hand, are simple to use and can easily be added to your workouts to maximize results. BFRT training allows you to adjust the pressure of the bands or straps yourself. However, it is still not recommended that one attempts this treatment on their own without first getting some guidance from a certified professional. The following illustration is an overall synopsis of how to administer Blood Flow Restriction Therapy. I still recommend that this not be attempted on your own. One needs instruction in this technique. This is the practical aspect on how to do this therapy but the real question is how does it work? THE PROPOSED METHODS AS TO HOW BLOOD FLOW RESTRICTION THERAPY (BFRT) WORKS Recent interest in using intentional blood flow restriction has focused on elucidating how exercise during periods of reduced blood flow affects typical training adaptations. The initial appeal for BFR training (BFRT) was driven by studies demonstrating rapid increases in muscle size, strength, and endurance capacity, even when notably low intensities and resistances were utilized. These levels would typically be incapable of stimulating change in healthy populations. The incorporation of BFRT exercise into the training of strength- and endurance-trained athletes has recently been shown to provide additive training effects that augment skeletal muscle and cardiovascular adaptation. It has been generally accepted that muscle hypertrophy requires high-intensity training utilizing loads of at least 70% of 1-repetition max or lower loads until failure. However, there is mounting evidence that now supports low-load resistance training (20-40%RM) combined with blood flow restriction can similarly induce muscle hypertrophy and strength gains. What we thought we knew and understood about muscle cell physiology and hypertrophy has been turned upside down through blood flow restriction research. BFRT exercise alters acute physiological stressors such as local muscle oxygen availability and vascular shear stress which may lead to adaptations that are not easily attained with conventional training. The above diagram is a good synopsis of the various changes that occur with BFRT. We can see that there are three categories, high intensity, low intensity with BFRT, and low intensity. There are many similarities between high intensity and low intensity with BFRT. One interesting fact is that the low intensity with blood flow restriction seems to cause little muscle damage meaning that the recovery time is much quicker. Also, there are significant increases in growth hormone, IGF-1, and mTOR in the low intensity exercises with BFRT. Actually, these increases outstrip those of high intensity training. BFRT seems to be a myostatin blocker. It will down regulate myostatin. Myostatin blockers are a holy grail for body builders. Myostatin is a protein that blocks muscle cell growth and differentiation. When you use BFRT, you get this unlocking ability to get more muscle cell growth with minimal exercise load. Below we see a picture of a steer who was born with genetic mutation which resulted as if a myostatin blocker were utilized. There is currently a great deal of research concerning myostatin blockers. A number of compounds are currently being studied but there is still no truly effective one. MORE ABOUT THE BIOCHEMISTRY AND PHYSIOLOGY OF BFRT The above illustration gives a better idea of the aspects of the biochemistry/physiology involved with BFRT. We have already discussed the fact that myostatin is blocked. In this diagram, we see there is formation of heat shock proteins. Heat shock proteins normally are stimulated by subjecting the body to heat or cold. However, other stresses, such as BFRT, can also stimulate their production. There are a number of different types of heat shock proteins. Heat shock proteins are important in that they help proteins fold properly into the cells. Many degenerative diseases including Alzheimers are associated with misfolded proteins. The following illustration shows the benefits of heat shock proteins. They rescue damaged proteins and fix them which will hopefully slow down aging and diseases. Another important aspect of BFRT is the generation of Nitric Oxide (NO). Nitric oxide is considered a signaling molecule in the body. It has implications in many different biological systems in the body. In the context of BFRT, the NO will have direct effect on muscle growth. It will also stimulate the blood vessels and cause them to dilate eventually increasing the blood supply. The illustration below gives us an idea of the importance of the Nitric Oxide molecule. In our clinic, we recommend the use of supplemental Nitric Oxide stimulators. By far the best one out there is Neo-40. Another regulator of growth to consider is called the mTOR pathway. The mTOR pathway integrates the input from upstream pathways which are dependent upon insulin and other growth factors such as IGF-1 and amino acids. The mTOR pathway also senses cellular nutrient, oxygen, and energy levels. It is a very important pathway when it comes to cellular growth. One must realize that the m TOR pathway is both good and bad. In some instances, stimulation of the m TOR pathway may speed up aging. In controlled circumstances, mTOR pathway may be beneficial. It will definitely contribute to cellular growth. But this can be a double-edged sword. We must remember that when we are concerned with anti-aging we wish to block this pathway with the mTOR inhibitors. Cellular growth speeds up aging. WHAT IS THE PHYSIOLOGY INVOLVED IN BFRT? Many of the findings of BFRT reinforce the findings of the Nobel Prize in Physiology 2019 which describes how varying levels of oxygen shape both physiology and pathology in the body. In the case of BFRT, muscles are exercised to fatigue in an environment that prevents (temporarily) the flushing out of metabolites, and thus providing a metabolic environment more prone to stress signaling, low oxygen etc. There are a variety of physiological mechanisms thought to provoke a hypertrophic response in skeletal muscle following BFRT. Although the exact mechanisms of BFRT are not completely known, most evidence alludes to a muscle cell swelling response and an indirect effect of metabolites. This will instigate an increased muscle activation through fatigue. Regardless of the initial signaling mechanism, the intracellular environment should favor a positive protein balance for muscle growth achieved by an increase in muscle protein synthesis, a decrease in muscle protein breakdown, or both. The proposed mechanisms of occlusion in BFRT indicate there are increases in blood lactic acid levels and alterations in blood pH similar to High Intensity Training. Lactate is typically a waste product produced by muscle metabolism in low oxygen situations. The increased lactic acid will stimulate increases in serum growth hormone which in turn promotes collagen synthesis for tissue repair and recovery. Ultimately, this results in muscle satellite stem cell proliferation. Skeletal muscle satellite cells are considered to play a crucial role in muscle fiber maintenance, repair and remodeling. Satellite cells are precursors to skeletal muscle cells. They are essentially a muscle stem cell. They have the potential to provide additional myonuclei to their parent muscle fiber, or return to a quiescent state. In response to mechanical strain, satellite cells become activated and produce muscle. BFRT will increase the number and activity of satellite cells. In the above schematic of the muscle stem cells, BFRT increases the number of satellite stem cells thus increasing the number of muscle fibers. The following illustration demonstrates the various conditions which diminish muscle fiber generation. These conditions, such as diabetes, obesity, etc. can be benefited by BFRT. The technique of BFRT in the muscle using a pneumatic tourniquet system involves applying an external pressure, typically using a tourniquet cuff, to the most proximal region of the upper and/or lower limbs. When the cuff is inflated, there is gradual mechanical compression of the vasculature underneath the cuff, resulting in partial restriction of arterial blood flow to structures distal to the cuff, but which more severely affects venous outflow from under the cuff that is proposed to also impede venous return. Compression of the vasculature proximal to the skeletal muscle results in inadequate oxygen supply (hypoxia) within the muscle tissue. Furthermore, the diminution of venous blood flow results in blood pooling within the capillaries of the occluded limbs, often reflected by visible erythema. For safety purposes, its important to understand were not cutting off blood flow all together for extended periods of time, which is foolishly dangerous. For the most part, were applying heavy circumferential compression. This is the reason why one should not experiment on ones self. The following is a good synopsis of BFRT: As of now I am not aware of any restrictions from professional leagues or the World Anti-Doping Agency concerning BFRT. There is little if any doubt that this technique will improve performance. There is no doubt about the validity of BFRT and how it will benefit and change the practice of Regenerative Medicine and performance enhancement. As time goes on, it will have even more influence as it is combined with other modalities. We will start utilizing this therapy and will hopefully make it an intrical part of our new state of the art facility which we expect to move into early next year. What will make this more unique is that we will combine BFRT with other modalities such as Hyperbaric Oxygen, Ozone Therapy (EBO2), Xenon Therapy and a few other modalities. Our new facility will be a one stop state of the art facility like nothing else around. Thanks, Dr. P

I recently posted an article on LinkedIn about Vitamin C and how it affects certain immune cells and stem cells in the body. Most of the articles I have posted on LinkedIn are aimed more towards scientists and physicians. They are fairly technical and my writeups have more of a technical blush than my blogs. I have included this article at the end of this blog. My blogs also contain a good bit of science but are not as intense. I thought this was an interesting article for everyone. The article discusses the aspects as to how Vitamin C boosts our immune system and helps control actions of our DNA. How Vitamin C works is a topic most of us think we know about but when asked how Vitamin C really works the discussion becomes silent. The article discusses the use of Vitamin C in increasing the health of a certain type of immune cell in the body and how Vitamin C ultimately effects our DNA function by controlling some of our genes. The diagram below shows the different immune cells we have. All of these cells have their place and at times they can save our life such as in the face of an infection. The cell we are most interested in this case is called a Regulatory T-cell or as it is more commonly called a T-reg cell. T-reg cells are of the upmost importance in that they help prevent autoimmune diseases. Regulatory T cells police the immune system and keep it in check. Just as important, T-regs promote tissue repair and regeneration by modulating inflammation. Extra T-reg cells will do nothing but improve results for a wide variety of conditions from the treatment of autoimmune diseases to the treatment of osteoarthritis. The problem many times is that we just do not have enough T-reg cells to go around. T-regs are not easy to culture expand (grow them in a lab). What scientists are attempting to do is get other immune cells which are more plentiful and convert them into T-reg cells. This is called an induced T-reg cell (i-T reg cell). In another word, one type of immune cell is being coaxed to turn into a T-reg cell. This is a newer realm in the stem cell world. The following illustration shows this concept. Usually, when we are dealing with induced cells we will take a skin or similar cell and treat it either with a virus or enzyme to reprogram the cell. They are now doing this by treating the cell with certain transcription factors. This treatment makes the cell go back in time and act as much younger cell having the capabilities of becoming many different types of cells. These are called induced pluripotential stem cells or IPS cells. We see in the above illustration that these induced cells act very similar to embryonic cells. There is a great deal of research currently underway with these cells. The problem with the induced T-reg cells is that they do not appear to be stable. The next portion of the article deals on how to increase the stability of the induced T-reg cells and for that matter regular T-reg cells. This has possible far reaching ramifications for our health. One important factor that affects the T-reg cell stability is something called a TET protein. Actually, TET stands for Ten-Eleven Transcription factor proteins. Transcription is the process where a gene's DNA sequence is copied (transcribed) into an RNA molecule. Transcription is a key step in using information from a gene to make a protein. The RNA will carry a message and it is thus called messenger RNA (mRNA). This is the basis for many of the Covid vaccines. Our DNA contains all information that cells in our body need to function by providing specific codes to produce specific proteins. Not all parts of DNA are accessible in all cells at all times. The regulated production of proteins ensures that different cells and organs can be developed from the same DNA. Remember one cell has all the genetic information to reproduce the whole body. What that one cell makes depends upon how the cell is regulated. An important regulatory mechanism is the reversible addition (methylation) or removal (demethylation) of certain chemical bonds, so-called methyl groups, to segments of DNA. This modifies the readout of the DNA segment. The next illustration demonstrates the concept of methylation and how transcription works. We have now broached an important scientific field called EPIGENETICS. Epigenetics deals with how certain genes get turned on or off. The illustration shows these concepts. In the course of life, aging processes, environmental influences and lifestyle factors such as smoking or diet induce biochemical alterations to the DNA. Frequently, these lead to DNA methylation, a process in which methyl groups (CH3) are added to particular DNA segments, without changing the DNA sequence. This causes changes in how the DNA behaves. Getting back to the TET Proteins, they can decrease the production of certain proteins in immune cells. How TET proteins play into the development of autoimmune diseases is still not completely understood. TET transcription factors, a family of cancer suppressive proteins, help regulate gene activity via their influence on chromosomal architecture. TET enzymes facilitate DNA demethylation ( removal of CH3). Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. Researchers have linked abnormal DNA methylation to several human diseases. DNA methylation is a commonly used epigenetic signaling tool that can fix genes in the off position. Remember Epigenetics deals with how reversible changes in DNA affect gene activity and protein expression. Disrupting this machinery can have dramatic effects on cellular function and overall health. What the article tells us is that Vitamin C has the ability to enhance the enzymatic activity of the TET proteins. So far, the problem has been that the converted iT-reg cells did not seem to function well. It has been very challenging to come up with the right molecular ingredients to allow the induced cells to survive. Vitamin C seems to change the dialog. The article discusses the symbiosis of Vitamin C and TET proteins and their effects on T-reg cells. This technique involves the reprogramming of effector or memory T cells into iT-regs. The bottom line is that the Vitamin C and the TET proteins will induce a stable i-Treg cell. Hopefully, in the not too distant future stable i-Treg cells will become a reality. Vitamin C is found to be a key mediator of the interface between genome and environment. It regulates DNA demethylation as a cofactor for TET. It is shown that vitamin C drives active removal of DNA methylation by enhancing TET enzymes. Thus, Vitamin C is not just an anti-oxidant but has other powerful regulatory function. THIS IS A BIG DEAL! Recent studies have shown that Vitamin C potentiates the effects of DNA methyltransferase inhibitors. DNA methyltransferases are a family of writer enzymes responsible for DNA methylation by the addition of a methyl group. Epigenetic alterations, along with genetic mutations contribute to onset of cancer. It is shown that Vitamin C drives active removal of DNA methylation by enhancing TET enzymes. This helps to erase DNA methylation which allows epigenetic memory encoded by it to improve reprogramming of differentiated cells to an embryonic-like state. In the above illustration we see Vitamin C at work. It is blocking a DNA writer. It is inhibiting the addition of the methyl group to the DNA. Here is the proof that Vitamin C affects how our DNA functions. The famous scientist, Linus Pauling, recommended mega doses of Vitamin C. He was mocked for recommending large doses of Vitamin C for preventing the common cold among other things. Ask your friends if they have been taking large doses of Vitamin C to try to help prevent Covid. It looks like Pauling will have the last laugh. It reminds me of a saying from Arthur Schopenhauer Truth passes through three stages: First it is Ridiculed. Second, it is violently opposed. Third, it is accepted as self-evident. The take away here is Vitamin C is an essential micronutrient and a free radical scavenger. These are well known facts. At the same time, it has functions such as blocking oncogenic transformation induced by carcinogens by its effects on epigenetics. The epigenetic effects of vitamin C and its effects on the health of the immune system far outweigh it acting as an anti-oxidant. One final thought, in our clinic we are able to offer multiple combinations of Vitamin C via an intravenous route. The intravenous route insures better bioavailability.Thanks, Dr P Here is the link to the article: https://scitechdaily.com/vitamin-c-is-a-key-ingredient-for-immune-cell-function-a-leg-up-in-treating-autoimmune-diseases/

Sometimes the government is the last to know. The U.S. military is about to start testing anti-aging compounds. Guess which one? Hint: It begins with an 'N', ends with a 'D' and has an 'A' in the middle. The answer is NAD. I was recently sent an article from a friend. It was interesting in that it was discussing the fact that the U.S. military will be testing NAD as an anti-aging supplement and performance enhancer. I looked up this up and found that this information was reported on a number of different sites. I happened to pick the Popular Science article and it is included below. The military is doing something that we have known about in the real world for some time. NAD supplements seem to act in an anti-aging fashion and seem to improve performance, both mentally and physically. I suspect over time they will also discover that giving the NAD intravenously with the oral supplements will work even better. I suspect over time they will also discover certain tricks to make NAD absorption better, more efficient and quicker. Finally, they will also learn that they will need to act against Senescent cells when NAD is given or we may have the opposite effect on the patient. These are treatment protocols that we have developed in our clinic over time. Below is the link. Enjoy the article:https://www.popularmechanics.com/science/health/a36905562/us-military-testing-anti-aging-pill/Thanks, Dr. P

If you move it, you will lose the cells/It needs rest The biggest misconception around the injection of PRP or Stem Cells as it is related to physical therapy (PT) is that post injection PT shouldn’t happen. There is the common misconception that if you move the area that was injected you will somehow push the cells out and the money you spent will be wasted. This couldn’t be further from the truth. The most up to date research in the field consistently advocates for movement in the form of physical therapy post injection. By moving the area and stressing the tissue intelligently you are actually telling those injected cells what to do. The cells are placed in the area, and it is referred to as their “microenvironment”. If the microenvironment goes unaltered the cells will not serve their intended purpose. If the microenvironment is stimulated it will signal to those cells what tissue is needed and the cells will respond accordingly. In summary, physical therapy post-injection is a crucial component to getting the most out of your treatment. Any PT post stem cell is good PT Along the same lines as our first misconception is the falsehood that any PT after Stem Cell/PRP is good PT. Unfortunately, that isn’t the case. The most affective physical therapy after a stem cell injection will be one that targets the tissue type that the injection was given for (ie. Bone, tendon, ligament, muscle, etc.). Each tissue type responds to stimulus differently and that needs to be understood by the physical therapist providing the treatment. Stress the tissue too much, too little, or incorrectly can be detrimental to the patient’s outcomes. Stressing the target tissue the correct ways and with the correct dosage is going to greatly improve the benefits of the injection. Finding a physical therapist that understands regenerative medicine and can balance the active and passive components of care properly is a must for optimal results. The Boost of Blood Flow Restriction (BFR) Training This third point is less of a misconception and more of a secret weapon to boosting outcomes after a regenerative injection. Blood flow restriction training, when done properly, can greatly assist in the recovery and repair process following PRP/Stem cell injections. BFR training involves measuring the patient’s blood pressure and using an equation to determine a proper occlusion pressure for them to train under. Once this pressure is found, we are able to mimic training under a heavy load with high intensity under a very low load and intensity. Simply put, we can trick the body into thinking it is working harder than it truly is. This is important after PRP/stem cell because it influences the body chemistry in a way that can magnify the response. BFR training puts the body in “rebuild and repair” mode safely while those injected cells are trying to do just that. Simply put: if the PRP and stem cells are the construction workers, BFR training is the 2pm coffee that keeps them working hard through the end of the day. Written by Dr. William “Bill" Kelley DPT, ATC, CSCSCo-Owner and Director of Physical Therapy:Aries Physical Therapy FTL1115 E Sunrise BlvdFort Lauderdale, FL 33304(o) 954-247-4929(f) 954-245-0697Aries Physical Therapy Boca807 N Federal HwyBoca Raton, FL 33432(o) 561-287-6486(f) 561-621-2944

We have known for some time that Ozone has some anti-aging properties. But there are also some other anti-aging aspects of Medical Ozone therapy that are not readily known. The above diagram shows some interesting effects of medical ozone. In this particular case the Ozone was administered intravenously. When Ozone is administered intravenously it will form two different types of compounds. The first compound is hydrogen peroxide (H2O2) which helps launch a cascade of reactions which ultimately reduce inflammation in the body. Less inflammation is less aging. More to come about this. In the above diagram we see that the Ozone is reacting with the Poly Unsaturated Fatty Acids (PUFAs) found in the cell membrane. Poly unsaturated fatty acids all have at least one double bond linkage between carbon atoms. These double bonds cause them to bend, kind of like how your arm bends at your elbow. This double bond limits the number of hydrogen atoms that can bind to the carbon atoms, so the molecule is not as saturated with hydrogen atoms as it could be. Thus, its considered unsaturated. Unsaturated fatty acids that have one double bond are called monounsaturated fatty acids (MUFAs). Unsaturated fatty acids with more than one double bond are called polyunsaturated fatty acids (PUFAs). Get it? mono for one and poly for many.Polyunsaturated fats can be divided into 2 groups: omega-3s and omega-6 fats. Two polyunsaturated fatty acids are regarded as essential because the body cant make them they must come from food. The two essential fatty acids are alpha linolenic acid (an omega 3 fat) and linoleic acid (an omega 6 fat). Omega 3 fats, especially those found in seafood, are vital to help control inflammatory reactions in the body. POLYUNSATURATED FATS ARE USED AS BUILDING BLOCKS IN THE MEMBRANES THAT SURROUND ALL THE CELLS OF YOUR BODY AND CONTRIBUTE TO THE STRUCTURE OF THE BRAIN. The cell membrane seems to be the major area of reaction between the Ozone and PUFAs. In the first diagram we see that the Ozone reacts with the Poly Unsaturated Fatty Acids located in the cell membrane. It forms a compound called a Lipid Oxidation Products also known as LOPs. These LOPs react with a variety of cells within the body. In the diagram I have circled in red two important pathways in the body. These two are the AMPK and mTOR pathways. The effects of these pathways have profound implications on our longevity. Other important pathways include: 1. Sirtuin Pathway 2. Nuclear factor-kappa B (NF-kB) pathway 3. NRF2 pathway 4. FOXO pathway. These are very important pathways especially when it comes to anti-aging and longevity. Let us take a better look at the AMPK and the mTOR pathways. The following illustration shows what happens when there is an AMPK deficit: We are able to see that AMPK deficits lead to many conditions associated with increased aging. While the opposite is true. Stimulate the AMPK pathway and you will increase longevity. The next illustration shows the rewards of increased 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 AMPK 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. AMPK deals how our body uses and transforms energy. 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 store. REMEMBER AMPK ACTIVATION WILL LOWER BLOOD GLUCOSE LEVELS. THIS IS WHY WHEN SOME PATIENTS RECEIVE AN EBO2 OZONE TREATMENT OR OTHER IV OZONE TREATMENTS, THEY SOMETIMES BECOME LIGHT HEADED. THEY ACTUALLY HAVE DROPPED THEIR BLOOD GLUCOSE WHICH CAN EASILY BE REMEDIED BY GIVING THE PATIENT A SOURCE OF GLUCOSE. THE AMPK PATHWAY HAS DRIVEN THE GLUCOSE INTO THE CELLS. Thus, in order to further enhance the effects of the Ozone it is suggested that that the patients follow through with supplements which further stimulate the AMPK pathway. These supplements include Resveratrol, Alpha Lipoic Acid, Gynostemma (a form of Ginseng), Curcumin, Quercetin, and last but not least is Berberine. These continue to stimulate the AMPK pathway. The bottom line is the stimulating the AMPK pathway will allow our bodies to utilize insulin much more efficiently which is a major hallmark of anti-aging and longevity. Another important anti-aging pathway is the mTOR pathway. Actually, the blocking of this pathway is the mechanism which results in anti-aging. mTOR means Mechanistic Target of Rapamycin. To slow down aging we want to block most actions of the mTOR pathway. A medication called Rapamycin will block the action of the mTOR pathway. Interestingly, Rapamycin can function as an immuno-suppressant. It is used to prevent organ transplant rejections among other things. When the mTOR pathway is over-activated by nutrients and insulin, it will act to inhibit insulin signaling, thereby causing insulin resistance. Insulin resistance is a hallmark of type II diabetes. Higher insulin levels are associated with increased aging and increased blood glucose. Acute treatment with Rapamycin abrogates insulin resistance in cells and animals including humans. One study showed that chronic treatment with Rapamycin prevented insulin resistance. There are currently a number of studies that are utilizing Rapamycin which blocks the mTOR pathway. The mTOR pathway is a master regulator of cell growth. Think of increased mTOR activity being an analog of the phrase LIVE FAST, DIE YOUNG, because too much activity is good for growth but bad for lifespan. However, too little mTOR activity is not beneficial either because it can disrupt healing and insulin sensitivity. Ozone has an effect on the mTOR pathway mainly by its influence on the AMPK pathway. AMPK hold the mTOR pathway in check. The following illustration shows what the mTOR pathway actually influences. Namely, the growth of the cells. mTOR is involved in every aspect of cellular life and existence. In the case of inhibition of mTOR, we are actually trying to apply the brakes to cell growth and proliferation. In addition, the mTOR pathway is a direct target of the IGF-1 signaling pathway, which is a major driver of aging. Rapamycin is now available as a treatment modality for anti-aging. Some supplements which simulate the effects of Rapamycin include Curcumin, Green Tea Extract, Resveratrol and Pterostilbene, and Fistin. The next illustration is an example of the mTOR pathway in action. What we see is that the mTOR pathway is great for cell growth but ultimately it leads to shorter life span, remember, LIVE FAST AND DIE YOUNG. We can see that blocking the mTOR pathway has very beneficial results. It brings on longevity. Both the AMPK pathway and the inhibition of the mTOR pathway leads to the process of autophagy. Autophagy seems to be a crucial component of many longevity protocols. What is autophagy? Once humans abandoned their hunter ancestors roaming lifestyle and settled down in permanent dwellings, they realized the importance and significance of housekeeping. Ironically, our cells long preceded us to this realization as they developed their own miniature housekeeping mechanism, known as autophagy (Greek for self-eating). Autophagy does not only serve as a detoxification tool but also supports cellular fitness by directing the resulting products from waste hydrolysis towards energy production and cellular recycling. Mounting evidence indicates that autophagy plays a key role in aging and aging-related diseases. Enhanced autophagy can delay aging and prolong life span. The absence of autophagy leads to the accumulation of mutant and misfolded proteins in the cell, which is the basis for the emergence and development of neurodegenerative diseases and other aging-related diseases. The following illustration explains autophagy. The autophagic activity has been found to decrease with age, likely contributing to the accumulation of damaged macromolecules and organelles during aging. Autophagy is becoming more and more important in the field of anti-aging medicine. Another aspect of Ozone Anti-Aging is the effect that Ozone has on the NQO1 pathway. NQO1 pathway is very important in the ratio of NAD+/NADH. Ideally, we like this ratio to be about 700/1. NQO1 keeps down the levels of NADH which is thought to be a marker of aging. Also important about the NQO1 pathway is the influences it holds on P-53 stimulation. P-53 is called the Tumor Suppressor Gene. It is very important in dealing with cells that have significant DNA damage. It will analyze a cell and either fix it or kill it. This is extremely important for anti-aging. If the damaged cells are allowed to accumulate they lead to Senescent cells. A Senescent cell is much like a Zombie cell. It is the living dead. It can cause havoc on our immune system which leads to aging. The next illustration is a good example just how the P-53 gene works. It will analyze the cells and determine their fate. They either survive or perish. There are also some more well-known aspects of aging that are associated with Ozone. One aspect includes the anti-aging aspect that Ozone has upon the Sirtuin pathways via the influence of NAD+ production. Ozone helps produce NAD+ which has significant implications on the function of the Sirtuin proteins. The Sirtuins are very important for mitochondrial health. The Sirtuins seem to have an influence on a number of other aging pathways. For instance, we see here the influences that Sirtuin One protein has on a number of processes concerned with aging. Lastly, and just as important, the effects that Ozone on the NRF2 pathway are very influential in increasing our longevity. We must remember that NRF2 pathway is a thermostat of anti-inflammation. This dovetails very nicely with a process the name of which was just coined a few years ago, namely Inflammaging. Inflammaging essentially means that inflammation leads to aging. This last illustration seems to sum up everything. Ozone has effects on all these aspects of aging.Thanks, Dr. P

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

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

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

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

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