Many people know me from my blogs that I write on the website. Unlike most people, I do not use ghost writers. I write my own material. There is another group of people who know me from my comments on LinkedIn. The above represents one of the articles I recently commented upon on LinkedIn. What I find interesting is that the above article gives a glimpse into my journey in Regenerative Medicine. As I stated, many years ago when I became involved in Regenerative Medicine, it was the dogma that Mesenchymal Stem Cells were the only cells that accomplished repair. Well, that certainly has changed, as can be seen by the 1900+ hits this short article has gotten. We now know that a symphony of cells accomplish repair.     This article reminded me of my journey into the field of Regenerative Medicine. The groundwork for my journey began as a typical Orthopedic surgeon. I was seeing patients in the office, and at the same time having a very busy operative practice. My week would consist of performing total joint replacements, performing arthroscopies, and doing spinal laminectomies. Of course, my occasional weekend was involved in repairing hip fractures and a variety of other fractures. In those days, there was not the specialization in Orthopedics as there is today. I did many of these surgeries, but at the same time I thought that these were rather barbaric operations.  I was basically doing carpentry on patients. When I finished my residency, the field of Arthroscopic Surgery was just getting started. I remember some of the more “seasoned” orthopedic surgeons that I met in private practice said to me that arthroscopy was just a fad that would die out in a few years. Initially, they looked at me in scorn thinking I was doing some type of quackery surgery. Well, I guess they were wrong! I became very proficient with the arthroscope, and did many surgeries, as did the rest of the Orthopedic community. Although the initial results in arthroscopic surgery were excellent, later on in my career I realized that these surgeries were actually causing patients to develop osteoarthritis at a young age, and this concept is now supported in the literature. I started to become disillusioned with this treatment protocol, but at the time did not know what could be a better option.        I would go to conferences to learn the latest techniques which, when all was said-and-done, was not much different from older techniques. One thing I was always drawn to was the cutting-edge techniques. I was at one time involved with injecting chymopapin into herniated discs. Chymopapin is the enzyme found in meat tenderizers. In this case, it would disolve the herniated disc. The results we obtained were very good. After this technique, I moved on to laser discectomies.  Both of these methods gave excellent success in the right patient. I would call these episodes my springboard for regenerative medicine.     Total joint replacements were my formal indoctrination to the world of Regenerative Medicine. I was doing joint replacements, and I went to a conference where they discussed a “new technique” called PRP or Platelet Rich Plasma. They said that this helps the joint replacement patient heal quicker and, in general, have less pain. I started using this “new technique” with excellent success. I started studying more about PRP, and realized that this is the way nature heals itself. This was my “A-ha!” moment. I realized that the PRP technique could be used in many other applications besides total joints. My second “A-ha!” moment was that perhaps this might eventually replace the joint replacement itself.   I was now at the fork in the road. I could continue doing everyday orthopedics, or I could get more involved in the path that led to the use of biologics for orthopedic conditions. I went down this path when few people even knew what a PRP was. Those that knew about a PRP typically did not know much about bone marrow aspirate or adipose tissue. Bone marrow and adipose were my next targets to learn and study. They fell into place quickly. This time period reminded me of the time when I first went into private practice, and began doing arthroscopic surgery.  The more established orthopedists said this was a fad and recommended against it. Well, fast-forward twenty years and the same comments were being made by the Orthopedic community about PRP. They said that PRP and Regenerative medicine was “Hocus Pocus Surgery.” They said that it was a fad with no scientific basis, and the talk behind my back was causing my ears to burn.   I stood steadfast in my convictions and I am so happy I did.  Slowly, more acceptance crept into the field. I was eventually lecturing all over the world, and continue to do so. As a matter of fact, I leave tonight for a quick teaching trip to Brazil. I will be there for about a day and a half and then return to the USA. In that time, I will talk about the basic science of stem cells and regenerative medicine. This is interesting, in that, most clinicians try to disregard basic science and usually are not involved in teaching. Well, low and behold, I now find myself teaching of all things about the basic science of stem cells and Regenerative Medicine. As a matter of fact, I have taught on all six continents. If someone would have told me this twenty years ago, I would have bet the farm against it. It is interesting how life takes some unexpected turns.  I realized that in order to become proficient in anything, one must learn to master the basics.    Every day, I try to learn more basic science in the field of Regenerative Medicine. It reminds me of one of my slides in my talks, “the more you know the more you don’t know.” That is actually a profound statement because of its simplicity. Using this knowledge of basic science has allowed me to expand the horizons and successes of our clinics.  We are involved in cutting-edge aspects of anti-aging medicine that down the road will become building blocks of mainstream medicine. I have learned that the way stem cells age is how we age. These aging pathways include eliminating senescent zombie cells and stimulating gene pathways to improve the health of our mitochondria. I have realized that Anti-Aging, Stem cells and Regenerative Medicine have a strong bond that ties all of them together. It has been an exciting journey that I look forward to continuing.    Regards, - Dr. P

     I am fortunate to have witnessed the development and subsequent registration of products which will completely change the complexion of the Regenerative Medicine world. Unlike umbilical cord blood products, exosomes, and amniotic products all of which the FDA has stated require either a biologics license or an Investigational New Drug (IND) application. These products have been cleared for use on patients. They are produced in a GMP registered lab by the Swiss company Contrad. They are the brainchild of my mentor and colleague Dr. Jo Serrentino. I have used this technology for a number of years now and have had tremendous success with this technology in all my procedures. Fortunately, this technology is now available to the Regenerative Medicine Health provider.      These are innovative technologies that will reframe the Regenerative Medicine field by bringing to the market effective biomedical remedies unlike any other. This new technology is called SIGMOLECS® Technology. It is an advanced chemical profiling through structural assembling of key molecules, mostly proteins and peptides, that form actuated molecules. It accomplishes this by specifically improving their bio-activity in solution and in vivo by increasing their transmembrane penetration. This creates precise specificity of action, particularly in intracellular signaling. This is essentially the method that the body uses to heal itself and is the essential basis of Regenerative Medicine and cytokine therapy.  SIGMOLECS molecules induce signals to key amino acid sensors that govern gene expression of amino acid metabolism that then trigger specific physiological and metabolic activity. The nuts and bolts of Sigmolecs molecules is quite simple. Sigmolecs® molecules are really like microchips carrying the information we want to program into the patient. So once designed and synthesized Sigmolecs are put into a proprietary gel that delivers them trans-dermally while at the same time causing essentially no reaction in the skin. We must also be cognizant of the fact that if you don’t have the right delivery system for your clinical application, even the most potent medicine will not work. So once designed and synthesized Sigmolecs are put into a proprietary gel that delivers them trans dermally.       These SIGMOLECS molecules are structured according to key amino acid sensors to trigger specific regenerative tasks. This is done by grafting bioactive peptides or amino acid (AA) sequences onto a source molecule, usually a natural source of protein like Soy protein or Collagen peptides. This becomes the template for the Sigmolecs molecule that will be structured to have very specific bioactivity. Many of the mini-proteins found in plants are desirable for this work because of the resistance they contribute to enzymatic degradation, and their native structure provides a chemical template conducive to various sequence designs.  Overall, this allows the synthesis of specific bioactive peptides while silencing signals and gene expression encoding undesirable processes; such as, proteinase secretion and expression of associated catabolic cytokines.       Sigmolecs® molecules are configured and assembled to mirror highly specific intracellular signaling factors.  These are the same factors that stem cells and other regenerative cells utilize to accomplish repair of damaged tissue. They are essentially clones of what the body produces.        SIGMOLECS designer molecules are part of the delivery package; that is, the gel carrier. It contains Sigmolecs® Technology in that it designs scaled molecules that can easily penetrate the skin and enter deep tissue. The molecules are fashioned according to sequences that are ‘skin friendly’ and can facilitate navigation through cell membranes. For example, when using native peptides from suis collagen peptides the molecules provide a chemical template to structure therapeutic specificity in a repair combination. The basic gel amalgam provides structural molecules conducive to crossing skin and cell barriers, and in this sense, is a completely functional product that is both a carrier and a therapeutic gel in one.  This gel enables the transfer of large molecules and solutes through cutaneous channels that normal dermal formulation or patches could not deliver. It allows penetration of large molecular weight molecules to cross the Stratum Corneum, deeply penetrating the epidermis and dermis, reaching vascular and cellular targets through tissue permeability akin to injection, but without any invasive needling.       There are two different type of products which are available in gel monodoses to be used with a patch.  The first gel monodose is called the AI (ANTI-INFLAMMATORY) monodose which is upgraded to code for IL-10 and IRAP.  These two entities are considered master anti-inflammatory cytokines. The raw material used to design the therapeutic Sigmolecs P3 AI gel is Soybean protein. This plant contains several small proteins that are already anti-inflammatory in nature, but more importantly, that are conducive to structural modification.  Many drugs have been fashioned from plant molecules; most are proteins such as cytokines. Many come from Tobacco plant cell cultures, such as IL-2, IL-4 and the famed Neupogen otherwise known as G-CSF!  Even Human Interferons have been successfully produced from plants, and many more human synthesized cytokines originate from plants.       The Anti-Inflammatory sequence provides vascular support, regulation of blood flow and platelet function, and very importantly, inhibition of inflammatory cytokines specifically, IL-6, IL-8 and TNF.  It mediates the inflammatory response to prevent and reduce edema and pain while also contributing considerable analgesic effect without invasive pain procedures.         The RG REGENERATIVE MONODOSE GEL invokes cell differentiation especially to chondrocytes and keratinocytes. The raw material used to design the therapeutic SIGMOLECS® P3 RG gel is suis collagen. The peptides extracted from this source naturally regulate neutrophils especially in stem cell procedures while at the same time they stimulate and induce mobilization of transplanted adult stem cells. The SIGMOLECS® combination of structures in the P3 RG gel regulates the cell cycle particularly by signaling resting phase cells to migrate to areas of repair. It combats oxidative reactions in synovial fluid while stimulating chondrocytes to repopulate decellularized tissue at the site of injury. It also provides the extracellular matrix with signals, such as those that mimic hematopoietic cytokines, which reinforce procedures such as PRP and stem cells treatments. Furthermore, in Regenerative Medicine, the use of RG gel monodose post regenerative therapy will enhance the treatments by sustaining stem cell niches enhancing the success of clinical treatments.      Moreover, suis collagen peptides, in particular, are structured cleaner than other types of collagen which allows for a larger spectrum of sequencing for specific therapeutic action. These actions include sequences that mimic growth factor signaling such as Insulin Like Growth Factor (IGF) and Fibroblast Growth Factor (FGF.) The suis collagen peptides have more affinity for human synthesized growth factors than other collagen sources. The RG gel is particularly good to apply after a stem cell treatment. It will enhance treatment protocols by providing the regenerative cytokine signals and also provides the needed elements to the extracellular stem cell niche. It signals repair pathways while inhibiting TNF-override that often occurs during repair processes.       Please notice that the opinions in this article are solely my own professional opinions intended for professionals only.      These gel monodoses are now available for sale in the U.S.A to health care providers. Please feel free to inquire about more information concerning the gels including their purchase. This is truly a paradigm shift in all of Regenerative medicine. FOR MORE INFORMATION PLEASE CALL 561 350-4465.   

At one time it was thought that there was little if any relationship between Senescent Cells and NAD supplements. We now know that this is far from the truth. Remember that the senescent cells are cells that should have died but continue to survive. By surviving they cause a multitude of problems. Senescent cells are believed to contribute to numerous age-associated diseases. Senescent cells are becoming a hot topic in the field of Regenerative Medicine. We now know they may be responsible for many of the failures in cellular therapy. Senescent cells are believed to contribute to numerous age-associated diseases. By the same token we now know that NAD, the supplement, is extremely important in general well-being and success in cellular therapy.   Below we see diagrams concerning Senescent cells. The two above diagrams represent the essence of Senescent cells (Please see some of my previous blogs concerning Senescent cells). Unfortunately, many of the effects of the Senescent cells are found in the dark side of the first diagram. The elimination of Senescent cells by senolytic regimens (programs designed to kill senescent cells) appears to help in numerous aging-associated diseases including atherosclerosis, pulmonary problems, diabetes, neurological problems, cancer and osteoarthritis. Senescent cells secrete pro-inflammatory factors which are called Senescence-Associated Secretory Phenotype (SASP). These are essentially the “bad growth factors”. By the mechanism of the inflammatory growth factors, the Senescent cells are believed to contribute to numerous age-associated diseases. The second diagram shows the causes of cell senescence. These causes of cell senescence are essentially the causes of aging. We can see that the causes are multiple. The causes involve the usual suspects including DNA damage, mitochondrial damage, damage to the ends of the DNA called the telomeres, and finally what we call epigenetic factors. Epigenetic factors have far reaching effects. They involve changes to gene expression that our cells experience as we get older. These are commonly called epigenetic alterations. The following diagram demonstrates these facts. There are many factors that can affect the genes. The diagram shows some of the examples. These genetic alterations harm the fundamental functions of our cells and can increase the risk of cancer and other age-related diseases. The DNA is affected by the inflammatory cytokines secreted by the Senescent cells. These secretions are modifying gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands. The genes which are turned on the cell can either be a friend or a foe. It can help prevent a cancer or help cause it. Here are two recent articles from two reliable sources concerning senolytic agents. As you can see Senescent cells are not some esoteric idea. They are becoming mainstream medicine. We are acutely aware of the importance of senolytic agents for overall health. They seem to be very important in NAD therapy also. Here are the articles: There is one other article which I will share with you which is more scientific discussing the Senescent cell problem. So, the real question is what do Senescent cells and NAD have to do with each other? Furthermore, are their paths on a collision course? Now I would like to discuss the collision course that NAD and Senescent cells are on. Recently I read a scientific article that was quite fascinating and thought provoking. The article discussed the ramifications of taking NAD+ supplements and their effect on Senescent cells. Let us do a quick review of NAD. NAD+ is a potent stimulator of the SIRT-1 gene pathway. This pathway is thought to be one of the major anti-aging pathways. This is the pathway that many people are familiar with by the effects of the compound Resveratrol which is found in red wine. Other methods of stimulating this pathway include calorie restriction, intermittent fasting, keto diet, high intensity exercise training, and perhaps most importantly NAD.  When all is said and done the Sirtuin pathway stimulates the production and efficiency of the mitochondria which provide the cells with energy. Typically, the more mitochondria the healthier the cell and for that matter the healthier the person. From the point of view of anti-aging, NAD has tremendous potential. However, it seems that NAD may act as a double edge sword as we get older. There is no doubt that we become deficient in NAD as we age. The reason for this is multifocal. One important reason is that certain enzymes in our body become large consumers of NAD. Some of these enzymes are involved in the process of repairing DNA damage. If there is not enough NAD to go around than the NAD gets shuffled to the cells where it is an absolute necessity or the cells die. However, the consuming enzymes continue to try to utilize NAD but they will unfortunately not be able to accomplish DNA repair. If we are able to consume adequate amounts of NAD these enzymes get turned back on and do their important repair work. We are able to increase the amount of NAD available to the body by a variety of methods. One of the secret weapons we utilize is an NAD kinase patch. The NAD kinase patch contains an enzyme, NAD kinase, and penetrating molecules. This combination will dramatically increase the amount of NAD that enters the cell. As we age, we become deficient in the NAD kinase enzyme. This enzyme is the cutting edge of the cutting-edge technology especially when it pertains to NAD administration. It allows greater amounts of NAD to enter the cell.   So far all seem good except for one detail. Both myself and my wife take NAD on a daily basis. We occasionally use the Kinase patches. We are doing this to hopefully “slow down” our aging. On the surface this makes perfect sense, yet some of the newest thinking demonstrates some potential problems when dealing with NAD administration. There is no doubt that I have Senescent cells in my body (recently I did a once a week x 2 regimen of Senolytic agents which has had some surprising beneficial effects). In the article I was referring to, on one hand it stated that the NAD+ levels decrease as we age leading to degenerative conditions. While at the same time, the number of senescent cells will increase with aging. The article states that decreased NAD+ levels that are associated with aging may actually decrease the effects of the senescent cells on the body. Conversely increasing NAD+ levels by supplementation either orally or intravenously or both methods may benefit tissue homeostasis, but also may worsen SASP and make the make the Senescent cells more aggressively inflammatory. This is certainly not a good thing.   TAKEN TOGETHER THESE FINDINGS SUGGEST A FUNDAMENTAL TRADE-OFF IN TREATING AGING RELATED DISEASES WITH DRUGS OR SUPPLEMENTS THAT INCREASE NAD+.   So, the bottom line is that we are increasing NAD levels which is a good thing but at the same time we are also making the Senescent cells increase the secretion of the inflammatory growth factors which is a bad thing. Another concern is a report that senescent cells can induce a cell surface protein called CD-38 on macrophages (a type of white blood cell in the immune system) and endothelial cells (Endothelium refers to cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall).  CD-38 is a molecule important for many different cellular processes, including calcium signaling, which regulates basic cell functions. CD-38 is the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, CD-38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases. However, too much CD-38 is a sign of inflammation. Research has linked overexpression of CD-38 to obesity, cancer, and infectious diseases, like HIV. Both the decline in NAD+ and the presence of Senescent cells are hallmarks of aging. We are aware that a supplement called Apigenin seems to help block the effects of CD-38. (Apigenin is found in many fruits and vegetables, but parsley, celery, celeriac, and chamomile tea.  Apigenin is particularly abundant in the flowers of chamomile plants). Apigenin may eventually be part of a regimen when administering NAD. Until recently, it was unclear exactly how rising CD-38, declining NAD+, and the presence of senescent cells were all related. Scientists also know that the presence of CD-38 levels increase with age, and that CD-38 is involved in lowering NAD+ levels. It is a major consumer of NAD. In turn increased CD-38 expression is believed to be the key modulator of lowered NAD+ levels with aging in mammals. CD-38 is intimately related to our immune system but unfortunately not in a good way.   In the following diagram, we see that the inflammatory growth factors from Senescent cells have a direct effect on what is called an M-1 macrophage. This is a type of white blood cell which is many times associated with inflammation in the body. Not a big problem when we are dealing with bacteria but not good for anti-aging. The accumulation of Senescent cells may itself be an important safeguard causing decreased NAD+ levels which in turn could promote a multitude of problems. On the other hand, the lower NAD+ levels may diminish the influence of Senescent cells which is the safeguard. What the scientists found was two-fold: First, they observed that inducing senescence did not lead the senescent cells themselves to produce more CD38. But, the senescent cells did, as expected, begin secreting a cascade of inflammatory chemicals that in turn, up-regulated CD38 in surrounding non-senescent cells. In other words, they infected normal cells much like a zombie infects normal people. Interestingly, they found that different inflammatory factors did not individually increase CD-38, but when combined led to a strong increase in CD-38 activity. In the end, the scientists observed this affect in all the types of cells tested. We are aware that Quercetin and Apigenin are two supplements that can diminish CD-38 effects. These also act as senolytic agents. As a matter of fact, Quercetin is found as a senolytic agent in many University studies. In these studies, Quercetin is combined with Dasatinib to act as a super senolytic agent. Dasatinib is a Leukemia medication that is being used “off-label”. Because the dosages are extremely small the side effects are minimal. The elimination of most senescent cells by senolysis (the killing of senescent cells) before initiating NAD+ therapies may be beneficial and increase safety. There is the possibility that it may eventually allow for need for little IV therapy and mainly rely on oral medication.   I think to treat the patient with some form of senolytic agent prior to NAD therapy may possibly the new standard of care for patients receiving NAD therapy. Unless we address the Senescent cell/CD-38 problem, trying to raise NAD+ levels with precursors may come with too many downsides, preventing us from both having our cake and eating it too.   So, what is the real bottom line? We strongly feel that    Senolytic agents are imperative when using NAD+ intravenously or orally. Actually, I think they have a place in almost everyone. We want to diminish Senescent cells and their inflammatory growth factors and at the same time increase cellular NAD levels. Luckily, we have been aware of the Senescent cell problem some time now. We have been treating our patients with a number of different senolytic agents for some time. Some of these have included a P-53 patch, certain supplements such as Quercetin, even utilizing Quercetin and Dasatinib together. We have worked out very specific regimens for this. If a physician is not taking steps to deal with Senescent cells his overall chance of success will be much lower in Regenerative procedures and overall patient health. Furthermore, there is the possibility that the patient’s overall health may take a turn for the worse in the long run by increasing the effects of the senescent cells.   Here is the bottom line from an article I read “reducing the senescent cell burden in persons around age 60 and middle-aged obese individuals may become a critical step in restoring youthful NAD+ cellular levels in a way that maximizes benefit. Younger, non-obese individuals may not have a significant senescent cell burden and thus may not need aggressive senolytic therapy before contemplating NAD+ restoration”.   These are excellent recommendations.   IF A PHYSICIAN WHO IS ADMINISTERING NAD+ IS NOT ADDRESSING THE SENESCENT CELLS PROBLEM THAN I SUGGEST THE PATIENT SEEK TREATMENT ELSEWHERE. YOUR HEALTH IS AT STAKE!!! Thanks, Dr. P

At one time it was thought that there was little if any relationship between Senescent Cells and NAD supplements. We now know that this is far from the truth. Remember that the senescent cells are cells that should have died but continue to survive. By surviving they cause a multitude of problems. Senescent cells are believed to contribute to numerous age-associated diseases. Senescent cells are becoming a hot topic in the field of Regenerative Medicine. We now know they may be responsible for many of the failures in cellular therapy. Senescent cells are believed to contribute to numerous age-associated diseases. By the same token we now know that NAD, the supplement, is extremely important in general well-being and success in cellular therapy.   Below we see diagrams concerning Senescent cells. The two above diagrams represent the essence of Senescent cells (Please see some of my previous blogs concerning Senescent cells).Unfortunately, many of the effects of the Senescent cells are found in the dark side of the first diagram. The elimination of Senescent cells by senolytic regimens (programs designed to kill senescent cells) appears to help in numerous aging-associated diseases including atherosclerosis, pulmonary problems, diabetes, neurological problems, cancer and osteoarthritis. Senescent cells secrete pro-inflammatory factors which are called Senescence-Associated Secretory Phenotype (SASP). These are essentially the “bad growth factors”. By the mechanism of the inflammatory growth factors, the Senescent cells are believed to contribute to numerous age-associated diseases. The second diagram shows the causes of cell senescence. These causes of cell senescence are essentially the causes of aging. We can see that the causes are multiple. The causes involve the usual suspects including DNA damage, mitochondrial damage, damage to the ends of the DNA called the telomeres, and finally what we call epigenetic factors.Epigenetic factors have far reaching effects. They involve changes to gene expression that our cells experience as we get older. These are commonly called epigenetic alterations. The following diagram demonstrates these facts.There are many factors that can affect the genes. The diagram shows some of the examples. These genetic alterations harm the fundamental functions of our cells and can increase the risk of cancer and other age-related diseases. The DNA is affected by the inflammatory cytokines secreted by the Senescent cells. These secretions are modifying gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands. The genes which are turned on the cell can either be a friend or a foe. It can help prevent a cancer or help cause it. Here are two recent articles from two reliable sources concerning senolytic agents. As you can see Senescent cells are not some esoteric idea. They are becoming mainstream medicine. We are acutely aware of the importance of senolytic agents for overall health. They seem to be very important in NAD therapy also. Here are the articles: There is one other article which I will share with you which is more scientific discussing the Senescent cell problem.So, the real question is what do Senescent cells and NAD have to do with each other? Furthermore, are their paths on a collision course?Now I would like to discuss the collision course that NAD and Senescent cells are on. Recently I read a scientific article that was quite fascinating and thought provoking. The article discussed the ramifications of taking NAD+ supplements and their effect on Senescent cells. Let us do a quick review of NAD. NAD+ is a potent stimulator of the SIRT-1 gene pathway. This pathway is thought to be one of the major anti-aging pathways. This is the pathway that many people are familiar with by the effects of the compound Resveratrol which is found in red wine. Other methods of stimulating this pathway include calorie restriction, intermittent fasting, keto diet, high intensity exercise training, and perhaps most importantly NAD.  When all is said and done the Sirtuin pathway stimulates the production and efficiency of the mitochondria which provide the cells with energy. Typically, the more mitochondria the healthier the cell and for that matter the healthier the person.From the point of view of anti-aging, NAD has tremendous potential. However, it seems that NAD may act as a double edge sword as we get older. There is no doubt that we become deficient in NAD as we age. The reason for this is multifocal. One important reason is that certain enzymes in our body become large consumers of NAD. Some of these enzymes are involved in the process of repairing DNA damage. If there is not enough NAD to go around than the NAD gets shuffled to the cells where it is an absolute necessity or the cells die. However, the consuming enzymes continue to try to utilize NAD but they will unfortunately not be able to accomplish DNA repair. If we are able to consume adequate amounts of NAD these enzymes get turned back on and do their important repair work. We are able to increase the amount of NAD available to the body by a variety of methods. One of the secret weapons we utilize is an NAD kinase patch. The NAD kinase patch contains an enzyme, NAD kinase, and penetrating molecules. This combination will dramatically increase the amount of NAD that enters the cell. As we age, we become deficient in the NAD kinase enzyme. This enzyme is the cutting edge of the cutting-edge technology especially when it pertains to NAD administration. It allows greater amounts of NAD to enter the cell. So far all seem good except for one detail. Both myself and my wife take NAD on a daily basis. We occasionally use the Kinase patches. We are doing this to hopefully “slow down” our aging. On the surface this makes perfect sense, yet some of the newest thinking demonstrates some potential problems when dealing with NAD administration. There is no doubt that I have Senescent cells in my body (recently I did a once a week x 2 regimen of Senolytic agents which has had some surprising beneficial effects). In the article I was referring to, on one hand it stated that the NAD+ levels decrease as we age leading to degenerative conditions. While at the same time, the number of senescent cells will increase with aging. The article states that decreased NAD+ levels that are associated with aging may actually decrease the effects of the senescent cells on the body. Conversely increasing NAD+ levels by supplementation either orally or intravenously or both methods may benefit tissue homeostasis, but also may worsen SASP and make the make the Senescent cells more aggressively inflammatory. This is certainly not a good thing. TAKEN TOGETHER THESE FINDINGS SUGGEST A FUNDAMENTAL TRADE-OFF IN TREATING AGING RELATED DISEASES WITH DRUGS OR SUPPLEMENTS THAT INCREASE NAD+. So, the bottom line is that we are increasing NAD levels which is a good thing but at the same time we are also making the Senescent cells increase the secretion of the inflammatory growth factors which is a bad thing.Another concern is a report that senescent cells can induce a cell surface protein called CD-38 on macrophages (a type of white blood cell in the immune system) and endothelial cells (Endothelium refers to cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall).  CD-38 is a molecule important for many different cellular processes, including calcium signaling, which regulates basic cell functions. CD-38 is the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, CD-38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases. However, too much CD-38 is a sign of inflammation. Research has linked overexpression of CD-38 to obesity, cancer, and infectious diseases, like HIV. Both the decline in NAD+ and the presence of Senescent cells are hallmarks of aging. We are aware that a supplement called Apigenin seems to help block the effects of CD-38. (Apigenin is found in many fruits and vegetables, but parsley, celery, celeriac, and chamomile tea.  Apigenin is particularly abundant in the flowers of chamomile plants). Apigenin may eventually be part of a regimen when administering NAD.Until recently, it was unclear exactly how rising CD-38, declining NAD+, and the presence of senescent cells were all related. Scientists also know that the presence of CD-38 levels increase with age, and that CD-38 is involved in lowering NAD+ levels. It is a major consumer of NAD. In turn increased CD-38 expression is believed to be the key modulator of lowered NAD+ levels with aging in mammals. CD-38 is intimately related to our immune system but unfortunately not in a good way.   In the following diagram, we see that the inflammatory growth factors from Senescent cells have a direct effect on what is called an M-1 macrophage. This is a type of white blood cell which is many times associated with inflammation in the body. Not a big problem when we are dealing with bacteria but not good for anti-aging.The accumulation of Senescent cells may itself be an important safeguard causing decreased NAD+ levels which in turn could promote a multitude of problems. On the other hand, the lower NAD+ levels may diminish the influence of Senescent cells which is the safeguard. What the scientists found was two-fold: First, they observed that inducing senescence did not lead the senescent cells themselves to produce more CD38. But, the senescent cells did, as expected, begin secreting a cascade of inflammatory chemicals that in turn, up-regulated CD38 in surrounding non-senescent cells. In other words, they infected normal cells much like a zombie infects normal people. Interestingly, they found that different inflammatory factors did not individually increase CD-38, but when combined led to a strong increase in CD-38 activity. In the end, the scientists observed this affect in all the types of cells tested. We are aware that Quercetin and Apigenin are two supplements that can diminish CD-38 effects. These also act as senolytic agents. As a matter of fact, Quercetin is found as a senolytic agent in many University studies. In these studies, Quercetin is combined with Dasatinib to act as a super senolytic agent. Dasatinib is a Leukemia medication that is being used “off-label”. Because the dosages are extremely small the side effects are minimal. The elimination of most senescent cells by senolysis (the killing of senescent cells) before initiating NAD+ therapies may be beneficial and increase safety. There is the possibility that it may eventually allow for need for little IV therapy and mainly rely on oral medication. I think to treat the patient with some form of senolytic agent prior to NAD therapy may possibly the new standard of care for patients receiving NAD therapy. Unless we address the Senescent cell/CD-38 problem, trying to raise NAD+ levels with precursors may come with too many downsides, preventing us from both having our cake and eating it too. So, what is the real bottom line? We strongly feel that    Senolytic agents are imperative when using NAD+ intravenously or orally. Actually, I think they have a place in almost everyone. We want to diminish Senescent cells and their inflammatory growth factors and at the same time increase cellular NAD levels. Luckily, we have been aware of the Senescent cell problem some time now. We have been treating our patients with a number of different senolytic agents for some time. Some of these have included a P-53 patch, certain supplements such as Quercetin, even utilizing Quercetin and Dasatinib together. We have worked out very specific regimens for this. If a physician is not taking steps to deal with Senescent cells his overall chance of success will be much lower in Regenerative procedures and overall patient health. Furthermore, there is the possibility that the patient’s overall health may take a turn for the worse in the long run by increasing the effects of the senescent cells.   Here is the bottom line from an article I read “reducing the senescent cell burden in persons around age 60 and middle-aged obese individuals may become a critical step in restoring youthful NAD+ cellular levels in a way that maximizes benefit.Younger, non-obese individuals may not have a significant senescent cell burden and thus may not need aggressive senolytic therapy before contemplating NAD+ restoration”.   These are excellent recommendations. IF A PHYSICIAN WHO IS ADMINISTERING NAD+ IS NOT ADDRESSING THE SENESCENT CELLS PROBLEM THAN I SUGGEST THE PATIENT SEEK TREATMENT ELSEWHERE. YOUR HEALTH IS AT STAKE!!!Thanks,Dr. P

Once in a while I like to write a blog that is not all science! I must say that I was initially a bit intimated by my schedule. I left Miami on Thursday evening, arriving in Sao Paulo 8 hours later on Friday morning. Interestingly, there were a number people that I knew at the meeting.  I have taught in Brazil on numerous occasions.  I will return in October to teach a course.  I received a warm Brazilian welcome.  I was very impressed by the quality of the meeting and the speakers.  I felt honored to be one of the Keynote speakers. My talk was an interesting one.  I discussed Stem Cell Aging Pathways.  As I have said “how Stem cells age is how we age”.  In my journey thru the world of Regenerative Medicine I have become convinced that these pathways may be the Holy Grail for Anti-Aging methods.  These pathways are what I call the upstream causes of aging.  If we correct these problems in the pathways we will affect downstream problems.  One pathway I stressed was the Sirtuin Gene pathway.  I discussed its dependence upon the supplement NAD and other methods of stimulating this pathway.  I mentioned our experiences with Intravenous NAD and one of our secrete weapons which is the NAD kinase patch.  I received a number of questions from the audience. One exciting aspect of the talk involved the introduction of some brand-new technology.  Actually, I have used this technology for years.  This technology involves transdermal patches which introduce signaling molecules to spine, tendons and joints.  These are called P3 AI and P3 R patches.  The name for this technology is SIGMOLECS.   This will be a quantum leap for many regenerative physicians. They now have technology that we have utilized for years.  These patches are now registered with the FDA.  Below is a picture of the packaging of the patches. I suspect this will become an integral aspect of most regenerative procedures.  Signaling molecules tell cells what to do and when to do it.  This is essentially the basis of a PRP preparation and a branch of medicine called Cytokine Therapy. This technology seemed to be well received by the audience.   Unfortunately, my time in Sao Paulo was very limited and later that afternoon I found myself in another 2-hour traffic jam on my way back to the airport facing my second night in a row on an airplane. After a 12-hour plane ride I arrived in Beverly Hills California where the Cell Surgical International Conference was being held. My lecture this time concerned the nuts and bolts of Regenerative Medicine as it pertains to stem cells.  I stressed the basic science but put a twist on it to show how if one knows the basic science he then has the intellectual tools to make procedures better. This is the essence of a new field of medicine called Translational Medicine.  Translational Medicine is a rapidly growing discipline in biomedical research and aims to expedite the discovery of new diagnostic tools and treatments by using a multi-disciplinary, highly collaborative, "bench-to-bedside" approach.  The lecture was a whirlwind of slides.  I showed how the immune system and the stem cells are so intimately related.  Hopefully I opened up a few eyes on these topics.  There were many different topics covered in the meeting all of which were engrossing.  Some of the topics covered musculoskeletal conditions while other dealt with neurological conditions. One of my friends, Dr. Nathan Bryant, who is a world leading expert in Nitric Oxide medicine gave a great slide that reminds me of my journey in Regenerative Medicine.  It is as follows “All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.”  - Arthur Schopenhauer   I always learn something from a meeting that I lecture at.  At this meeting I met many old friends and some new ones. My staff from the Cayman Islands attended the meeting: All-in-all, it was a hectic weekend but it was rewarding on many different levels.  I enjoy teaching and the comradery of the meetings. BTW people are asking me if I had Jet Lag.  The answer is a resounding, "no."  By using my laser watch, jet lag is never an issue for me.  The laser wrist watch helps my body produce various compounds which helps my body fight jet lag. Thanks, - Dr. P

Once in a while I like to write a blog that is not all science! I must say that I was initially a bit intimated by my schedule.I left Miami on Thursday evening, arriving in Sao Paulo 8 hours later on Friday morning.Interestingly, there were a number people that I knew at the meeting.  I have taught in Brazil on numerous occasions.  I will return in October to teach a course.  I received a warm Brazilian welcome.  I was very impressed by the quality of the meeting and the speakers.  I felt honored to be one of the Keynote speakers.My talk was an interesting one.  I discussed Stem Cell Aging Pathways.  As I have said “how Stem cells age is how we age”.  In my journey thru the world of Regenerative Medicine I have become convinced that these pathways may be the Holy Grail for Anti-Aging methods.  These pathways are what I call the upstream causes of aging.  If we correct these problems in the pathways we will affect downstream problems.  One pathway I stressed was the Sirtuin Gene pathway.  I discussed its dependence upon the supplement NAD and other methods of stimulating this pathway.  I mentioned our experiences with Intravenous NAD and one of our secrete weapons which is the NAD kinase patch.  I received a number of questions from the audience. One exciting aspect of the talk involved the introduction of some brand-new technology.  Actually, I have used this technology for years.  This technology involves transdermal patches which introduce signaling molecules to spine, tendons and joints.  These are called P3 AI and P3 R patches.  The name for this technology is SIGMOLECS.   This will be a quantum leap for many regenerative physicians. They now have technology that we have utilized for years.  These patches are now registered with the FDA.  Below is a picture of the packaging of the patches.I suspect this will become an integral aspect of most regenerative procedures.  Signaling molecules tell cells what to do and when to do it.  This is essentially the basis of a PRP preparation and a branch of medicine called Cytokine Therapy.This technology seemed to be well received by the audience.   Unfortunately, my time in Sao Paulo was very limited and later that afternoon I found myself in another 2-hour traffic jam on my way back to the airport facing my second night in a row on an airplane.After a 12-hour plane ride I arrived in Beverly Hills California where the Cell Surgical International Conference was being held.My lecture this time concerned the nuts and bolts of Regenerative Medicine as it pertains to stem cells.  I stressed the basic science but put a twist on it to show how if one knows the basic science he then has the intellectual tools to make procedures better. This is the essence of a new field of medicine called Translational Medicine.  Translational Medicine is a rapidly growing discipline in biomedical research and aims to expedite the discovery of new diagnostic tools and treatments by using a multi-disciplinary, highly collaborative, “bench-to-bedside” approach.  The lecture was a whirlwind of slides.  I showed how the immune system and the stem cells are so intimately related.  Hopefully I opened up a few eyes on these topics.  There were many different topics covered in the meeting all of which were engrossing.  Some of the topics covered musculoskeletal conditions while other dealt with neurological conditions.One of my friends, Dr. Nathan Bryant, who is a world leading expert in Nitric Oxide medicine gave a great slide that reminds me of my journey in Regenerative Medicine.  It is as follows“All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.” – Arthur Schopenhauer I always learn something from a meeting that I lecture at.  At this meeting I met many old friends and some new ones.My staff from the Cayman Islands attended the meeting:All-in-all, it was a hectic weekend but it was rewarding on many different levels.  I enjoy teaching and the comradery of the meetings.BTW people are asking me if I had Jet Lag.  The answer is a resounding, “no.”  By using my laser watch, jet lag is never an issue for me.  The laser wrist watch helps my body produce various compounds which helps my body fight jet lag.Thanks, – Dr. P

Osteoporosis is a disease that weakens bones to the point where they break easily—most often, bones in the hip, spine, and wrist. Osteoporosis is called a “silent disease” because you may not notice any changes until a bone breaks. All the while, though, your bones had been losing strength for many years. Some risk factors for osteoporosis such as being older and female or having a family history of the condition cannot be avoided. But others can, like smoking cigarettes, consuming alcohol, taking certain medications, or being exposed to environmental pollutants. But until now researchers haven't gained a firm picture of how these exposures link up with bone loss. But now the fog is begging to lift. We now know that these environmental hazards seem to affect a very important of genes called the Sirtuin genes which ultimately affect the mitochondria. Recently, in my reading I discovered some very interesting articles. It now appears the one of the main causes of Osteoporosis may be damage to mitochondria. The mitochondria are the powerhouses of the cells. They help produce energy of the cell in the form of ATP. We are now aware that many of the diseases of aging are related to mitochondria damage and degeneration. The following is a diagram of the mitochondria and its relationship to the rest of the cell. It seems that when mitochondria are damaged it will lead to a surge in a cell type called an osteoclast. An Osteoclasts is a cell that nibbles at and breaks down bone and is responsible for bone resorption. Recent animal studies indicate that longevity-associated Sirtuin genes (especially the SIRT1 gene) may serve as an attractive pharmacological target for the treatment of osteoporosis and other bone related disorders. Now let us talk a bit about the Sirtuin genes of which SIRT1 is a very important member. The Sirtuin genes are also called the longevity genes. There are seven of these genes which are intimately involved in mitochondrial health and numbers.  They have a profound effect on many of the different aging pathways in the body. One extremely important fact is that they seem to influence mitochondrial health and numbers. Healthier and increased numbers of mitochondria ultimately lead to more ATP production. Furthermore, we are now aware of the fact that mitochondria do many other tasks other than producing ATP. They may act as signaling beacons directing different cells to different tasks. A new study led by researchers from Penn's School of Veterinary Medicine reveals a mechanism by which Sirtuin factors and osteoporosis may be linked. Damage to mitochondria—key cellular organelles and energy generators—leads to a surge in the creation of cells called osteoclasts, which are responsible for breaking down bone. The researchers reported these findings in the FASEB journal (Federation of American Societies for Experimental Biology). Here is a quote from the paper “ In a normal individual, the process of bone degradation and rebuilding proceeds in a very balanced way, but in some people they somehow produce a lot more osteoclasts, and this leads to bone loss and osteoporosis," said Narayan Avadhani, a biochemist at Penn Vet and senior author on the work. "We show in this paper that, when mitochondrial function is affected, it not only affects energy production but also triggers a type of stress signaling that induces the overproduction of osteoclasts.”   This is consistent with other findings that mitochondria are involved in much more than energy production. For instance, we know that mitochondria can be involved in neurogenesis signaling. The paper goes on to say that affecting mitochondrial function will trigger a type of stress signaling that induces the overproduction of osteoclasts which are the cells that nibble away on the bone. It appears that the mitochondria effect a certain type of immune cell called a macrophage. Macrophages are a front line for the immune system, engulfing and digesting foreign invaders to the body. Macrophages are very important cells of the immune system. They have the ability of morph into many different types of cells. Depending upon their environment they can cause tissues to heal or encourage the breakdown of tissue. Macrophages can diversify and transform into osteoclasts when the circumstances are right. This research was performed at Mount Sinai School of Medicine. In this study when the mitochondria were damaged the macrophages underwent stress signaling and transformed into osteoclasts at a much faster rate. We now see that relationship between environmental factors and Osteoporosis may be related to mitochondrial damage.   There are other studies which show a distinct relationship between the Sirtuin genes and Osteoporosis. This makes complete sense given the fact that the Sirtuins and Mitochondria are intimately related. WHAT TIES EVERYTHING TOGETHER? NAD! NAD stands for nicotinamide adenine dinucleotide. It is a potent stimulator of the Sirtuin genes especially SirT1. The diagram below is an excellent illustration of this relationship.   We want to block the bone eating osteoclasts and encourage the bone building osteoblasts.     Another good example of this phenomenon is the following illustration of a human thigh bone.       In this diagram we see what seems to cause bone formation by the stimulation of Osteoblasts (CR stands for Calorie Restriction). An agonist is a compound that encourages action. Some of the agonists of the SIRT1 genes include Resveratrol, Pterostilbene, and a host of other phytonutrients. We can also see that calorie restriction and the Keto diet should also have a beneficial effect on osteoporosis. I would like to show an article published this month on just what we are talking about. Here is a picture of the front page of the article       This article is one of many ground-breaking articles. It appears that compounds that target the SIRT1 gene (THINK NAD etc.) may be new SAFE WEAPONS in the war on Osteoporosis. A similar study from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences confirmed the same findings. Their conclusion “Our findings suggested the potential therapeutic role of resveratrol in osteoporosis treatment and stressed the importance of effective doses when applied”. We are now aware that NAD+ is a game changer on many different levels but there is good scientific evidence that it can have a profound effect on Osteoporosis. One step we are already doing for osteoporosis is using peripheral blood stem cells and cytokine therapy to help improve osteoporosis.   But wait there is one more aspect in our treatment protocol. This is the aspect of Senescent cells. These are cells that should have died but continue to survive. They cause havoc on the body by their secretion of various “bad growth factors.       In the above diagram SC stands for a senescent cell.   A senolytic is a compound that kills the senescent cells. More can be found about these cells at my recent blog  https://stemcellorthopedic.com/possible-new-way-treating-osteoarthritis-senolytic-agents/).     Mayo Clinic researchers in Rochester, Minnesota, have found that targeting senescent cells led to an increase in bone mass and strength. The findings, titled “Targeting cellular senescence prevents age-related bone loss in mice” appear online in the August 21, 2017 edition of Nature Medicine. Here is a paragraph from their work:   "While we know from previous work that the accumulation of senescent cells causes tissue dysfunction, the role of cell senescence in osteoporosis up to this point has been unclear," says Sundeep Khosla, M.D., director of the Aging Bone and Muscle program at Mayo Clinic's Robert and Arlene Kogod Center on Aging and a co-author on the study, in the August 21, 2017 news release. "The novelty of this work for the bone field lies in the fact that, rather than targeting a bone-specific pathway, as is the case for all current treatments for osteoporosis, we targeted a fundamental aging process that has the potential to improve not only bone mass, but also alleviate other age-related conditions”.   I think the above paragraphs are the essence of our approach in targeting Osteoporosis. We are targeting the UPSTREAM AGING EVENTS which lead to Osteoporosis. I believe our approach is totally unique and unlike any other program in the world. Our approach is multi-fold: Targeting of senescent cells Using peripheral blood stem cells which have been shown to give improvements in Osteoporosis Utilizing initially IV loading doses of NAD+ with the NAD Kinase patches and then maintaining NAD levels with oral formulations which are typically higher doses than usually recommended.   Utilizing various supplements which also target the Sirtuin genes. Proper diet and exercise also are important.     This regimen is unique and at the same time seems to have an excellent safety profile especially when looking at the side effects of various Osteoporosis medicines. Furthermore, this regimen also has significant anti-aging benefits.   Thanks, - Dr. P

I think we need to look at senescent cells in a bit more depth.I have written about Senescent cells in the past.   I have been aware of senolytic agents for a few years now. Actually, I wrote a blog about this back in 2017 which can be found here (https://stemcellorthopedic.com/possible-new-way-treating-osteoarthritis-senolytic-agents/). I am convinced that senolytic agents will help change the face of regenerative medicine and for that matter most of medicine. More importantly they will dramatically increase success in Regenerative procedures. Let us again discuss senescent cells. These are cells that should have died but did not. There are a number of studies in the field of osteoarthritis and its relationship to senescent cells. Eliminating a portion of these cells may produce significant results! Osteoarthritis is but one disease of aging. There seems to be great promise of senolytic agents in combating degenerative conditions. The following diagram gives us an idea of the damage that these cells can cause. I found an excellent diagram from a site called CellAge This diagram hits upon the highlights of senescent cells.   The essence is that they are producing growth factors that are causing havoc on other neighboring cells. In the preceding diagram we get a true appreciation of clinical significance of Senescent cells. Once they reach the senescent stage they stop replicating but continue to survive. In the above diagram we see initially the cells have some sort of trigger which causes them to switch to senescence. Once they are in the senescence mode bad things begin to happen. These cells begin to send out signaling molecules called cytokines. These cytokines have far reaching effects. Under normal circumstances the cells of the immune system will attack the senescent cells and destroy them. Actually, these cells will also stimulate a process called Autophagy. Autophagy is an important aging pathway in the body. It is the method that the body will recycle various cellular parts into new cells. Autophagy by itself has significant ramifications in anti-aging and overall health. Eliminating the senescent cells will stimulate autophagy in the right circumstances. Unfortunately, many times the senescent cells escape detection, they increase in numbers and become like terrorists in our body. They will cause havoc to other cells. Senescent cells look very different from healthy cells. They express different genes, they are prohibited from reproducing or dividing naturally, and they pump out inflammatory “SOS” signals in an attempt to recruit other healthy cells to come to their rescue, usually in vain. These signals include proinflammatory cytokines, chemokines, proteases (enzymes that break down proteins) and other factors that together make up what is called the senescence-associated secretory phenotype (SASP). The inflammation created by senescent cells can lead to tissue dysfunction and even turn healthy cells senescent, like a zombie virus that spreads and eventually causes the zombie apocalypse of late-life frailty and disease. This spreading of cellular senescence may even happen at a distance, with senescent cells in one tissue, like fat, spreading senescence-causing inflammatory signals to cells in another tissue, like muscle. This is why a pendulous belly can be so detrimental to our health. The agents that go after senescent cells are called a senolytic agents. The breakdown of the word senolytic is as follows: seno refers senescent cells while lytic refers to lysis which means to rupture the cell. So, a senolytic agent is one that kills the senescent cell. One exciting aspect of our treatment protocols is employing the use of P-53 protein transdermal patch. P-53 in our body is a very potent senolytic agent. unfortunately, it sometimes undergoes a mutation and loses its effectiveness leading to some big problems such as cancers. Another name for the P-53 is “the tumor suppressor gene”. P-53, unlike other agents, can actually repair the cell under the right circumstances. It will analyze the cell and proceed with DNA repair if the damage is not too great. However, if the P-53 determines that the DNA damage is too great it will disable the cell and cause it to go on to death. The P-53 is beneficial in ferreting out senescent cells that may lead to cancers. Unfortunately, as we age the P-53 may undergo mutation and lose its effectiveness. This loss of effectiveness may lead to the development of a cancer. The following diagram shows the P-53 agent in action. More information on P-53 can be found in a recent blog https://stemcellorthopedic.com/elephants_longevity_p53/ The P-53 patch is quite revolutionary. It is definitely part of our armamentarium in our anti-aging.  We have had excellent success with the P-53 patches. However, not wanting to rest on our laurels we want to take the treatment of senescent cells down a second road to use in conjunction with the P-53 transdermal patch.   The next diagram shows senolytic agents in action. We can see when the senescent cells accumulate they wreak havoc causing cancer, aging, osteoporosis, osteoarthritis and a host of other degenerative diseases.     We can definitely see the benefits when the senescent cells are cleared away. We also see that the immune system is instrumental in clearing away the senescent cells. It stands to reason that clearing away these cells will lead to anti-aging and most likely better success in Regenerative Medicine which employs stem cells and other regenerative cells.   Senescent cells, however, are not all bad, and evidence shows that they play a role in cellular reprogramming and wound healing. Like all things in biology, it is therefore clearly a question of balance: too much clearance of senescent cells would be bad for wound healing and cellular reprogramming, but too many senescent cells lead to damage. I would like to present a short article that was recently published concerning the use of Senolytic agents, in this case, in pulmonary disease.   Small Pilot Study Points to Feasibility of Larger Trials in Age-Related Diseases Senolytics target cellular senescence, a process in which damaged cells, rather than dying, persist and become toxic to cells around them. Cellular senescence has been shown to drive multiple age-related diseases, including idiopathic pulmonary fibrosis (IPF), a chronic, irreversible and progressive disease that results in scarring of the lungs. In animal studies, run by Mayo Clinic collaborators James Kirkland, M.D., Ph.D.; Nathan LeBrasseur, Ph.D., M.S., and Tamara Tchkonia, Ph.D., senolytics selectively cleared these toxic cells in mice that model IPF. A Lethal Disease for Which There are Few Options "IPF is a devastating and progressive fibrotic lung disease with a median survival of less than five years in newly diagnosed adults usually over 60 years of age," said Anoop M. Nambiar, M.D., M.S., associate professor of medicine at UT Health San Antonio and founding director of the university's Interstitial Lung Disease Program, one of 60 Pulmonary Fibrosis Foundation Care Centers in the United States. Dr. Nambiar is co-first author of the research manuscript and enrolled 12 of the patients at UT Health San Antonio and the South Texas Veterans Health Care System. Despite the current availability of two U.S. Food and Drug Administration-approved therapies that may slow down disease progression in some IPF patients, the prognosis remains poor and is worse than for many common cancers, Dr. Nambiar said. Lung transplantation may be lifesaving, but often is only an option for younger, healthier patients. "There remains a significant unmet need for safer and better treatments for patients with IPF," Dr. Nambiar said. Patients Enrolled in Texas, North Carolina In this first-in-human pilot study, the investigators enrolled 14 older adults diagnosed with stable, primarily mild-to-moderate IPF. Participants were enrolled at both UT Health San Antonio, which served as the primary patient recruitment site, and Wake Forest medical school, which initiated the trial and served as the study coordinating center. "Though small, this pilot study marks a major breakthrough in how we treat age-related diseases such as IPF," said Jamie Justice, Ph.D., assistant professor at Wake Forest medical school, co-lead investigator and corresponding study author. "Here, we've therapeutically targeted a fundamental biological hallmark of aging that is implicated in IPF, and we show early but promising results for the first time in human patients. This small study represents a major paradigm shift in treatment strategy." Each participant received two senolytic drugs, dasatinib and quercetin (DQ), taken by mouth for three consecutive days each week for three consecutive weeks (nine doses total). All patients were able to comply with this regimen without any discontinuation of the study drugs. The research team measured clinical laboratory chemistries before and after DQ administration, and performed rigorous symptom questionnaires weekly of health, quality of life and side effects to obtain preliminary evidence of safety and tolerability. The team also evaluated markers of physical function including six-minute walk distance, walking speed, sitting-to-standing repetitions, a frailty index based on clinical laboratory chemistries, and biological assays of senescence-associated proteins secreted by the toxic cells. Results The most consistent improvements following senolytic therapy were observed in participants' mobility. The six-minute walk test, timed sitting-to-standing repetitions and other measures were significantly improved after completion of the treatment. The majority of patients exhibited mobility gains of greater than 5 percent. Other physical function markers, including grip strength and pulmonary function testing, did not change. "No drug therapies, including the available anti-fibrotic drugs, have ever shown to stabilize, let alone improve, an IPF patient's six-minute walk distance," Dr. Nambiar said. "But in this pilot study of DQ, participants' six-minute walk distance improved an average of 21.5 meters. "We should be cautious about whether this finding is true based upon this small study without a placebo control group," Dr. Nambiar said. "However, this and other results warrant further study in larger randomized, controlled trials." Preliminary but Encouraging "Cellular senescence is clearly emerging as a main player in aging," said manuscript co-author Nicolas Musi, M.D., professor of medicine at UT Health San Antonio and director of the university's Sam and Ann Barshop Institute for Longevity and Aging Studies. "Previously, no published data existed to demonstrate that drugs targeting cellular senescence could be safely given to older patients, or that they might be used to treat diseases of aging such as IPF. The pilot research we've reported is preliminary but encouraging." Dasatinib and quercetin are U.S. FDA-approved for other indications. Moreover, they are effective in eliminating senescent cells originating from different cell types. "This is the same combination of drugs that was shown to improve pathology in animal models of Alzheimer's disease, which our group, including Dr. Miranda Orr at UT Health San Antonio, demonstrated three months ago for the first time," Dr. Musi said. Side Effects Did Not Discontinue the Treatment The most frequent side effects reported after DQ therapy were mild to moderate in severity, including respiratory symptoms such as cough and shortness of breath, and gastrointestinal discomfort or heartburn. Some patients reported skin irritation or bruising related to tissue biopsies obtained for biological measurement purposes. Limitations and Goals This pilot study has obvious limitations. First, it was small (14 patients), and substantially larger numbers of research participants are needed to definitively evaluate change in biological markers of cellular senescence. In addition, the study did not enroll a control group of IPF patients who took a placebo rather than the senolytic. "Therefore, any improvements in physical function should be interpreted with caution and require further study," Dr. Nambiar said. Materials provided by University of Texas Health Science Center at San Antonio. Note: Content may be edited for style and length. What we gather from this note is that senolytic agents seem to have a very beneficial effect on the senescent cells. Which in turn effects the patient’s health. We should realize that this benefit most likely carries over to all types of senescent cells. Here is the significance this has on clinical practice. Very few if any doctors, clinics etc are addressing senescent cells. I suspect a good bit of the problem is they are not acutely aware of them and their significance. THIS WILL BE THE NEXT BIG ASPECT OF REGENERATIVE MEDICINE. We are already entrenched in treating senescent cells. We have been utilizing the P-53 patches on some of our patients. Now we are going to take the next step. We have found a source of Quercetin which was fairly easy. The difficult aspect was to find a source of Dasatinib. Luckily, we were successful in this regard. The last piece of the puzzle was figuring out the protocol for dosage regimen.   We have now put a very unique protocol together utilizing the P-53 patches, Quercetin and Dasatinib. Typically, the treatment regimen will be one dosage a week  for either two or three weeks. Taking senolytic agents for a long period of time can have a detrimental effect on the body. It could actually speed up aging if not done properly. Hence a regimen of only 2 or 3 per year. Senolytic therapy has not only demonstrated profound             rejuvenating properties by itself, but may also help open up opportunities for other rejuvenation strategies to be more effective. It is but one step in our anti-aging protocols. When used with some of our other regimens we feel we have one of the most unique Regenerative and Anti-aging programs around. With time I am sure other progressive clinics will catch on to the topics of senolytic agents.   Thanks, - Dr. P  

We recently received a letter from the Florida Dept. of Health. A copy of this letter is below.   In the letter it states that any patient who received a Liveyon product should be tested for a host of different potential problems such as HIV, Hepatitis, Syphilis, and a host of other serious viral infections. To refresh the minds of everyone, Liveyon is a producer of cord blood products which the FDA has called on the carpet for contaminated products and the lack of a biologics license.  How this company and similar other ones still remains in business is beyond me!  Please read the letter and draw your own conclusions.   REMEMBER YOUR OWN CELLS DO NOT POSE THE RISK OF THESE DISEASES UNLESS YOU ALREADY HAVE THEM!   - Dr. P         February 22, 2019 Dr. Joseph Purita Institute of Regenerative Medicine 200 Glades Rd., Suite 1 Boca Raton, FL 33432   Dear: Dr. Purita The Florida Department of Health (Florida Health) is working with the Centers for Disease Control and Prevention (CDC) on an investigation of bacterial infections linked to contamination of an umbilical cord blood-derived stem cell product from the ReGen Series (distributed by Liveyon, LLC). You may already be aware of Liveyon's recall of this product issued on September 28, 2018 (www.fda.gov/Safety/Reca11s/ucm623039.htm). [YOU or CLINIC] have been identified as receiving shipment(s) of this product and possibly administering it to patients. The CDC and the U.S. Food and Drug Administration (FDA) have received reports of patients developing bacterial infections of the joints, bloodstream, or spine, among others, after receiving the ReGen Series products. Additionally, an inspection of the processing facility by the FDA identified deviations in the requirements for processing these products, and for the testing and screening of the umbilical cord blood donors for these products for the following communicable diseases:   • Human immunodeficiency virus (HIV) • Hepatitis B virus • Hepatitis C virus • Syphilis • Cytomegalovirus • Human T-lymphotropic virus 1/11 • West Nile virus • Zika virus An FDA warning letter issued to the manufacturer outlines these deviations: (www.fda.gov/lCEC I/EnforcementActions/Warn ingletters/ucm628019. htm ). We are not currently aware of any HIV, hepatitis B, or hepatitis C infections linked to the ReGen Series products and transmission risk is very low. However, Florida Health is requesting that you notify all of your patients who received this product at Institute of Regenerative Medicine that they should consider being tested for HIV, hepatitis B virus, hepatitis C virus, and possibly for the other infections listed above after discussion with their health care providers. A template letter is available for your use to notify patients and can be provided upon request. If you believe you have a patient who has had a bacterial or other infection related to the administration of this product, please notify the Health Care-Associated Infection Prevention Program at 850-245-4401 or email [email protected] If you have any remaining product, please do not administer it to patients and contact us to receive further instructions. If you have any questions about talking to your patients or anything else regarding this letter, please do not hesitate to contact us.   Sincerely, Russell W. Eggert, MD, MPH, FACPM, FAAFP Chief Bureau of Epidemiology

  When I see many different advertisements from different “anti-aging” clinics, I sort of chuckle a bit.  There is no doubt that these clinics are helping many patients, but quite honestly, they are usually not doing anything that is a game changer. They will often concentrate on correcting hormonal imbalances, and at the same time, attempt to correct some problems with a variety of supplements.  I am guilty of this on myself, and so are many of my stem cell patients.  I take a handful of supplements every day to try an fend off aging, or at least slow it down.  The problem with many supplements is that they have poor absorption.  On paper they should work, but in real life they have some effect. Many times the effect is not as much as we like.  It is well documented that many of these compounds could at least slow down the clock of aging, but the real question is -- even if we increase the absorption, will it be a game changer?  The simple answer is -- probably not, but there may be two big exceptions.  These exceptions might be NAD/NADH and another compound called P-53.  I would like to discuss NAD in this blog.   If we look at the above diagram we can see that most of the major perimeters of anti- aging are found here.  We want to increase longevity.  What can help increase longevity?   We increase longevity by giving the cells more energy, increasing their telomere length, boosting the immune system, repairing DNA, and stimulating certain genes which foster longevity. One compound which is attracting much attention is NAD/NADH.  NAD stands for Nicotinamide adenine dinucleotide (NAD). It is 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.  It would seem simple enough to just replace the levels to keep things working at an appropriate level.  Just exactly what does NAD seem to effect in the body?  The simple answer is that it effects the mitochondria.  The mitochondria are the power houses of the cell.  Mitochondria seem to misbehave as we age.  They ultimately decline in their function and cause us to age. A prominent theory of aging holds that decaying of mitochondria is a key driver of aging.  NAD deficiencies are thought to lead to a multitude of problems stemming from heart disease to various neurological conditions.     Much of the work concerning NAD comes from the research of David Sinclair of Harvard.  Dr. Sinclair first shed light on the compound called Resveratrol.  It was thought that Resveratrol stimulated a certain set of genes called the Sirtuin genes.  It was discovered that these genes were turned on by exercise and the one other entity that has scientific background of slowing down aging, namely starvation. It is felt that resveratrol mimics starvation.  It appears now that another compound called pterostilbene which is found in blueberries and grapes may have a better effect than resveratrol because it is more bioavailable. In 2013, Sinclair further reported scientific studies that demonstrated NAD fuels the activity of a group of proteins called the sirtuin proteins, including SIRT1. Although the field of sirtuin research has gone through intensive controversies, an increasing number of recent studies have put those controversies to rest and fully established the significance of sirtuins as an aging/longevity regulator.  Sirtuins are a fascinating family of enzyme-genes.  It is now clear that sirtuins are involved in theregulation of many fundamental biological processes throughout the body.  I would like to give a diagram of the various Sirtuin genes and where they are found in the cell. We can see that some are found in the mitochondria while others are found in the nucleus.  While a third group is found in the cytoplasm of the cell.  It is the communication of these various genes with each other that control the health, numbers and function of the mitochondria.  Remember that the mitochondria have a downstream effect of most cellular functions. Sirtuins have evolved to respond to the availability of NAD+, an essential element of cellular metabolism and DNA damage repair.  The sirtuins are a family of proteins that are intimately associated with NAD.  It has been demonstrated that NAD+ availability decreases over age, reducing sirtuin activities and affecting the communication between the nucleus and mitochondria at a cellular level and also between the hypothalamus and adipose tissue at a systemic level.  The hypothalamus acts as the connector between the endocrine and nervous systems.  It plays a part in many essential functions of the body such as:body temperature, thirst, appetite, weight control, emotions, sleep cycles, and a host of other functions.  These dynamic cellular and systemic processes likely contribute to the development of age-associated functional decline and result in the diseases of aging.       In mammals seven sirtuin family members exist, including three members, Sirt3, Sirt4, and Sirt5, that localize exclusively within the mitochondria while Sirt1, Sirt6, and Sirt 7 are found in the nucleolus.  Although originally linked to life-span regulation in simple organisms such as yeast, this family of proteins appears to have various and diverse functions in higher organisms including man.  An emerging consensus from recent studies is that sirtuins may act as metabolic sensors, using intracellular metabolites such as NAD to modulate mitochondrial function to match nutrient supply.  The more NAD there is in cells, the more Sirt genes do beneficial things.  Notice I said “IN THE CELLS”.  We will talk more about that later.      There are studies that show the SIRT1 protein induces the formation of new mitochondria.  NAD can also activate another sirtuin, SIRT3, which is thought to keep mitochondria running smoothly.  We are able to see that there is great potential for using NAD. The relationship between mitochondria and our health is extremely important on many different levels from aging to cancer.  The question becomes how much of the NAD do we absorb in an oral form?  The answer is probably not much. For some time now, it is thought that the best way to deliver NAD to the cells is via an Intravenous (IV) method.  Until now this was considered the gold standard of delivery.  However, the intravenous method has many drawbacks.  First off it is very time-consuming requiring at least 8 hours to be properly delivered.  There are potential serious side effects.  Even with the IV route there is still a question if enough NAD is being delivered to the cells.  We can measure levels in the serum but does that translate to adequate levels in the cells? We have found that one of the main precursors or building blocks of NAD is nicotinamide ribose.  We have investigated this further and found that on its own, nicotinamide riboside (NR) does not promote longevity or cell health.  In most organisms it is the kinase precursors (nicotinamide riboside kinase 1 &2 NRK) that signal conversion of supplemental NR to NAD.  In easy words to understand, the kinase acts as an enzyme in the reaction to convert NR to NAD.  This Kinase enzyme is thought to be the missing link.  This is the enzyme that we have in diminished amounts as we age.  Any clinical treatment, especially in regenerative medicine and stem cell treatments, should be done with this pathway in mind.  Unfortunately, this pathway is where we ultimately run into problems as we age.  It essentially starts to shut down requiring us to go in a roundabout way to produce NAD.  Let me give a great analogy about this concept.  Think about the NAD as a supply being stored in a warehouse.  We need a method to deliver the NAD from the warehouse to the consumers, in this case the cells.  One way we can deliver the supplies in the warehouse to the consumers (cells) is by a horse drawn cart.  We will get some supplies to the consumers but not in a very efficient manner. On the flip side we can deliver the warehouse supply of NAD via a fleet of modern trucks.  In this case the kinase enzyme acts as a fleet of trucks. We get plenty of supplies to the cells. My good friend Dr. Jo Serrentino has done the work on the NRK 1+2 kinase enzymes.  Dr. Serrentino is an expert in the field of growth factors and their delivery to the cells. She has worked with me for years with growth factors and their ramifications.  We have utilized her growth factor patch systems for years with excellent results.  She has enabled us to deliver growth factors to the joint when combined with penetrating molecules.  This mixture is placed on a simple patch left on for about 8 hours.  I asked her to look at the NAD question and come up with some game changing conclusions. She opened my eyes about the kinases and their actions and importance. We know that NAD levels decrease with age and so we can surmise that the mechanisms of NAD pathways also decrease with age.  Therefore, restoring the pathway is key because supplementing with vitamins, whether orally or intravenously, will only provide limited results; especially in the age-related metabolism.  So, the bottom line is that the supplementation of nicotinamide ribose (NR) can improve the mechanism by allowing more production of NAD, however, the process of getting the net NAD to cells through supplementation with an IV of NR is rather archaic not to mention expensive and invasive.  Remember what I said earlier it is the cells that need the NAD. They are the consumers of NAD.  A better way is to shortcut through the pathway itself and provide the precursors that will work at the cellular level rather than through the serum and excipient nutraceutical level.  The important thing to remember is that in real life (in vivo) you want to get the NAD to the cells. This is quite different than a simple serum level of a vitamin such as NAD.  Many complex biochemical paths are involved and most especially cell membrane traversing, to reach mitochondria.  This is where the penetrating molecules come into play.  They help to deliver the compounds thru the cell membrane NAD is important to Cellular Function,Cell Cycle and ENERGY METABOLISM.  Using the kinases is a direct route into the cells.  This is the main difference between the patches and the current IV method.  The latter simply infuses a concentration of active NAD into the blood.  Once in the blood the difficulty is getting the NAD into the cell.  The Patchless patch infuses signaling molecules to engage the pathway, programming the cell environment.  The pathway can use Nano (meaning very small amounts) concentrations of nicotinamide from food or from a nutraceutical (supplement), but does not require a micro-concentration (much larger amounts) of vitaminas does the IV. The protocol/product we propose can be a truly restorative and a preventative protocol for anti-age clinical application. More importantly, it is likely a safer way to induce NAD, because IV can cause rapid increase of NAD+ (by 2-3-fold) in the circulation which can have some serious side effects.  Also, the IV application may cause methyl donor dysfunction in the long run and subsequent kidney dysfunction as well as liver dysfunction.  Methylation is the process of taking a single carbon and three hydrogens, known as a methyl group, and applying it to countless critical functions in your body such as repairing DNA, turning on and off genes, fighting infections and getting rid of environmental toxins to name a few. Methylation defects are tied to a wide variety of conditions including cancer, diabetes etc.  This is an important consideration when dealing with any vitamin drip, but particularly NR or NA. The kinase protocol is in part a regulator and can safeguard these considered flaws in the current IV protocol. The protocol we suggest contributes safer and better effects within the pharmacokinetic (the branch of pharmacology concerned with the movement of drugs within the body) parameters at hand. Some parting thoughts about NAD and our special pathway.  We feel this will revolutionize applications of NAD and make their applications work much better clinically.  This will be revolutionary for anti-aging but also should help in all our stem cell procedures.  The other aspect of this new type of NAD treatment pertains to addiction problems. We are aware of NAD treatments alone seem to help with many different types of addiction problems.  We think that combining our new NAD treatment with our V cell treatment may open up some new horizons in this challenging field. We are quite excited about this new division our of clinic.  We have named it the Advanced Cellular Repair Division. Anti-aging and well-being are all about cellular repair.  This new technology will take anti-aging and all of its collateral interests to the next levels   We will continue to add different components to this division.  We will start Co-Q-10, NAD and P-53 (the subject of my next blog). The Co-Q-10 and P-53 will be delivered directly to the body while the NAD will be optimized by the kinase   We will attain high cellular levels of these compounds via the delivery of a patch.  With these new technologies the sky may be the limit.    Thanks Dr. P