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
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?
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
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
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 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
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
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
Calorie restriction remains the surest path to increased longevity and resilience to diseases of aging across many organisms including humans. As an added bonus it is a good to lose those extra pounds especially during the holidays. Calorie restriction seems to affect many aging pathways. If we affect these pathways in a positive manner we can slow down and perhaps turn back the clock of aging. Many of the beneficial effects of calorie restriction appear to be due to modification of specific nutrient-responsive pathways such as the insulin/insulin-like growth factor (IGF-1 which can be considered the active form of human growth hormone) pathway, the target of rapamycin (TOR) signaling pathway, and the NAD+-dependent sirtuin genes. These are the same pathways that control stem cell aging. Remember how our stem cells age is how we age. For example, genetic modulation of any one step in the IGF-1 signaling pathway enhances lifespan in many species. Rapamycin, the first small molecule found to extend lifespan in mammals, works by inhibiting the nutrient-responsive TOR pathway. Finally, the mitochondrial NAD+ pathway stimulates the sirtuin 3 (SIRT3) gene which is required for increased production of ATP and mitochondrial health. These pathways may seem complicated and they are. But realize at the same time they control our fate. What the lay person needs to know about these pathways is they have profound effects on health and aging. Calorie restriction on the surface is great but it is not practical. However, one dietary regimen that mimics healthspan-promoting effects of caloric restriction is the Ketogenic Diet (KD), which consists of high-fat and low-or no-carbohydrates. When glucose is not readily available, fat is broken down by the liver into glycerol and fatty acid molecules. The fatty acid is then broken down further, in a process called ketogenesis. During this process, acetoacetate is the first ketone body that is produced. Acetoacetate is then converted into either Beta-hydroxybutyrate (BHB) or acetone. Acetone is the least abundant ketone body, but it may be produced in higher quantities when you first start the ketogenic diet. This is a reason while some people when first starting the ketogenic diet have bad breath for a short time. As your cells adapt to carbohydrate restriction, BHB becomes the most prevalent ketone body and your brain and muscle cells start using it as their primary fuel. In fact, when you are keto-adapted, ketones can supply up to 50% of your basal energy requirements and 70% of your brain’s energy needs. Let us do a quick comparison between a ketogenic diet and a regular diet which depends on glucose. Glucose is the primary energy source for almost every cell in the body. This is because it can be broken down into energy much more quickly than any other fuel source, and it does this without the help of the mitochondria (the main energy producing component of the cell). Using glucose for fuel, however, comes with some negative effects. What we gain in quickness, we lose in efficiency. During the process of sugar burning more free radicals also called Reactive Oxygen Species (harmful compounds that can cause cell damage these are referred to as ROS) are released and less energy is created than when we use ketones and fat for fuel. The ROS harm cells in many different ways and advance aging on many different levels. On the other hand, Ketones are a more efficient fuel source that inhibits the production of free radicals and reactive oxygen species. This leads to a host of benefits, especially for the brain cells that use ketones instead of sugar for fuel when glucose levels are low. For example, studies done on people with different types of cognitive issues from Parkinson’s disease to epilepsy confirm that using ketones as fuel can improve brain function tremendously. However, the benefits of burning ketones for energy doesn’t stop in the brain. Many other cells like muscle cells also benefit from the use of ketones (more on that later), but you can’t reap these benefits unless you use up your sugar reserves first. A standard Ketogenic Diet efficiently reduces body weight and stimulates liver synthesis of ketone bodies. Ketone bodies are released into the bloodstream and provide energy-efficient fuel to highly oxidative organs, including liver, brain and the heart. In many respects the Ketogenic Diet is similar to calorie restriction in that both produce similar beneficial side effects. There is certainly nothing new about the Keto-Diet. It is mentioned by many people yet few of them have a good understanding of what is really going on. We became more aware of the Keto-Diet when we began working of the new division we are about to launch. This division is called the ADVANCED CELLULAR REPAIR DIVISION. We feel this division will be a game changer on many different levels including anti-aging and success with stem cell procedures. In forming this division, we have learned some of the mechanics of the Keto-Diet and why it is successful in many aspects of health including success with stem cells. I have done a survey of some of the articles on the Ketogenic diet and most of them are parroting the same information. Most of these sites are missing some salient points about the Keto diet. They are not aware of the implications that the ketone bodies have on aging pathways which have a profound effect on our health landscape. The ketogenic diet tries to bring carbohydrates down to less than 5 percent of a person’s daily caloric intake – which means eliminating most grains, fruit, starchy vegetables, legumes and sweets. Instead, it replaces those calories with fat. One myth that needs to be mentioned is that proteins are contra-indicated in a keto diet. Typically, proteins are not a problem. In some circles there is a misconception. Many low carb, high fat advocates believe excess protein can turn into sugar in your bloodstream through a process called gluconeogenesis and knock down your ketone levels. There is no evidence that consuming excess protein will increase glucose production from gluconeogenesis. Gluconeogenesis (GNG) is a metabolic pathway that allows your liver and kidneys to make glucose from non-carbohydrate sources. To clarify, you don’t need to eat any high carb foods to survive, but make no mistake — your body needs glucose and glycogen to keep you healthy (even on ketosis) and it will get this via survival mechanisms like gluconeogenesis. There are a handful of cells in your body that can only use glucose to survive, including red blood cells, kidney medulla (inner part of the kidney), testicles and some parts of your brain. Ketones can cover up to 70% of your brain’s energy needs while glucose from GNG covers the rest. The other organs can’t metabolize ketones at all, so gluconeogenesis provides them with enough glucose to remain healthy. One of the mainstays of the Keto diet is fat. That fat is turned into ketone bodies, which are an alternative energy source: besides glucose derived from carbohydrates, ketones from fat are the only fuel the brain can use in the absence of glucose. Most people are well aware that sugars are inflammatory. When we block glucose metabolism we are having a suppressive effect on inflammatory genes. When we start mentioning genes this should be a tipoff. When you start affecting genes you start affecting cellular pathways. Most people are aware of the benefits of the Keto-diet but when asked why it really works we get a variety of answers. Low glucose is certainly important but what is the overall effect. The following diagram is of the upmost importance in the message we are trying to convey. Instead of Stem Cell Aging Pathways we can easily substitute the name Human Aging Pathways for how our stem cells age are how we age. The Ketogenic Diet seems to have a direct effect on many of these aging pathways. Let us take a look at how the Ketogenic Diet may affect the various pathways. It is well known that caloric restriction extends lifespan. No generally accepted theory has been proposed to explain these observations. However, we now realize that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. Ketone bodies protect neurons against multiple types of neuronal injury and the underlying mechanisms are similar to those of calorie restriction and of the ketogenic diet. The following diagram gives an idea of some of the duties of ketone bodies.The diet’s high fat, low carbohydrate composition reduces glucose utilization and promotes the production of ketone bodies. Ketone bodies are a more efficient energy source than glucose and improve mitochondrial function and biogenesis, increased health span and lifespan and cellular energy production. When we are improving mitochondrial function, we are stimulating the Sirtuin genes which can be found on the first diagram as Sirt1,3, and 6. These same Sirtuin genes are the same ones that are stimulated by vigorous exercise, certain supplements such as Resveratrol, Pterostilbene, NAD, and finally calorie restriction. Thus, we can see the ketone bodies can dramatically affect the Sirtuin genes to help up regulate the production of ATP by stimulating the mitochondria. In many anti-aging circles ATP stimulation is considered one of the holy grails. Ketone bodies as fuel source are more efficient to burn into energy: ketone bodies require only one molecule of NAD+ per molecule of Co-enzyme A, whereas glucose needs 4 molecules of NAD+. As we can see ketone bodies as fuel allow us to have more NAD available. Co-enzyme A is important component in the Krebs cycle. The Krebs cycle is where ATP is made. The more NAD+ available the more ATP that can be produced. But Ketone bodies go beyond being used as a fuel source. They themselves perform signaling activities in a way similar to growth factors. Intriguingly, the ketone body (which is also called BHB) might also be a metabolic intermediary of the benefits of calorie restriction and fasting. Long viewed as a simple carrier of energy from the liver to peripheral tissues during prolonged fasting or exercise, βOHB or Ketone bodies also possesses signaling activities. It therefore joins a small but growing list of metabolic intermediaries that affect gene expression via modifications of the DNA. These changes on the DNA ultimately affect the production of messenger RNA. Messenger RNA than turns on certain genes by giving them commands to produce certain growth factors etc. The following diagram gives us an idea of some of the various effects of ketone bodies in our bodies. Many of the effects we see in the following diagram are the result of Ketone body signaling. We can see that the effects of Ketone bodies are wide ranging. These ketone bodies and their intermediaries may be key links between variations in the cellular environment and the epigenetic changes associated with increased health span and lifespan. Epigenetics, as a simplified definition, is the study of biological mechanisms that will switch genes on and off. Epigenetics affects how genes are read by cells, and subsequently whether the cells should produce certain proteins. Environmental factors such as nutrition dramatically alters cellular metabolism and many also alter the epigenetic regulation of gene expression. Ketones will increase the metabolic coenzyme nicotinamide adenine dinucleotide (NAD), a marker formitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes) associated with major benefits such as longevity and reduced inflammation; thus, increasing NAD is a coveted therapeutic endpoint. The literature is now ablaze with information on NAD and earlier this year Time Magazine presented an article calling NAD based supplements a possible true “Anti-aging Pill”. This assumption is not very far off the mark. Based on differential NAD+ utilization during glucose vs. ketone body during energy generation, it appears that a Ketogenic Diet will increase the NAD+/NADH ratio. The more NAD+ available the more ATP that can be produced. ATP production is thought to be a key factor in health and anti-aging. What else do ketone bodies stimulate? Another important pathway in the body is called the NRF2 pathway. The NRF2 (nuclear factor erythroid-derived 2-related factor 2) pathway is the cellular antioxidant system. The Nrf2 pathway has been referred to as the master regulator of antioxidant, detoxification and cell defense gene expression. We can think of Nrf2 pathway as a “thermostat” within our cells that senses the level of oxidative stress and other stressors and turns on internal protective mechanisms. Nrf2 is a potent modulator of antioxidant response and can rapidly target oxidative stressors. Ketone bodies increase mitochondrial glutathione levels by activating the Nrf2 pathway, thus reducing oxidative stress. It modulates the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH) which ultimately raises the ATP production. The following diagram shows the NrF2 pathway. We can see the difference between a normal cell and a cell that has suffered from oxidative stress. Ketone bodies are also a stimulator of Autophagy. Autophagy is a necessary part of our survival because it involves killing off pathogens and cells that are potentially dangerous. It involves recycling old, damaged cellular parts into newer ones to keep our bodies free from disease. Below is a diagram that shows the principle of Autophagy.One characteristic of aging is the accumulation of damage, and this is largely due to the failure of autophagy to attain normal functional levels. It can be seen that bringing levels of autophagy to youthful levels can ameliorate aging by clearing out damaged parts of the cell. Cells use autophagy to get rid of damaged proteins and organelles, to counteract the negative effects of ageing on the body. Most anti-aging treatments and protocols have something in common: they all cause an increase in autophagy. Autophagy is central to extending lifespan and to avoiding the diseases of aging. Ketone bodies also seem to have a significant impact in the field of Cellular Senescence. Although senescent cells can no longer replicate, they remain metabolically active and commonly adopt characteristics consisting of a pro-inflammatory growth factors. These cells are capable of doing damage not only on a molecular level but to the entire body. There is much interest on many different fronts in the field of cellular senescence. Lately, senescent cells have been making the headlines several times, as they are a very promising target for medical intervention to delay or even reverse some aspects of aging; while a certain number of senescent cells is tolerable and even beneficial, the accumulation of senescent cells in old age drives several age-related pathologies. My feeling is that the controlling of and eliminating senescent cells may be the next big breakthrough in anti-aging science and other medical fields. We are well aware that senescent cells can have a significant impact on the success of stem cell treatments. The following diagram shows the extent of how senescent cells can cause damage on many different levels.Senescent cells will accumulate growth factors, proteases, and inflammatory factors that disrupt normal tissue function. Senescent cells have long been implicated in aging and decreased success in stem cell procedures. By contrast, cellular quiescence is a reversible state of arrested growth; quiescent cells do not divide, but under the right conditions, they can re-enter the cell cycle and divide again. This state usually occurs when nutrition or growth factors are lacking, and it is thought to be a way that cells can avoid entering a senescent state. The cellular quiescence mechanism also helps cells to preserve stemness and resist stress to their genes. Senescent cells can no longer multiple and divide. The researchers found that ketone bodies can promote cell division and prevent cells from becoming senescent.Although the above diagram is somewhat technical, it shows the difference between a quiescent cell and a senescent cell. We see that the senescent cell has a good deal of damage which has passed the point of no return. We now understand that a ketone body which is produced during calorie restriction or thru the Ketogenic diet will have anti-aging properties. In addition, the researchers found when the ketone body ( BBH also called β-Hydroxybutyrate) binds to a certain RNA-binding protein, this increases activity of a stem cell factor called Octamer-binding transcriptional factor (Oct4) in vascular smooth muscle 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). Oct4 increases a key factor against DNA damage-induced senescence. It is thought that vascular aging is one of the root causes of whole-body aging. Another interesting fact is that there seems to be a distinct relationship between ketone bodies and a certain protein that stimulates what is called the P-53 gene. The P-53 gene is also called the tumor suppressor gene. It attacks senescent cells and causes their demise. At the same time, it can cause repair of some damaged cells making them younger. As we can see a diet ketogenic diet can be a very potent force for anti-aging and general health. I have given a quick review of the benefits of this regimen but tried to base it on science. As we can see it has a profound effect on a number of aging pathways in a very beneficial manner. Below is a diagram of a pyramid of the effects of the Ketogenic diet. We see its effects are far flinging.We must remember that success in stem cell procedures is dependent on successful manipulation of the Stem Cell Aging Pathways. I would like to impart one final thought. We need to use some common sense about this diet and “cheat” once in a while. Like I said when it comes to the ketogenic diet we need to use common sense but sometimes common sense is not very common. However, an occasional slice of pizza is not that bad. Thanks ,Dr. P