recently posted an article on LinkedIn about Vitamin C and how it affects
certain immune cells and stem cells in the body. Most of the articles I have
posted on LinkedIn are aimed more towards scientists and physicians. They are
fairly technical and my writeups have more of a technical blush than my blogs.
I have included this article at the end of this blog. My blogs also contain a
good bit of science but are not as intense.
thought this was an interesting article for everyone. The article discusses the
aspects as to how Vitamin C boosts our immune system and helps control actions
of our DNA. How Vitamin C works is a topic most of us think we know about but when
asked how Vitamin C really works the discussion becomes silent. The article discusses
the use of Vitamin C in increasing the health of a certain type of immune cell
in the body and how Vitamin C ultimately effects our DNA function by
controlling some of our genes. The diagram below shows the different immune
cells we have. All of these cells have their place and at times they can save
our life such as in the face of an infection.
cell we are most interested in this case is called a Regulatory T-cell or as it
is more commonly called a T-reg cell. T-reg cells are of the upmost importance
in that they help prevent autoimmune diseases. Regulatory T cells police the immune system and keep it in
check. Just as important,
T-regs promote tissue repair and
regeneration by modulating inflammation. Extra T-reg cells will do nothing but
improve results for a wide variety of conditions from the treatment of
autoimmune diseases to the treatment of osteoarthritis. The problem many times
is that we just do not have enough T-reg cells to go around. T-regs are not
easy to culture expand (grow them in a lab). What scientists are attempting to
do is get other immune cells which are more plentiful and convert them into
T-reg cells. This is called an induced T-reg cell
(i-T reg cell). In
another word, one type of immune cell is being coaxed to turn into a T-reg cell.
This is a newer realm in the stem cell world. The following illustration shows
Usually, when we are
dealing with induced cells we will take a skin or similar cell and treat it either
with a virus or enzyme to reprogram the cell. They are now doing this by
treating the cell with certain transcription factors. This treatment makes the
cell go back in time and act as much younger cell having the capabilities of
becoming many different types of cells. These are called induced pluripotential
stem cells or IPS cells. We see in the
above illustration that these induced cells act very similar to embryonic cells.
There is a great deal of research currently underway with these cells. The
problem with the induced T-reg cells is that they do not appear to be stable.
next portion of the article deals on how to increase the stability of the
induced T-reg cells and for that matter regular T-reg cells. This has possible
far reaching ramifications for our health. One important factor that affects
the T-reg cell stability is something called a TET protein. Actually, TET
stands for Ten-Eleven Transcription factor proteins. Transcription is the process where a gene's DNA
sequence is copied (transcribed) into an RNA molecule. Transcription is a key
step in using information from a gene to make a protein. The RNA will carry a
message and it is thus called messenger RNA (mRNA). This is the basis for many
of the Covid vaccines.
DNA contains all information that
cells in our body need to function by providing specific codes to produce
specific proteins. Not all parts of DNA are accessible in all cells at all
times. The regulated production of proteins ensures that different cells and
organs can be developed from the same DNA. Remember one cell has all the
genetic information to reproduce the whole body. What that one cell makes
depends upon how the cell is regulated. An important regulatory mechanism is
the reversible addition (methylation) or removal (demethylation) of certain chemical
bonds, so-called methyl groups, to segments of DNA. This modifies the readout
of the DNA segment. The next illustration demonstrates the concept of
methylation and how transcription works. We have now broached an important
scientific field called EPIGENETICS. Epigenetics deals with how certain genes get turned on or off. The illustration shows these concepts.
In the course of life, aging processes, environmental influences and lifestyle factors
such as smoking or diet induce biochemical alterations to the
DNA. Frequently, these lead to DNA methylation, a process in which methyl
groups (CH3) are added to particular DNA segments, without changing
the DNA sequence. This causes changes in how the DNA behaves.
Getting back to the TET Proteins, they can
decrease the production of certain proteins in immune cells. How TET proteins
play into the development of autoimmune diseases is still not completely
understood. TET transcription factors, a family of cancer
suppressive proteins, help regulate gene activity via their influence on
chromosomal architecture. TET enzymes facilitate DNA demethylation (
removal of CH3).
Methylation can change the activity of a DNA
segment without changing the sequence. When located in a gene promoter, DNA
methylation typically acts to repress gene transcription. Researchers
have linked abnormal DNA methylation to several human diseases. DNA methylation
is a commonly used epigenetic signaling tool that can fix genes in the off
position. Remember Epigenetics deals with how reversible changes in
DNA affect gene activity and protein expression. Disrupting this machinery can
have dramatic effects on cellular function and overall health.
What the article tells us is that Vitamin C has
the ability to enhance the enzymatic activity of the TET proteins. So far, the problem has been that the converted iT-reg cells did
not seem to function well. It has been very challenging to come up with the
right molecular ingredients to allow the induced cells to survive. Vitamin C
seems to change the dialog. The article discusses the symbiosis of Vitamin C and TET proteins and their
effects on T-reg cells. This technique involves the reprogramming of
effector or memory T cells into iT-regs. The bottom line is that the Vitamin C
and the TET proteins will induce a stable i-Treg cell. Hopefully, in the not
too distant future stable i-Treg cells will become a reality.
C is found to be a key mediator of the interface between genome and
environment. It regulates DNA demethylation as a cofactor for TET. It is shown
that vitamin C drives active removal of DNA methylation by enhancing TET enzymes. Thus, Vitamin C is not
just an anti-oxidant but has other powerful regulatory function. THIS IS A BIG DEAL!
Recent studies have shown that Vitamin C
potentiates the effects of DNA methyltransferase inhibitors. DNA methyltransferases are a family of writer
enzymes responsible for DNA methylation by the addition of a methyl group. Epigenetic
alterations, along with genetic mutations contribute to onset of cancer. It is
shown that Vitamin C drives active removal of DNA methylation by enhancing TET
enzymes. This helps to erase DNA methylation which allows epigenetic memory
encoded by it to improve reprogramming of differentiated cells to an embryonic-like
In the above illustration we see Vitamin C at
work. It is blocking a DNA writer. It is inhibiting the addition of the
methyl group to the DNA. Here is the proof that Vitamin C affects how our DNA
functions. The famous scientist, Linus Pauling, recommended mega doses of
Vitamin C. He was mocked for recommending large doses of Vitamin C for
preventing the common cold among other things. Ask your friends if they have
been taking large doses of Vitamin C to try to help prevent Covid. It looks
like Pauling will have the last laugh. It reminds me of a saying from Arthur
Schopenhauer Truth passes through three stages: First it is Ridiculed. Second,
it is violently opposed. Third, it is accepted as self-evident.
The take away here is Vitamin
C is an essential micronutrient and a free radical scavenger. These are well
known facts. At the same time, it has functions such as blocking oncogenic
transformation induced by carcinogens by its effects on epigenetics. The
epigenetic effects of vitamin C and its effects on the health of the immune
system far outweigh it acting as an anti-oxidant. One final thought, in our
clinic we are able to offer multiple combinations of Vitamin C via an
intravenous route. The intravenous route insures better bioavailability.Thanks, Dr P
is the link to the article: https://scitechdaily.com/vitamin-c-is-a-key-ingredient-for-immune-cell-function-a-leg-up-in-treating-autoimmune-diseases/
Sometimes the government is the last to know. The U.S.
military is about to start testing anti-aging compounds. Guess which one? Hint: It begins with an 'N', ends with a 'D' and has an 'A' in the middle. The answer is NAD.
I was recently sent an article from a friend. It was
interesting in that it was discussing the fact that the U.S. military will be
testing NAD as an anti-aging supplement and performance enhancer. I looked up
this up and found that this information was reported on a number of different
sites. I happened to pick the Popular Science article and it is included below.
The military is doing something that we have known about in the real world for
some time. NAD supplements seem to act in an anti-aging fashion and seem to
improve performance, both mentally and physically. I suspect over time they
will also discover that giving the NAD intravenously with the oral supplements
will work even better. I suspect over time they will also discover certain
tricks to make NAD absorption better, more efficient and quicker. Finally, they
will also learn that they will need to act against Senescent cells when NAD is
given or we may have the opposite effect on the patient. These are treatment
protocols that we have developed in our clinic over time. Below is the link.
Enjoy the article:https://www.popularmechanics.com/science/health/a36905562/us-military-testing-anti-aging-pill/Thanks, Dr. P
If you move it, you will lose the cells/It needs rest
The biggest misconception around the injection of PRP or Stem Cells as it is related to physical therapy (PT) is that post injection PT shouldn’t happen. There is the common misconception that if you move the area that was injected you will somehow push the cells out and the money you spent will be wasted. This couldn’t be further from the truth. The most up to date research in the field consistently advocates for movement in the form of physical therapy post injection. By moving the area and stressing the tissue intelligently you are actually telling those injected cells what to do. The cells are placed in the area, and it is referred to as their “microenvironment”. If the microenvironment goes unaltered the cells will not serve their intended purpose. If the microenvironment is stimulated it will signal to those cells what tissue is needed and the cells will respond accordingly. In summary, physical therapy post-injection is a crucial component to getting the most out of your treatment.
Any PT post stem cell is good PT
Along the same lines as our first misconception is the falsehood that any PT after Stem Cell/PRP is good PT. Unfortunately, that isn’t the case. The most affective physical therapy after a stem cell injection will be one that targets the tissue type that the injection was given for (ie. Bone, tendon, ligament, muscle, etc.). Each tissue type responds to stimulus differently and that needs to be understood by the physical therapist providing the treatment. Stress the tissue too much, too little, or incorrectly can be detrimental to the patient’s outcomes. Stressing the target tissue the correct ways and with the correct dosage is going to greatly improve the benefits of the injection. Finding a physical therapist that understands regenerative medicine and can balance the active and passive components of care properly is a must for optimal results.
The Boost of Blood Flow Restriction (BFR) Training
This third point is less of a misconception and more of a secret weapon to boosting outcomes after a regenerative injection. Blood flow restriction training, when done properly, can greatly assist in the recovery and repair process following PRP/Stem cell injections. BFR training involves measuring the patient’s blood pressure and using an equation to determine a proper occlusion pressure for them to train under. Once this pressure is found, we are able to mimic training under a heavy load with high intensity under a very low load and intensity. Simply put, we can trick the body into thinking it is working harder than it truly is. This is important after PRP/stem cell because it influences the body chemistry in a way that can magnify the response. BFR training puts the body in “rebuild and repair” mode safely while those injected cells are trying to do just that. Simply put: if the PRP and stem cells are the construction workers, BFR training is the 2pm coffee that keeps them working hard through the end of the day.
Written by Dr. William “Bill" Kelley DPT, ATC, CSCSCo-Owner and Director of Physical Therapy:Aries Physical Therapy FTL1115 E Sunrise BlvdFort Lauderdale, FL 33304(o) 954-247-4929(f) 954-245-0697Aries Physical Therapy Boca807 N Federal HwyBoca Raton, FL 33432(o) 561-287-6486(f) 561-621-2944
We have known for some time that Ozone has some
anti-aging properties. But there are also some other anti-aging aspects of
Medical Ozone therapy that are not readily known. The above diagram
shows some interesting effects of medical ozone. In this particular case the
Ozone was administered intravenously. When Ozone is administered intravenously it
will form two different types of compounds. The first compound is hydrogen
peroxide (H2O2) which helps launch a cascade of reactions
which ultimately reduce inflammation in the body. Less inflammation is less
aging. More to come about this. In the above diagram we see that the Ozone is
reacting with the Poly Unsaturated Fatty Acids (PUFAs) found in the cell
membrane. Poly unsaturated fatty acids all have at least one double bond
linkage between carbon atoms. These double bonds cause them to bend, kind of
like how your arm bends at your elbow. This double bond limits the number of
hydrogen atoms that can bind to the carbon atoms, so the molecule is not as
saturated with hydrogen atoms as it could be. Thus, its considered
unsaturated. Unsaturated fatty acids that have one double bond are called
monounsaturated fatty acids (MUFAs). Unsaturated fatty acids with more than one
double bond are called polyunsaturated fatty acids (PUFAs). Get it? mono for one and poly for many.Polyunsaturated fats can be divided into 2 groups: omega-3s
and omega-6 fats. Two polyunsaturated fatty acids are regarded as essential
because the body cant make them they must come from food. The two essential
fatty acids are alpha linolenic acid (an omega 3 fat) and linoleic acid (an
omega 6 fat). Omega 3 fats, especially those found in seafood, are vital to
help control inflammatory reactions in the body.
POLYUNSATURATED FATS ARE USED AS BUILDING BLOCKS IN THE
MEMBRANES THAT SURROUND ALL THE CELLS OF YOUR BODY AND CONTRIBUTE TO THE
STRUCTURE OF THE BRAIN. The cell membrane seems to be the major area of
reaction between the Ozone and PUFAs.
In the first diagram we see that the Ozone reacts with the
Poly Unsaturated Fatty Acids located in the cell membrane. It forms a compound
called a Lipid Oxidation Products also known as LOPs. These LOPs react with a variety
of cells within the body. In the diagram I have circled in red two important
pathways in the body. These two are the AMPK and mTOR pathways. The effects of
these pathways have profound implications on our longevity. Other important
pathways include: 1. Sirtuin Pathway 2. Nuclear factor-kappa B (NF-kB) pathway 3. NRF2 pathway 4. FOXO pathway. These are very important pathways
especially when it comes to anti-aging and longevity.
Let us take a better look at the AMPK and the mTOR pathways.
The following illustration shows what happens when there is an AMPK deficit:
We are able to see that AMPK deficits lead to many conditions
associated with increased aging. While the opposite is true. Stimulate the AMPK
pathway and you will increase longevity.
The next illustration shows the rewards of increased AMPK:
The metabolic protein AMPK
has been described as a kind of magic bullet for health. Studies in animal
models have shown that compounds that activate the AMPK protein have
health-promoting effects to reverse diabetes, improve cardiovascular health,
treat mitochondrial disease and even extend life span. AMP-activated protein kinase, or AMPK, is known as a
master regulator of metabolism. AMPK deals how our body uses and transforms
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
Nrf2 is also called the Nuclear factor erythroid 2-related factor 2. NRF2 is a transcription factor that activates over 500 genes. The main reason NRF2 is so highly sought, is because it is a key transcriptional regulator of several antioxidant and anti-inflammatory enzymes. Nrf2 is now recognized to be involved in the cellular response to multiple stressors including foreign substances, excessive nutrient/metabolite supply, inflammation, and the accumulation of misfolded proteins. The Nrf2 protein, known as a transcription factor because of its ability to control genes, is the key component of a pathway (a sequence of biochemical reactions in a cell) that senses and responds to changes in oxidative balance. Nrf2 is one of the body’s major pathways. We need to think of the pathways as the body’s computer software and the cells and organs as the computer hardware. Nrf2, in fact, regulates many hundreds of genes that have nothing to do antioxidant enzymes per se, but rather provide protection from a broader range of stress-related events that are encountered by cells, organs, and organisms, under both normal and pathological circumstances. The Nrf2 pathway is under tight control. When the Nrf2 protein in bound in the cytoplasm it is essentially inactive. The following illustration shows this concept. This illustration is essentially the essence of how the Nrf2 pathway functions. We must remember that Nrf2 is a protein. Proteins, although they are typically confined within the cell or on a cell, have a complicated life cycle. The illustration shows the complicated cycle of the Nrf2 ecosystem. It actually demonstrates its actions in the cell. For example, soon after NRF2 is made by ribosomes in the cytoplasm, it is normally sequestered by KEAP1, which quickly loops the Nrf2 protein with ubiquitin ligase Cullin3 for transport to the proteasome. Here, the ubiquitin is stripped off and NRF2 is degraded and recycled. If all is well in the cell, this process gives NRF2 a half-life of about 20 minutes. Remember, if all is well in the cell Nrf2 is typically not active. Looking at the diagram in a different manner we see that the Nrf2 is held “prisoner” in the cytoplasm. The “prison guard” is called Keap1. If given the opportunity Keap1 will go on and destroy the Nrf2 protein. This is called proteasomal degradation. Given the right conditions (in this case a stress to the body) the Nrf2 protein breaks the stranglehold that the Keap1 proteins maintain. The Nrf2 protein then makes its way to the nucleus where it can eventually react with certain genes and produce certain beneficial compounds. A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway. This explanation is basic but it gives the essentials of how the Nrf2 protein functions. WHAT ARE THE STRESS CONDITIONS THAT STIMULATE THE NRF2 PATHWAY?The Nrf2 pathway senses the need for antioxidant enzymes and regulates their production to maintain metabolic balance. The sensing components of the pathway chemically modify and release Nrf2 so that it may diffuse into the nucleus of the cell where the DNA resides. Once in the nucleus, the Nrf2 will start reacting with a variety of genes found in the DNA of the nucleus. It can then “switch on” or “turn off” the genes it controls (often termed survival genes) to produce the protected state within the cell. Our DNA encodes about 20,000 genes, each representing a “blueprint” for the production of a protein or enzyme necessary for a healthy existence. Each of these “blueprints” requires a regulating control called a “promoter” that determines precisely how much of each product is produced, and under what circumstances. By binding to one specific type of these switch-like promoter regions called the “Antioxidant Response Element (ARE)”, the Nrf2 factor controls the rate of production from hundreds of different genes that allow cells to survive under stressful conditions.NRF2 is part of a group of transcription factors called nuclear receptors. Transcription factors are proteins involved in the process of converting, or transcribing, DNA into RNA. Transcription factors include a wide number of proteins that initiate and regulate the transcription of genes. Once the Nrf2 translocates to the nucleus, it results in the production of Anti-Oxidant Response Elements. There are a number of these elements including Glutathione, Catalase, and a number of other anti-oxidants. We should think of these as endogenous antioxidants. Meaning they are made by the body. These are quite powerful. The next illustration shows more of the whole picture of the Nrf2 pathway. From the Nrtf2 stimulators to the actual response elements to the blocking of the reactive oxygen species (ROS) by the response elements. Ultimately, like many pathways in the body, the Nrf2 pathway targets the mitochondria. The illustration shows certain agents which block the Nrf2 and others which encourage its activation by disabling the stranglehold the Keap1 protein has on the Nrf2 protein. The following is a diagram of transcription factors:The illustration shows how Nrf2 handles the inflammation caused by the ROS. Inflammation is the most common feature of most chronic diseases and complications. Several studies have demonstrated that Nrf2 contributes to the anti-inflammatory process by orchestrating the recruitment of inflammatory cells and regulating gene expression through the antioxidant response elements (ARE). These genes produce a large variety of antioxidant enzymes that create a network of protection by neutralizing primary and secondarily generated oxidants and by cleaning up the toxic byproducts they leave in their wake. Also, they help to repair the damage the oxidants have caused. This is especially important for mitochondrial health. Mitochondria help produce free radicals (Reactive Oxygen Species=ROS) and at the same time are very susceptible to their damage. Oxidants such as the superoxide radical (O2-) and hydrogen peroxide (H2O2) are produced by the process of “burning” the foods that sustain us. The Nrf2 pathway senses the need for these antioxidant enzymes and regulates their production to maintain metabolic balance. Several things can upset this delicate balance, the most significant one is aging. Unfortunately, aging slowly tips the balance toward the oxidative side resulting in “oxidative stress.” Disease processes can also result in overproduction of oxidants. Many major diseases associated with aging, such as heart attacks, stroke, cancer, and neurodegenerative conditions such as Alzheimer’s disease also increase production of oxidants thus creating oxidative stress and inflammation. When our immune cells are stimulated they can produce reactive oxidants (O2-, H2O2, OH, and HOCl) to deal with both bacteria and viruses. This can result in the destruction of the viruses and bacteria. But the problem with these compounds is that our otherwise healthy cells get caught in the cross-fire and sustain collateral damage that we see and feel as inflammation. Unfortunately, we have seen this phenomenon in patients with a Covid 19 infection. They get such a vigorous immune response it is called a cytokine storm. Cytokine storms are one of the contributing factors to the high numbers of Covid deaths.HOW CAN WE HELP STIMULATE NRF2?The above diagram shows many of the moving parts of the Nrf2 pathway and its stimulation and resulting end products. In this illustration we see the arch villain of the Nrf2 pathway. This villain is called the NFkB pathway. This pathway is the opposite of the Nrf2 pathway. It is the thermostat of inflammation. It is a very important pathway. We must remember that some inflammation is essential. It is when the NFkB pathway gets over-stimulated that problems arise. Recent research has identified certain processes to be very effective at stimulating our body’s natural mechanisms for creating antioxidants through NRF2 activation. NRF2 activation can be achieved thru exercise, calorie restriction (including fasting) and ingestion of natural nutrients that are NRF2 activators. In our office we have found that intravenous Ozone is a potent stimulator of the Nrf2 pathway. The intravenous Ozone is part of a protocol called the EBO2 protocol. The intravenous Ozone momentarily produces Hydrogen Peroxide. The Hydrogen Peroxide is quickly converted into compounds called Ozone Messengers. These Ozone Messengers result in the stimulation of the Nrf2 pathway. They ultimately help to reduce inflammation. Other in office Nrf2 stimulants include intravenous Curcumin, Quercetin, and Resveratrol. Intravenously, these are very potent Nrf2 stimulants. Since they are given intravenously they become very bioavailable compared to their oral formulations. The question becomes what else can we do stimulate the Nrf2 pathway without a trip to the doctor’s office? We have already mentioned the usual suspects such as exercise, calorie restriction, modified keto type diet etc. However, we can still help to supplement Nrf2 stimulation with some oral compounds. In an ideal world one would first get some supplements intravenously and then proceed with lifestyle changes and oral compounds. Common NRF2 activators include Curcumin which is a widely studied and potent Nrf2 activator. The problem with Curcumin is its bioavailability. Not all Curcumin compounds are the same. Other stimulators include Pterostilbene and its weaker cousin Resveratrol. The problem with oral Resveratrol is also its bioavailability. Other stimulators include Quercetin (from onions) and sulforaphane (from broccoli) and antioxidants found in green tea, chocolate, and other sources. Different nutrients may activate NRF2 by different mechanisms and, when taken together, may be synergistic. I have taken the bull by the horns and designed a supplement which I feel will be unlike anything out there. The propriety blend of ingredients are:Fumaric AcidBrassicaUltracurAlpha Lipoic AcidQuercetinResveratrolPterostilbeneSome of these are well known while others may be new. One of the common threads with these particular compounds is that by and large they have much better bioavailability then their similar counterparts. Brassica is a broccoli derivative. Ultracur is a Curcumin derivative. They both have much higher bioavailability then competing products. One interesting item in this list is Fumaric acid. Fumaric acid is the “Crown Jewel” of this formula. A derivative of Fumaric acid has been approved by the FDA in the treatment of relapsing forms of Multiple Sclerosis. It is also used in the treatment of psoriasis. Currently I am not aware of any Nrf2 supplement blend that is utilizing Fumaric acid derivative mixed with other supplements to stimulate Nrf2. This product should be available shortly. By raising Nrf2 levels, we are able to tap into one of nature’s most powerful mechanisms for the maintenance of good health. Regular consumption of these Nrf2 stimulating foods and supplements may substantially lower many of the health risks of modern living and increase our resistance to many diseases.IN REVIEW WHAT ARE THE PRACTICAL BENEFITS OF THE NRF2 ACTIVATORS?Recent research has found that “NRF2 activation” is very effective at stimulating our body’s natural protective mechanisms including promoting endogenous (natural) antioxidant production. Activation of NRF2 is believed to provide many health benefits including:REDUCING SYSTEMIC INFLAMMATIONLOWERING OF OXIDATIVE STRESS (REDUCING CELLULAR DNA, RNA AND PROTEIN DAMAGE)IMPROVING MITOCHONDRIAL FUNCTION (CELLULAR ENERGY PRODUCTION) ALL ROADS LEAD TO THE MITOCHONDRIANrf2 activation may have a positive impact on chronic inflammation and oxidative stress and so may be useful in the prevention or treatment of many common chronic disease processes including obesity, high blood pressure, reducing the risk of diabetes, cardiovascular disease, stroke, and the list goes on and on. NRF2 activators have been shown to protect the liver in conditions of chronic hepatitis and fatty liver. Let’s look at some more specific conditions that are directly affected by the Nrf2 pathway. Nrf2 ACTIVATION AND OBESITY AND INSULIN RESISTANCEObesity is now thought to be a systemic disease characterized by increased systemic inflammation and oxidative stress. As a consequence, obesity is clearly understood to be a major contributor to the development of hypertension, heart disease, stroke and some cancers. The importance of Nrf2 in obesity and insulin resistance is clearly evident and the potential use of an Nrf2 activator as a treatment method will continue to be an exciting area to advance. Nrf2 ACTIVATION AND PAINNrf2 activation is thought to reduce pain related to many conditions. The muscle pain and fatigue associated with fibromyalgia is believed to respond to NRF2 activation. Nrf2 activation may reduce the central sensitivity associated with many chronic pain conditions including chronic headaches, chronic back pain, and fibromyalgia etc. Nrf2 ACTIVATION AND ADDICTIONMany of the brain’s neurotransmitters and neurochemical processes are impaired in conditions of chemical and behavioral addiction. NRT2 activation may play a role in facilitating restoration of these neurochemical processes and facilitate addiction recovery. Nrf2 ACTIVATION AND STEM CELLS ACTIVATION AND SURVIVALAs a cellular metabolic and stress sensor, Nrf2 is a pivotal regulator of stem cell self-renewal, proliferation, and differentiation. Nrf2 displays cell type-specific and/or stage-dependent impact on stem cell biology in response to various environmental cues. Nrf2 maintain ASCs self-renewal, quiescence, and regenerative capacity while protecting against ASC depletion in response to stress and aging.I suspect this will take on increasing importance in Regenerative Medicine stem cell procedures. We have seen this concept already in organ transplants and rejection. As time goes on, we may depend more on allogeneic sources of stem cells which exhibit immune evasive rather than privileged responses to the immune system.Thanks,Dr. P
is a gene which controls the production of the enzyme NAD(P)H dehydrogenase, quinone 1. The above diagram shows some
of the many functions of the NQO1 pathway. We can see that there are three
major pillars of health that NQO1 directly influences. These pillars include
detoxification which entails the ratio of NAD to NADH, its ability as an
antioxidant, and lastly how it helps to stabilize the P-53 gene. Detoxification
and antioxidant activity go hand and hand. They are intertwined with each
other. Each of these pillars have extreme importance for our health and
detoxification pillar is a very important aspect of NQO1 functions. Much of the
detoxification deals with compounds called Quinones. Quinonoid compounds
generate reactive oxygen species (ROS). Quinones are ubiquitous in nature and
constitute an important class of naturally occurring compounds found in plants,
fungi and bacteria. Human exposure to quinones therefore occurs via the diet,
but also clinically or via airborne pollutants. For example, the quinones of
hydrocarbons are prevalent as environmental contaminants and provide a major
source of current human exposure to quinones. The inevitable human exposure to
quinones, and the inherent reactivity of quinones, has stimulated substantial
research on the chemistry and toxicology of these compounds. NQO1 is employed
in the removal of a quinone from biological systems as a detoxification
reaction: NAD(P)H + a quinone → NAD(P)+ + a hydroquinone.
The hydroquinone is excreted. This reaction ensures complete oxidation of the
substrate without the formation of semiquinones and reactive oxygen radicals
that are deleterious to cells. The localization of NQO1 in epithelial and
endothelial tissues of mice, rats and humans indicates their importance as
detoxifying agents, since their location facilitates exposure to compounds
entering the body. In addition to the detoxification, NQO1 helps produce NAD+
which in its own right is very important.
ratio of NAD+/NADH is of extreme importance. We are well aware of
the importance of NAD+ for our body. NAD+ is instrumental
in the production of ATP which is the body’s energy currency. However, NAD+
is also used in a variety of biological processes in the body. Nicotinamide
adenine dinucleotide (NAD+) is an essential pyridine nucleotide that
serves as an essential cofactor and substrate for a number of critical cellular
processes involved in oxidative phosphorylation and ATP production, DNA repair,
epigenetically modulated gene expression, intracellular calcium signaling, and
immunological functions. NAD+depletion
may occur in response to excessive DNA damage due to free radicals. This damage
results in significant poly (ADP-ribose) polymerase (PARP) activation and a
high turnover and subsequent depletion of NAD+. PARP is instrumental
in DNA repair. Also, chronic immune activation and inflammatory cytokine
production results in accelerated CD38 activity and subsequent decline in NAD+ levels.
now think that the NAD+/NADH ratio may be as important if not more
important than the levels of NAD+. One of the insights arising from
the scientific studies of calorie restriction is that the ratio of NAD+ to
NADH (NAD+/NADH ratio) might be important for the lifespan extension
benefits. This ratio has been reported to decline with age, with NAD+ being
decreased and NADH increased in older individuals. While boosting the amount
of NAD+ has been getting a lot of attention, improving the
ratio between NAD+ and NADH might be more significant than the
amount of cellular NAD+ in isolation. In yeast experiments,
calorie restriction decreases NADH much more dramatically than it affects NAD+.
This decrease in NADH is important for enhancing lifespan, because, on its own,
it increases activity of the NAD+ consuming enzymes that boost
longevity processes (e.g., Sirtuins) and DNA repair (e.g. PARPs) in yeast. This
is thought to occur because NADH is an inhibitor of these enzymes, so lowering
it releases the inhibition. As an example, inducing the enzyme NQO1—an enzyme
that uses NADH as an electron donor increases intracellular NAD+ levels
because it shifts the NAD+/NADH redox ratio in favor of oxidation
(NAD+). A side effect of this reaction is that intracellular NAD+
levels increase. Upregulation of the pathway that induces NQO1 occurs in
calorie restriction and appears to be an important component of producing the benefits.
We must remember that cellular levels of NAD+ are more important
than the serum levels.
review, what NQO1 does is convert NADH to NAD+ while at the same
time it maintains a very delicate ratio of NAD/NADH. This ratio is not affected
by dietary or IV intake. One important fact is that NQO1 will oxidize NADH to
NAD+ and thus it increases NAD+ in the cell.
HOW IS THE NQO1 PATHWAY REGULATED?
Another name for the NQO1 gene is the longevity
gene. NQO1, regulates the NAD+/NADH
ratio in cells. NQO1 does this by oxidizing NADH to NAD+.
During aging the ratio of NAD+ to NADH changes in part to a reduced
level of the expression of NQO1. As we age the cells accumulate a type of
protein called BET proteins. The BET proteins are Bromodomain and Extraterminal
Proteins. They are referred to as epigenetic readers. The following diagram
shows the various components involved in epigenetics, namely the writers,
erasers, and readers all of which effect gene behavior.
this case, the BET proteins will suppress the induction of the NQO1 gene. There
is now much research looking for inhibitors of BET proteins for a variety of
conditions including cancer.
levels of NQO1 will affect the amounts of a compound called Peroxisome
proliferator-activated receptor-gamma coactivator (PGC-1alpha). PGC-1a is a
member of a family of transcription coactivators that plays a central role in
the regulation of cellular energy metabolism. It is strongly induced by cold
exposure, linking this environmental stimulus to adaptive thermogenesis.
PGC-1alpha stimulates mitochondrial biogenesis and promotes the remodeling of
muscle tissue to a fiber-type composition that is metabolically more oxidative
and less glycolytic in nature, and it participates in the regulation of both
carbohydrate and lipid metabolism. Oxidative metabolism produces far more ATP
than the glycolytic type. It is highly likely that PGC-1alpha is intimately
involved in disorders such as obesity, diabetes, and cardiomyopathy. In
particular, its regulatory function in lipid metabolism makes it an inviting
target for pharmacological intervention in the treatment of obesity and Type 2
is regulated by the oxidative state of the cell. NQO1 will regulate the PGC-1a
levels by controlling the rate of PGC-1a degradation not its synthesis. Like many
regulatory factors, PGC-1a has an extremely short half-life. All of these
extremely short-lived proteins are regulated by degradation rates, not
synthesis rates. Higher levels of NQO1 shift the ratio of NAD+/NADH
and protect proteins from being oxidized. PGC-1 plays an important role in
regulating mitochondrial function. Higher levels of PGC-1a help prevent age
related mitochondrial dysfunction. Thus,
it appears that under conditions of oxidative stress, such as with aging,
NQO1 may be a major factor that controls the concentration of
PGC-1a in the cell. PGC-1a is not some esoteric co factor, it is
extremely important in many different functions as can be seen from the
following diagram. PGC-1α is a transcriptional coactivator that is a central
inducer of mitochondrial biogenesis in cells.
Thus, it appears that under conditions of oxidative
stress, such as with aging, NQO1 may be a major factor that controls
the concentration of PGC-1a in the cell.
ELSE DOES NQO1 STIMULATE?
seems to have a significant effect on the P-53 gene. It helps to stabilize the
P-53 gene. P-53 is many times referred to an the “Tumor Suppressor Gene”. It is
a potent sentinel in the body looking for and destroying cells which may go on
to tumor lines. It has the ability to fix DNA damage if it is not too severe or
if too severe it will destroy the cell. The following diagram shows P-53 in
is now thought that many cancers arise from a defect in the P-53 gene. It
appears that the NQO1-dependent (ubiquitin-independent) pathway is the most
important pathway for regulating p53 levels within the cell. Ubiquitin is a
small protein that is found in almost all cellular tissues in humans and other
organisms. It helps to regulate the processes of other proteins in the body.
Through a process known as ubiquitination or ubiquitylation, a ubiquitin
molecule can bind to a substrate protein, changing the way it functions. This
can lead to a number of different outcomes. It is most widely recognized for
its role in apoptosis of proteins, earning it the title of the molecular “kiss
of death” for proteins, although it also plays a major part in several other
cellular processes related to the regulation of proteins. If P-53 is working
properly hopefully the chances of a cancer arising are significantly
diminished. Treatment with curcumin augments the levels of P53 in tumor cell
lines through incrementing its half-life in a NQO1 dependent manner. Curcumin
treatment promotes the interaction between NQO1-p53.
CAN WE INCREASE THE PRESENCE OF NQO1?
statement that can be made across the board is that anything which increases
the NRf2 pathway will increase the NQO1 gene action. The NRf2 pathway has a
profound effect on the NQO1 gene. One can read my previous blogs concerning the
NRf2 pathway. I call this pathway the thermostat of anti-inflammation. One of
the important stimulators of the NRf2 pathway are ozone messengers which are
produced by intravenous ozone such as is delivered by the EBO2 protocol. These
messengers will allow the NRf2 to enter the nucleus and activate certain genes.
Another offshoot of the EBO2 protocol is the use of photodynamic therapy which
stimulated the NQO1 gene. Phototherapy also includes the stimulation of heat
shock proteins which are encouraged by the exposure of UVA light.
for those people unaware of the EBO2 protocol, it is a protocol which uses a
dialysis filter, intravenous Ozone gas, and photo modulation. The following is
a picture of the set up used in the EBO2 protocol:
compounds which seem to have stimulating influences on NQO1 include
resveratrol, Pterostilbene, Taxifolin (also called dihydroquercetin), sulforaphane (broccoli), curcumin, and
Fumaric acid derivatives.
important supplement perhaps the most important, to stimulate the NQO1 gene is Beta-lapachone, a compound found in
the bark of the South American Lapacho tree. It is a potent activator of the NQO1
gene and produces ROS in cancer cells, but reduces ROS in non-cancer
cells. Beta-Lapachone is a NQO1
activator. In addition to stimulating the NQO1 gene it stimulates the NRf2
pathway which helps to lower inflammation. Beta-lapacho was very popular a
number of years ago. It then seemed to lose it way. Now there is a resurgence
in the use of Beta-lapachone on multiple fronts including clinical studies in a
variety of universities. A few final thoughts, if a clinic is utilizing NAD+
but not stimulating the NQO1 pathway then they are behind the times. There are
a number of clinics which like to dabble in utilizing NAD on their patients. Unfortunately,
they are not aware of the basic science of NAD, its effect on senescent cells,
methods allowing the body to handle NAD better, and the importance of the NQO1
gene. If you encounter a clinic which is “just” utilizing NAD without
addressing these related matters, your best bet is to seek treatment
elsewhere!! This will ensure you the best chance of success. It is all a matter
of knowing the basic science of the various pathways and how these can be
manipulated to the benefit of the patient.
following illustration gives all the salient points about the NQO1 gene. There
is a reason why this is called the Longevity Gene. The answers lie in the
illustration. When all is said and done this seems to represent the essence of
The above was a recent headline. I know what my political persuasions are, and they should obviously never get in the way of science or the health of a patient. Furthermore, I always try to be non-political in my posts. I see that some members of the press have tried to ridicule President Trump for an idea of “getting light inside the body.” Here are the quotes attributed to the President: “Suppose that we hit the body with a tremendous, whether it’s ultraviolet or just very powerful light,” Trump said at the White House coronavirus press briefing, adding: “Supposing you brought the light inside the body, which you can do either through the skin or in some other way.” Well, low and behold, if reporters find this a ridiculous statement, then they need to do their homework and learn some science, and have a more analytical mind.I would like to mention a paper that was published a few years ago by Dr. Michael Hamblin. Michael Hamblin is a Principal Investigator at the Wellman Center for Photomedicine (see below) at Massachusetts General Hospital, an Associate Professor of Dermatology at Harvard Medical School and a member of the Affiliated Faculty of Harvard-MIT Division of Health Science and Technology.The next insert is a copy of the title page of a paper written and published by Dr. Hamblin in 2017.We can see that the title of the article is Ultraviolet Irradiation of Blood: “The Cure that Time Forget”. As one can see we have a PHD from Harvard and MIT who is a main principle investigator at Harvard’s photomedicine center state that ultraviolet light to the blood is a cure that time forget. So, it seems that that President was not off the mark at all. I think he is owed an apology by those in the media and in the medical community who ridiculed him. I have been fortunate to meet Dr. Hamblin when we were both lecturing at a regenerative medicine meeting. I consider him one of the world’s experts on photo-therapy. I read the above article a few years ago and found it intriguing. There are many similar articles. In this article there is a discussion of the potential of Ultraviolet Blood Irradiation (UBI) as an alternative approach to current methods used to treat infections. It goes on to say that this therapy can also be an immune-modulating therapy and also as a method for normalizing blood parameters. The article states there is no resistance of microorganisms to UV irradiation. Low and mild doses of UV kill microorganisms by damaging the DNA, while any DNA damage in host cells can be rapidly repaired by DNA repair enzymes. Ultraviolet light when used for sterilization purposes causes the direct destruction of pathogens. Many people believe that this is also the mechanism of action for UBI which is absolutely not the case. It is the stimulation of the immune system and its various components that gives ultraviolet light therapy is effectiveness in addition to destroying the micro-organisms.The following diagram is from the article by Dr. Hamblin. It shows some of the various aspects of UBI on the immune system. This may be a complicated picture but when all is said and done it is stimulating the immune system in many different ways. It is somewhat complicated to the lay person.UBI appears to have three broadly different classes of effects on different blood components. In the case of various white blood cells which are called neutrophils, monocytes, macrophages, and dendritic cells. UBI can activate phagocytosis. Phagocytosis is a process wherein a cell, in this case a type of white blood cell, binds to a microbe such as a bacteria or virus and engulfs it. UBI also increases the secretion of Nitric Oxide which stimulates the production of cells which can calm down an inflammatory reaction. By reducing the inflammatory response, we are lessening the effects of a “cytokine storm” as is often found in infections and seems to be the crux of many Covid-19 complications. The oxidative nature of UBI may have mechanisms in common with ozone therapy and other oxygen therapies. Namely, we are reducing the oxidative stress on the immune system. Oxidative stress is an imbalance between free radicals and antioxidants in your body. Free radicals are oxygen-containing molecules with an uneven number of electrons. The uneven number allows them to easily react with other molecules. Free radicals can cause large chain chemical reactions in your body because they react so easily with other molecules. These reactions are called oxidation. They can be beneficial or harmfulThink of oxidative stress as synonymous with inflammation and inflammation is the root of most medical problems.Dr. Hamblin’s article is but one article concerning the use of light therapy. I think there is little doubt there is strong science behind the use of ultraviolet blood irradiation and for that matter phototherapy to treat a number of medical conditions. Although this seems like cutting edge therapy it is actually old. Ultraviolet blood irradiation (UBI) was extensively used in the 1940s and 1950s to treat many diseases including septicemia, pneumonia, tuberculosis, arthritis, asthma and even poliomyelitis. The early studies were carried out by several physicians in USA and published in the American Journal of Surgery. However, with the development of antibiotics, UBI use declined and it has now been called “the cure that time forgot”. Hopefully more research on various types of blood irradiation will be performed. I would also like to include a few slides from my lectures. These slides concern the use of phototherapy. The first slide is a summary of phototherapy.As we can see there are a myriad of beneficial aspect to light therapy. I will draw your attention to sentence six, “Whatever cells are designed to do will be improved by light therapy”. The next slide shows some of the many benefits of phototherapy in pictorial form.The takeaways from the above slide is that light therapy is intimately involved in cell energy production, positively impacts cellular repair and healing, stimulates the immune system. As President Trump said “GET THE LIGHT INSIDE THE BODY” and hopefully control the covid-19 virus. Certainly, no guarantees or cures but it might be a step in the right direction. Actually, we can take things to the next level by giving the patient certain medications which are called photosensitizers. Photosensitizers make light therapy work even better. However, this is a discussion for a different day. I will end this quick blog with a rather somber thought. Covid -19 is certainly a serious problem for our planet and I believe we will conquer it. I would like to present some information by the Rand Europe Think Tank. Unfortunately, there are much greater biological time bombs that may be facing us. One ticking time bomb we are facing is that of antibiotic resistance. Here is the chart of what we are facing, namely approximately 10,000,000 deaths per year caused by antibiotic resistance. It might just be that blood irradiation may save the day. Meantime, stay safe and get some sunshine which is a primitive form of blood irradiation.Thanks,Dr. P DEATHS PER YEAR SECONDARY TO ANTIBIOTIC RESISTANCE 2050 2050Thanks,- Dr. P