blood oxygenation + ozonation is a protocol that begins with the placement of
two IV catheters. One of these catheters is used to pull blood out of the body,
run it through a dialysis filter, the blood then gets ozonated and infused into
the other catheter in the other arm. As the blood comes out it is typically a
dark color, but after it is filtered and ozonated, it becomes a clean bright
top 3 benefits of EBO2 are as follows:
stimulates a pathway in the body that dramatically decreases inflammation and
even continues to loosen up the inflammation hiding away in the tissues for
some time after the protocol! This inflammation can even be seen as foam in the
waste container. Yes, you'll be able to see the inflammation leaving your body!
This makes the protocol excellent for anyone with an autoimmune disease.
Lowers cholesterol & fat in
○ As the
blood comes out of the body, many times you'll be able to see the yellow globs
of fat leaving the body. These get trapped in the filter and leave your body
for good! Triglycerides and Cholesterol levels can be lowered significantly
with a number of treatments.
Kills Virus, Bacteria, &
has amazing antibacterial, antiviral and anti-fungal properties. To take this a
step further, we use an Ultraviolet light to further impose its antimicrobial
effect. This makes the protocol excellent for patients suffering with Lyme
disease and mold exposure.
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
We have recently obtained another key weapon in our
office. This weapon is a true Class 4 COLD LASER. But this is not like the
typical class 4 laser. Many people know about lasers but are not exactly sure
how they achieve their goals. The basic science of lasers is that they use the
principle of Photobiomodulation. The following illustration shows this concept.
Photobiomodulation is defined as a form of
light therapy that utilizes non-ionizing light sources. These include near ultraviolet, visible light, infrared, microwave, radio waves,
and low-frequency radio frequency (long-wave) are all examples of non-ionizing radiation. By contrast, far
ultraviolet light, X-rays, gamma-rays, and all particle radiation from
radioactive decay are ionizing
light sources. Photobiomodulation is a NON-THERMAL process involving endogenous
chromophores. The first law of photobiology
explains that for a low power visible light to have any effect on a living
biological system, the photons must be absorbed by electronic absorption bands
belonging to some molecular photo-acceptors, which are called chromophores.
Here is a good explanation of chromophores.
A chromophore is the part of a molecule
responsible for its color. The color that is seen by our eyes is the one not
absorbed by the reflecting object within a certain wavelength spectrum of
visible light hence the objects steal the objects from the wheel. Chromophores will elicit reactions at various biological sites. This process
results in beneficial therapeutic outcomes including but not limited to the
alleviation of pain or inflammation, immunomodulation, and promotion of wound
healing and tissue regeneration. We can see this principle in
the following illustration:
What we are able to see is that a very
important aspect of laser therapy involves the mitochondria. The mitochondria
produce ATP which is the body's energy currency. It does this by stimulating
the Cytochrome C Oxidase which is an enzyme in the electron transport chain of
the Krebs cycle. Laser therapy produces a
shift in overall cell redox potential in the direction of greater oxidation and increased Reactive Oxygen Species
(ROS) generation. In a biological
context, ROS are formed as a natural byproduct of the normal aerobic metabolism
of oxygen and have important roles in cell signaling and homeostasis. ROS are well known to stimulate
cellular proliferation of low levels, but inhibit proliferation and kill cells
at high levels. Nitric oxide is also involved in laser therapy. It may be
photo-released from its binding sites in the respiratory chain and elsewhere.
Nitric oxide will increase vasodilation and thus increasing blood supply.
Nitric oxide may also act as a neurotransmitter helping with pain control. Also,
not to be overlooked is the fact that the mitochondria have many important
tasks in many other aspects of cell biology and cell signaling pathways.
It has been proposed that
the redox state of a cell regulates cellular signaling pathways that control
gene expression. Modulation of the cellular redox state can activate or inhibit
signaling pathways. When we start affecting the various pathways and affecting
gene expression we have now crossed into the field of Epigenetics. Several
regulation pathways are mediated through the cellular redox state. Changes in
redox state induce the activation of numerous intracellular signaling pathways,
such as nucleic acid synthesis, protein synthesis, enzyme activation and cell
When all is said and done the application of a
therapeutic dose of light to impaired or dysfunctional
tissue leads to a cellular response mediated by mitochondrial mechanisms that
reduce pain and inflammation, speed healing, and cell hemostasis. These cellular mechanisms responsible for the effect of
visible light on cells include cytochrome c oxidase. Mitochondria are thought
to be a likely site for the initial effects of light, leading to increased ATP
production, modulation of reactive oxygen species, induction of transcription
factors, and possible changes in mitochondrial DNA. These effects in turn lead
to increased cell proliferation and migration particularly by fibroblasts.
Fibroblasts are responsible for the production of collagen which is a basic
building block for many of the bodys tissues including bone, cartilage etc. The
lasers overall effect is that it will
bio stimulate cells to increase cellular growth and regenerative activity,
while simultaneously deactivating 7 or the 9 enzymes that cause inflammation by
up to 70%.
Another unique aspect of lasers is that they are considered to be monochromatic,
coherent and collimated. Monochromatic means that there is a single wavelength
which stimulates particular human tissues that will only respond to that
specific wavelength being utilized. Coherent means that it minimizes the photon
scatter as light interacts with the tissue. Lastly, because lasers have a
higher power that works with a specific wavelength, they are collimated which
allows it to actually reach the deep tissues. The following illustration drives
home these points.
ARE LASERS CLASSIFIED?
One may ask how are the lasers classified? The FDA classifies lasers from I to IV. For instance, a Class IV Laser is any laser
device that the FDA has determined is powerful enough to pose a significant
risk of injury to the eye. Consequently, being Class IV does not necessarily
laser more effective, as that would depend upon
what you intend to do with it and how you use it. Some Class IV lasers are used
in health and medical settings for a wide range of therapeutic applications.
Others are used for construction, cutting, burning and by hobbyists such as
high-powered laser pointers.
Let us look at some further
perimeters of the Class IV Lasers. Hot lasers are known as Class IV lasers. Class IV lasers
have a power output above 500 milliwatts (mW). At a lower power range, hot
lasers are used for therapeutic purposes. Class IV lasers can cut tissue during
surgical procedures. Most Class IV lasers are called hot lasers because they
can rapidly increase tissue temperatures. The one common tread with class IV
lasers is that they have higher power outputs and most translate the energy to
On the other hand, most, cold lasers are also known
as low-level lasers, they are among Class II and Class III lasers. Cold lasers
have a power output of less than 500 mW. These lasers are called cold because
they do not generate a thermal effect. But we must realize that the decreased
power will also decrease the penetration depth of the laser. The vast majority
of lasers in medical use are not true class IV cold lasers but class III
lasers. Many of them are advertised as a Class IV lasers but in reality, they
are Class III lasers. If they happen to a Class IV laser then most of the
energy is expended as heat. They may have some bells and whistles and other
gimmicks. But it does not make them any more effective. As we can see in the
following illustration, typically a Class IV laser will need much less
treatment time than a Class III laser. Also, we will obtain a much greater
depth of penetration with the Class IV laser. What most medical professionals
do not seem to understand is that a laser with many medical benefits produces
it benefits with LIGHT ENERGY NOT HEAT. Thus, when one is looking to
derive benefits from the laser, heat should not be a consideration. THE
PHOTONIC ENERGY IS WHAT ONE NEEDS TO BE CONCERNED ABOUT. The following
illustration will give an idea about the difference. The most significant
difference in the various types of lasers is the depth of penetration.
There is a misunderstanding
that a more efficient laser will produce heat.
This is simply not the case. Most of the time when we are utilizing a laser we
are interested in the depth of penetration. We also do not wish to subject the
patient to long hours of treatment. So, if we can eliminate the heat and get
penetration of depth than we may have something special. When all is said and
done IT IS THE PHOTONIC ENERGY WHICH ACCOMPLISHES THE REPAIR.
WHAT WOULD BE MY CHOICE FOR AN OPTIMAL LASER?
I have used lasers for many years. The use of lasers
for musculoskeletal conditions has long passed the point of being experimental.
There are many different types of lasers in use. In our clinic we have been
very happy with our laser sleeves and our original hand-held Class IV type
laser. The original Class IV laser which we have been using requires eyewear
protection and it will produce heat which could burn the skin. Nevertheless, it
was efficient but at the same time there was a risk of thermal injury and
because of the thermal considerations I believe the penetration was limited.
If I were able to design a laser I would want one to
be a Class IV laser that essentially did not cause any thermal damage. To be
effective, the laser would have to have a power output of greater than 500
milliwatts. It would need to be monochromatic and have a wavelength of
approximately 680 mM which is the ideal wavelength to stimulate the
mitochondria. This is the sweet spot in the red spectrum range.
It obviously requires eyewear. Also, it is cold laser. What are the differences
between and hot and cold laser? Again, Cold Lasers are therapeutic
lasers that produce an insignificant amount of heat and are extremely safe for
use by professionals.
us take a look at the specs of the new laser. The output of the new laser is
750 milliwatts. Remember, the energy output for the Class IV laser is above 500
milliwatts. So, we definitely classify as a Class IV laser by power output. The
new laser is monochromatic so it essentially stays on one wavelength and its
wavelength is 680 nM which is the sweet spot for mitochondrial stimulation etc. The
wavelength is 680 nm. This is the sweet spot in the red spectrum range. This
provides both a large safety margin and potent force. If
we were to lower the wavelength we could lower the safety margin. The last
aspect to an ideal laser is what is called lumen intensity. We need to look at
some physical aspects of light when looking at lumen intensity. There are three
terms we want to know when assessing lumen intensity. These are lumens, lux and
candela. A good way to remember the differences
between terms is:
are how much light is given off
how bright your surface will be
measures the visible intensity from the light source.
The lumen intensity of the new laser is 550 lumens per millimeter
of tissue radiated. The beam profile is one millimeter. This last spec will
allow the user to pinpoint targeting tissue. Example would be a meniscus tear
located posteriorly in the medial compartment, or a tear in the supraspinatus
located inferior to the acromion for example. This later spec you can only
utilize the function of when the laser is a true class four. You need the power
of penetration without the heat damaging aspect. This is a very important aspect
and the one important principle which needs to be conveyed and understood - not
easy to do! True photonic intervention is dependent on absorption of the light
force or energy. Not in the heat transmission normally incorporated into laser
modules. The light is the energy! Again, we see a picture of our new Class IV
laser. Notice it is a hand-held laser. It is battery powered. Many times,
simplicity is a goal strived for but many times seldom achieved.
The next illustration is a summation of all the
benefits our new Class IV laser is able to achieve while at the same time being
extremely safe to the patient as long as the proper eye precautions are taken. The
last two illustrations are videos comparing the new class IV cold laser with a
typical Class IV laser. The differences between the two are remarkable.
The last two items really drive home the point of what
makes this Class IV cold laser a truly unique laser. They are pictures and
videos on two types of Class IV lasers. One is a typical Class IV laser which
most medical professionals are familiar with. The other is the new Class IV
cold laser. I did an experiment with two Class IV lasers. The first
illustration is the typical Class IV laser. Now the wattage used with this
laser is in the 6-watt range. This would probably cause a burn to the skin at
this power especially if it were kept in the same spot. On the other hand, the
second image is the true Class IV cold laser. Notice the difference in light
I suspect this new Class IV cold laser may be a game
changer. The preliminary results in the office are quite impressive. We are
truly making use of photonic energy to make a difference. Time will tell, but
this seems to be exactly what we asked for.
Below is the Class IV hot laser shined into a container having a mixture and saline. We can see the red color from the laser is not vibrant. Realize that when the laser is being used on the body it will need to penetrate a mixture of saline and blood.
The next picture and video are of the new Class IV cold laser. Notice how vibrant the color is. The same will happen in your body. Realize that the only difference between these pictures is the lasers. The container is the same container.
This is an especially fascinating study as far as
aging is concerned. I left the article link at the end of my write up. What
this study looked at was the ability of long-lived people to repair DNA damage.
In this particular case they looked at inherited
and naturally occurring genetic changes in older people. They found in the
long-lived population two particular genes COA1 and STK17A. These are rather
esoteric names but the importance is there! COA1 is involved with energy
production and communication between the mitochondria and the cell nucleus.
COA1 performed three functions that are part of the blue prints for anti-aging
platforms. They directed cell response to DNA damage, they prompted badly
damaged cells to die off, and controlled the amounts of Reactive Oxygen
Species. I suspect these genes are stimulating the P-53 gene. P -53 is called
the tumor suppressor gene. Taking things one step further, remember that NAD+ is a substrate for DNA
repair proteins such as PARP1, PARP2 and PARP3 as well as
enzymes that can influence DNA
repair capacity such as SIRT1 and SIRT6. The PARP enzymes
typically get shut off when the body does not have enough NAD+ to go
around. Looks like there may be some
overlap here. Activate the DNA repair genes and you may live longer. At least
you are giving yourself better odds. This is why I feel it is of paramount
importance to take NAD supplements both orally and intravenously. Also remember,
there is much science out there that shows Ozone therapy can increase the NAD
levels in the body in addition to dramatically decreasing damage from Reactive
Oxygen Species. The moral of the story here is:
MAKE SURE YOU TAKE YOUR NAD TO
STAY YOUNG.Here is the article I am talking about:https://bigthink.com/surprising-science/semi-supercentenarians-dna-repairThanks,Dr. P
The more involved I become with stem cells and
the field of Regenerative Medicine, the more convinced I become of the
importance of the mitochondria. Many of us in clinical medicine seem to brush
over mitochondria. We now realize that many diseases are related in some way to
deficiencies of the mitochondria. Success in stem cell procedures may depend on
the health of the mitochondria. The above illustration shows the structure of
the mitochondria. Mitochondria
are rod-shaped organelles that can be considered the power generators of the
cell, converting oxygen and nutrients into adenosine triphosphate (ATP).
ATP is the chemical energy "currency" of the cell that powers the
cell's metabolic activities. Mitochondria
are often referred to as the powerhouses of the cell. They help turn the energy
we take from food into energy that the cell can use. But, there is more to
mitochondria than energy production. In
fact, only about 3 percent of the genes needed to make a mitochondrion go
into its energy production equipment. The vast majority are involved in other
jobs that are specific to the cell type where they are found. Here is another illustration of the inner
workings of the mitochondria
The mitochondria have two
membranes, an outer one and an inner one. Each membrane has different
functions. The Outer membrane allows small molecules to pass freely through the
outer membrane. This outer portion includes proteins called porins, which form
channels that allow proteins to cross. Most cellular stress
responses converge on the mitochondria. Consequently, the mitochondria must
rapidly respond to maintain cellular homeostasis and physiological demands by
fine-tuning a plethora of mitochondria-associated processes. The outer
mitochondrial membrane proteins are central to mediating mitochondrial
dynamics, coupled with continuous fission and fusion. These proteins also have
vital roles in controlling mitochondrial quality. When
cellular components like mitochondria become damaged or defective, they can be
recycled by cells through a process called autophagy, which literally means
self-eating. When mitochondria are degraded by autophagy, the process is
specifically referred to as mitophagy. Mitophagy often
occurs in defective mitochondria following damage or stress. This is
actually one of the important aspects of aging. As we age, mitophagy will
diminish resulting in increased damaged mitochondria. This has a snowball effect
in that it leads to increased reactive oxygen species (ROS), decreased
bioenergetics, and many age-related diseases. Mitochondrial damage may be the
seminal event in many different diseases. If we increase mitophagy we will slow
down aging. The following illustration shows the consequences of accumulated
The next structure to discuss is the inner mitochondrial membrane. It is
extensively folded and compartmentalized. The numerous invaginations of the
membrane are called cristae. Which are separated by crista
junctions from the inner boundary membrane juxtaposed to the outer membrane.
Cristae significantly increases the total membrane surface area compared to a
smooth inner membrane and thereby the available working space. The inner membrane is also loaded with proteins involved in electron transport and
ATP synthesis. This membrane surrounds the mitochondrial matrix, where the citric
acid cycle produces the electrons that travel from one protein complex to the
next in the inner membrane. The crista membranes contain most, if not all, of
the fully assembled complexes of the electron transport chain and the ATP
synthase. The following illustration demonstrates this concept. We see the two
membranes and subsequent ATP production. In review, at the inner mitochondrial
membrane a high energy electron is passed along the electron
released pumps hydrogen out of the matrix
space. The gradient created by this drives hydrogen back through the membrane,
through ATP synthase. As this happens, the enzymatic activity of ATP synthase
synthesizes ATP from ADP. This whole process is called oxidative
phosphorylation (OXPHOS), which is the main method and most efficient method
the body uses to make ATP. The more efficient this process the better in shape
Another structure present is the
mitochondrial ribosomes. Mitochondrial
ribosomes (mitoribosomes) perform protein synthesis inside mitochondria.
Throughout evolution, mitoribosomes have become functionally specialized for
synthesizing mitochondrial membrane proteins. Mitochondrial ribosomes resemble bacterial ribosomes and both bacteria
and mitochondria ribosomes share a slightly different genetic code from that in
the nucleus. Actually, we see that ribosomes have two parts, a large and a
Although most DNA is packaged in chromosomes within the nucleus, mitochondria also have a small amount of their own DNA. This genetic material is known as mitochondrial DNA or mtDNA. Mitochondria are a trans-kingdom enigma. At the molecular level, the components of Human mitochondria are assembled from viruses, bacteria, and other organisms. As such, the organelle we see in human cells today is called a trans-kingdom mixture that doesn't fully resemble any of its ancestors.
genome is built of
16,569 DNA base pairs, whereas the nuclear genome is made of 3.3 billion DNA base pairs. In keeping with its bacterial ancestry, mtDNA
is also circular and multicopy with hundreds to thousands of copies present in
every cell. mtDNA is very genetically compact and encodes only 13 proteins, all
of which are core subunits of the oxidative phosphorylation (OXPHOS) complexes.
These OXPHOS complexes, found only within mitochondria, are unique in human
biology as they are the only cellular structures formed of proteins encoded by
genes from the two separate genomes. The nuclear DNA provides around 90% of the
required proteins for OXPHOS, and the mtDNA provides the remaining 10%.
Remember that the OXPHOS complexes are responsible for ATP production.
Mitochondria are the only organelle to have their own DNA. Mitochondrial
DNA (mtDNA) is more susceptible to damage (including mutations) than nuclear
DNA. The reason for this is many folds. Most likely this is due to a lack
of histones to protect the DNA from damage. The below diagram gives a brief
explanation of histones. Histones package and order the DNA into structural units called nucleosomes. They
act as spools around which the DNA gets coiled and thus a very long strand of
DNA can be fit into a much smaller space. This is demonstrated in the
DNA damage is also caused by the proximity of mtDNA to
Reactive Oxygen Species (ROS) production. We must remember that the
mitochondria are engaged in oxidative phosphorylation which means that they are
using oxygen to produce energy. The by-product of the energy production is the
ROS. Also, mtDNA has limited DNA repair systems and limited proofreading
capacity during replication all of which can lead to accumulated mitochondrial
DNA damage. Furthermore, the mitochondrial DNA is ever changing. When a cell divides, its
mitochondria are partitioned between the two daughter cells. However, the
process of mitochondrial segregation occurs in a random manner and is much
less organized than the highly accurate process involved in nuclear DNA
division during cell replication commonly called cell mitosis. As a result,
daughter cells receive similar, but not identical, copies of their
WHAT REGULATES THE
MITOCHONDRIA? THE SIRTUIN FAMILY OF PROTEINS
Sirtuins are a
family of proteins that regulate cellular health. Sirtuins play a key role in
regulating cellular homeostasis. Homeostasis involves keeping the cell in
balance. Sirtuins can only function in the presence of NAD+,
nicotinamide adenine dinucleotide, a coenzyme found in all living cells. NAD+
is vital to cellular metabolism and hundreds of other biological
processes. Humans contain
seven sirtuins (SIRT1-7) that modulate distinct metabolic and stress response
pathways. Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in the mitochondrion.
The others are found in the nucleus and one in the cytoplasm. The basic role of sirtuins, however, is that they remove
acetyl groups from other proteins. Acetyl groups control specific reactions.
They are physical tags on proteins that other proteins recognize will react
with them. Sirtuins work with acetyl groups by doing whats called
deacetylation. This means they recognize theres an acetyl group on a molecule
then remove the acetyl group, which tees up the molecule for its job. One way
that sirtuins work is by removing acetyl groups (deacetylating) biological
proteins such as histones. When the histones have an acetyl group, the chromatin is
open, or unwound. When the histones
are deacetylated by sirtuins, the chromatin is closed, or tightly and neatly
wound, meaning gene expression is stopped, or silenced. This is not that common
for the Sirtuins in the mitochondria.
Mitochondria regulation is where things get interesting. If we start
manipulating the regulation of the mitochondria then there are a whole host of
conditions from aging to chronic neuro-degenerative conditions which we might
be able to impact. Recent findings have shed light on how the mitochondrial
Sirtuin functions in the control of basic mitochondrial biology, including
energy production, metabolism, apoptosis, intracellular signaling and perhaps
most importantly mitochondrial genesis. The following diagram shows some of
What these Sirtuins
do is help in the generation of cellular energy. As high-energy
electrons derived from glucose, amino acids or fatty acids fuels are passed
through a series of protein complexes (I-IV), their energy is used to pump
protons from the mitochondrial matrix through the inner membrane into the
inner-membrane space. This is referred to as the electron transport chain.
Ultimately, the electrons reduce oxygen to form water, and the protons flow
down their gradient through ATP synthase, driving the formation of ATP from
ADP. Reactive oxygen species (ROS) are a normal side-product of the respiration
process. ROS are essentially free radicals. During cellular stress or damage,
mitochondria release a variety of signals to the cytoplasm and the nucleus to
alert the cell of changes in mitochondrial function. In response, the nucleus
generates transcriptional changes (stimulates certain genes) to activate a
stress response or repair the damage. The main function of mitochondria is to metabolize or
break down carbohydrates and fatty acids in order to generate energy.
In review, ATP
generation occurs within the mitochondrial matrix, though the initial steps of
carbohydrate (glucose) metabolism occur outside the organelle. Glucose is first
converted into pyruvate and then transported into the matrix. Fatty acids on
the other hand, enter the mitochondria as is.
ATP is produced
through the course of three linked steps. First, using enzymes present in the
matrix, pyruvate and fatty acids are converted into a molecule known as
acetyl-CoA. This then becomes the starting material for a second chemical
reaction known as the citric acid cycle or Krebs Cycle. This step produces
plenty of carbon dioxide and two additional molecules, NADH and FADH2,
which are rich in electrons. The two molecules move to the inner mitochondrial
membrane and begin the third step: oxidative phosphorylation. In this last
chemical reaction, NADH and FADH2 donate their electrons to
oxygen, which leads to conditions suitable for the formation of ATP. As an
interesting aside, the optimal ratio of NAD+ /NADH is 700/1. Greater
amounts of NADH lead to aging. NADH is considered a marker of aging. A
secondary function of mitochondria is to synthesize proteins for their own use.
They work independently, and execute the transcription of DNA to RNA, and translation
of RNA to amino acids (the building blocks of protein), without using any
components of the cell.
Another aspect that the Sirtuins control is the control of
Apoptosis. Apoptosis is a cellular process of programmed cell death. This
occurs when the mitochondrial outer membrane allows much more permeability than
normal. This will ultimately commit the
cell to death. Mitochondrial
sirtuins act in synergistic or antagonistic ways to promote respiratory
function, antioxidant defense, insulin response and adipogenesis all of which
can protect individuals from aging and aging-related metabolic abnormalities.
If these cells are not dealt with they might become senescent cells. A
senescent cell is one that should have died but continues to remain alive. The problem
with the senescent cells is that they will release a number of inflammatory
growth factors which can cause havoc in the body.
HOW DO WE KEEP OUR
We have seen the ins and outs of the mitochondrial structure and
function. The question that begs is how do we keep the mitochondria healthy? More and more research
articles demonstrate the foundational importance of optimal mitochondrial
function for health. There is a growing body of research
showing that mitochondrial dysfunction is surprisingly common and associated
with most chronic diseases. The above and below illustrations give us an idea
of how to keep our mitochondria running smoothly. The first illustration shows
some supplements which keep things running smoothly:
The second illustration shows not only specific supplements but also
classes of supplements such as polyphenols (Polyphenols are micronutrients that we get through certain
plant-based foods) and proanthocyanidins (these are chemical
compounds that give the fruit or flowers of many plants their red, blue, or purple
colors). It also stresses some lifestyle factors that can increase mitochondrial
efficiency. The specific supplements that enhance mitochondria function are
evident in the list. Let us talk specifically about some of the polyphenols. They are included in many supplements, though they're also
easy to get in your diet from foods like fruits, vegetables, teas, and spices.
There are more than 8,000 types of polyphenols. A lack of polyphenols isnt associated with specific
side effects. However, they are regarded as lifespan essentials'' for
their potential to reduce the risk of chronic diseases. This is especially true
based on their effects on the mitochondria. Research suggests that supplementation with
pyrroloquinoline quinone, also known as PQQ, can improve the number of
mitochondria in the body while enhancing their functionality. This research
also suggests that effective treatment for many diseases caused
by mitochondrial dysfunction may rest at least partly in this
coenzyme. PQQ is readily found in the soil, so it
makes sense that the best dietary sources are fruits and vegetables grown in
that soil. Fermented foods are rich in these molecules. One of the best sources of PQQ is very dark chocolate.
The above illustration shows some of the main peptides produced by the
mitochondria. Mitochondria derived peptides (MDPs) are a series of peptides encoded by mitochondrial DNA, and have similar
functions to mitochondria. They are new metabolic regulators of human body, and play a
cytoprotective role in maintaining mitochondrial function and cell viability
under pressure. Peptides
are biomolecules comprised of amino acids which play an important role in
modulating many physiological processes in our body. Peptides are
short strings of amino acids, typically comprising 250 amino acids. Amino
acids are also the building blocks of proteins, but proteins contain
more. Peptides may
be easier for the body to absorb than proteins because they are smaller and
more broken down than proteins.
Mitochondria produce numerous small polypeptides from their short open
reading frame (sORF) regions of mtDNA that have significant biological
activity. These include humanin, six small-humanin like peptides, and MOTS-c
(mitochondrial open reading frame of the 12S rRNA type-c), together termed
mitochondrial derived peptides (MDP). MOTS-c is a peptide which is called an exercise mimetic. Exercise
Mimetics are novel ways
of getting the benefits of exercising, without having to exercise. Multiple
studies have demonstrated MOTSc's ability to enhance lipid
beta-oxidation, increase thermogenic brown fat, decrease fat gain on a high-fat
diet, and improve glucose uptake during glycolysis. Various mitochondrial
peptides are produced but their use is not allowed in the USA under the current
regulations. Hopefully, this will change with time.
As time goes on we are discovering more and more about the importance of
the mitochondria and their ramifications to our health lifespan. We see that
methods to boost mitochondria efficiency are varied. But when all is said and
done. Some of the most important factors are exercise especially intermittent
high intensity training, intermittent fasting, a variety of supplements
including NAD. Low levels of oxidative stress such as is produced by
intravenous ozone therapy are also important in the proper function of the
mitochondria. We must remember that mitochondrial decay is inevitable; it cannot be prevented, at least with todays technology.
What is not inevitable is the rate of decay. The mitochondrial rate of
decay is determined by one thing: oxygen efficiency. Perhaps the following
diagram sums it all up:
We see many bad things happen when our mitochondria are not working
Nrf2 is also called the Nuclear factor erythroid 2-related factor 2. NRF2 is a transcription factor that activates over 500 genes. The main reason NRF2 is so highly sought, is because it is a key transcriptional regulator of several antioxidant and anti-inflammatory enzymes. Nrf2 is now recognized to be involved in the cellular response to multiple stressors including foreign substances, excessive nutrient/metabolite supply, inflammation, and the accumulation of misfolded proteins. The Nrf2 protein, known as a transcription factor because of its ability to control genes, is the key component of a pathway (a sequence of biochemical reactions in a cell) that senses and responds to changes in oxidative balance. Nrf2 is one of the body’s major pathways. We need to think of the pathways as the body’s computer software and the cells and organs as the computer hardware. Nrf2, in fact, regulates many hundreds of genes that have nothing to do antioxidant enzymes per se, but rather provide protection from a broader range of stress-related events that are encountered by cells, organs, and organisms, under both normal and pathological circumstances. The Nrf2 pathway is under tight control. When the Nrf2 protein in bound in the cytoplasm it is essentially inactive. The following illustration shows this concept. This illustration is essentially the essence of how the Nrf2 pathway functions. We must remember that Nrf2 is a protein. Proteins, although they are typically confined within the cell or on a cell, have a complicated life cycle. The illustration shows the complicated cycle of the Nrf2 ecosystem. It actually demonstrates its actions in the cell. For example, soon after NRF2 is made by ribosomes in the cytoplasm, it is normally sequestered by KEAP1, which quickly loops the Nrf2 protein with ubiquitin ligase Cullin3 for transport to the proteasome. Here, the ubiquitin is stripped off and NRF2 is degraded and recycled. If all is well in the cell, this process gives NRF2 a half-life of about 20 minutes. Remember, if all is well in the cell Nrf2 is typically not active. Looking at the diagram in a different manner we see that the Nrf2 is held “prisoner” in the cytoplasm. The “prison guard” is called Keap1. If given the opportunity Keap1 will go on and destroy the Nrf2 protein. This is called proteasomal degradation. Given the right conditions (in this case a stress to the body) the Nrf2 protein breaks the stranglehold that the Keap1 proteins maintain. The Nrf2 protein then makes its way to the nucleus where it can eventually react with certain genes and produce certain beneficial compounds. A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway. This explanation is basic but it gives the essentials of how the Nrf2 protein functions. WHAT ARE THE STRESS CONDITIONS THAT STIMULATE THE NRF2 PATHWAY?The Nrf2 pathway senses the need for antioxidant enzymes and regulates their production to maintain metabolic balance. The sensing components of the pathway chemically modify and release Nrf2 so that it may diffuse into the nucleus of the cell where the DNA resides. Once in the nucleus, the Nrf2 will start reacting with a variety of genes found in the DNA of the nucleus. It can then “switch on” or “turn off” the genes it controls (often termed survival genes) to produce the protected state within the cell. Our DNA encodes about 20,000 genes, each representing a “blueprint” for the production of a protein or enzyme necessary for a healthy existence. Each of these “blueprints” requires a regulating control called a “promoter” that determines precisely how much of each product is produced, and under what circumstances. By binding to one specific type of these switch-like promoter regions called the “Antioxidant Response Element (ARE)”, the Nrf2 factor controls the rate of production from hundreds of different genes that allow cells to survive under stressful conditions.NRF2 is part of a group of transcription factors called nuclear receptors. Transcription factors are proteins involved in the process of converting, or transcribing, DNA into RNA. Transcription factors include a wide number of proteins that initiate and regulate the transcription of genes. Once the Nrf2 translocates to the nucleus, it results in the production of Anti-Oxidant Response Elements. There are a number of these elements including Glutathione, Catalase, and a number of other anti-oxidants. We should think of these as endogenous antioxidants. Meaning they are made by the body. These are quite powerful. The next illustration shows more of the whole picture of the Nrf2 pathway. From the Nrtf2 stimulators to the actual response elements to the blocking of the reactive oxygen species (ROS) by the response elements. Ultimately, like many pathways in the body, the Nrf2 pathway targets the mitochondria. The illustration shows certain agents which block the Nrf2 and others which encourage its activation by disabling the stranglehold the Keap1 protein has on the Nrf2 protein. The following is a diagram of transcription factors:The illustration shows how Nrf2 handles the inflammation caused by the ROS. Inflammation is the most common feature of most chronic diseases and complications. Several studies have demonstrated that Nrf2 contributes to the anti-inflammatory process by orchestrating the recruitment of inflammatory cells and regulating gene expression through the antioxidant response elements (ARE). These genes produce a large variety of antioxidant enzymes that create a network of protection by neutralizing primary and secondarily generated oxidants and by cleaning up the toxic byproducts they leave in their wake. Also, they help to repair the damage the oxidants have caused. This is especially important for mitochondrial health. Mitochondria help produce free radicals (Reactive Oxygen Species=ROS) and at the same time are very susceptible to their damage. Oxidants such as the superoxide radical (O2-) and hydrogen peroxide (H2O2) are produced by the process of “burning” the foods that sustain us. The Nrf2 pathway senses the need for these antioxidant enzymes and regulates their production to maintain metabolic balance. Several things can upset this delicate balance, the most significant one is aging. Unfortunately, aging slowly tips the balance toward the oxidative side resulting in “oxidative stress.” Disease processes can also result in overproduction of oxidants. Many major diseases associated with aging, such as heart attacks, stroke, cancer, and neurodegenerative conditions such as Alzheimer’s disease also increase production of oxidants thus creating oxidative stress and inflammation. When our immune cells are stimulated they can produce reactive oxidants (O2-, H2O2, OH, and HOCl) to deal with both bacteria and viruses. This can result in the destruction of the viruses and bacteria. But the problem with these compounds is that our otherwise healthy cells get caught in the cross-fire and sustain collateral damage that we see and feel as inflammation. Unfortunately, we have seen this phenomenon in patients with a Covid 19 infection. They get such a vigorous immune response it is called a cytokine storm. Cytokine storms are one of the contributing factors to the high numbers of Covid deaths.HOW CAN WE HELP STIMULATE NRF2?The above diagram shows many of the moving parts of the Nrf2 pathway and its stimulation and resulting end products. In this illustration we see the arch villain of the Nrf2 pathway. This villain is called the NFkB pathway. This pathway is the opposite of the Nrf2 pathway. It is the thermostat of inflammation. It is a very important pathway. We must remember that some inflammation is essential. It is when the NFkB pathway gets over-stimulated that problems arise. Recent research has identified certain processes to be very effective at stimulating our body’s natural mechanisms for creating antioxidants through NRF2 activation. NRF2 activation can be achieved thru exercise, calorie restriction (including fasting) and ingestion of natural nutrients that are NRF2 activators. In our office we have found that intravenous Ozone is a potent stimulator of the Nrf2 pathway. The intravenous Ozone is part of a protocol called the EBO2 protocol. The intravenous Ozone momentarily produces Hydrogen Peroxide. The Hydrogen Peroxide is quickly converted into compounds called Ozone Messengers. These Ozone Messengers result in the stimulation of the Nrf2 pathway. They ultimately help to reduce inflammation. Other in office Nrf2 stimulants include intravenous Curcumin, Quercetin, and Resveratrol. Intravenously, these are very potent Nrf2 stimulants. Since they are given intravenously they become very bioavailable compared to their oral formulations. The question becomes what else can we do stimulate the Nrf2 pathway without a trip to the doctor’s office? We have already mentioned the usual suspects such as exercise, calorie restriction, modified keto type diet etc. However, we can still help to supplement Nrf2 stimulation with some oral compounds. In an ideal world one would first get some supplements intravenously and then proceed with lifestyle changes and oral compounds. Common NRF2 activators include Curcumin which is a widely studied and potent Nrf2 activator. The problem with Curcumin is its bioavailability. Not all Curcumin compounds are the same. Other stimulators include Pterostilbene and its weaker cousin Resveratrol. The problem with oral Resveratrol is also its bioavailability. Other stimulators include Quercetin (from onions) and sulforaphane (from broccoli) and antioxidants found in green tea, chocolate, and other sources. Different nutrients may activate NRF2 by different mechanisms and, when taken together, may be synergistic. I have taken the bull by the horns and designed a supplement which I feel will be unlike anything out there. The propriety blend of ingredients are:Fumaric AcidBrassicaUltracurAlpha Lipoic AcidQuercetinResveratrolPterostilbeneSome of these are well known while others may be new. One of the common threads with these particular compounds is that by and large they have much better bioavailability then their similar counterparts. Brassica is a broccoli derivative. Ultracur is a Curcumin derivative. They both have much higher bioavailability then competing products. One interesting item in this list is Fumaric acid. Fumaric acid is the “Crown Jewel” of this formula. A derivative of Fumaric acid has been approved by the FDA in the treatment of relapsing forms of Multiple Sclerosis. It is also used in the treatment of psoriasis. Currently I am not aware of any Nrf2 supplement blend that is utilizing Fumaric acid derivative mixed with other supplements to stimulate Nrf2. This product should be available shortly. By raising Nrf2 levels, we are able to tap into one of nature’s most powerful mechanisms for the maintenance of good health. Regular consumption of these Nrf2 stimulating foods and supplements may substantially lower many of the health risks of modern living and increase our resistance to many diseases.IN REVIEW WHAT ARE THE PRACTICAL BENEFITS OF THE NRF2 ACTIVATORS?Recent research has found that “NRF2 activation” is very effective at stimulating our body’s natural protective mechanisms including promoting endogenous (natural) antioxidant production. Activation of NRF2 is believed to provide many health benefits including:REDUCING SYSTEMIC INFLAMMATIONLOWERING OF OXIDATIVE STRESS (REDUCING CELLULAR DNA, RNA AND PROTEIN DAMAGE)IMPROVING MITOCHONDRIAL FUNCTION (CELLULAR ENERGY PRODUCTION) ALL ROADS LEAD TO THE MITOCHONDRIANrf2 activation may have a positive impact on chronic inflammation and oxidative stress and so may be useful in the prevention or treatment of many common chronic disease processes including obesity, high blood pressure, reducing the risk of diabetes, cardiovascular disease, stroke, and the list goes on and on. NRF2 activators have been shown to protect the liver in conditions of chronic hepatitis and fatty liver. Let’s look at some more specific conditions that are directly affected by the Nrf2 pathway. Nrf2 ACTIVATION AND OBESITY AND INSULIN RESISTANCEObesity is now thought to be a systemic disease characterized by increased systemic inflammation and oxidative stress. As a consequence, obesity is clearly understood to be a major contributor to the development of hypertension, heart disease, stroke and some cancers. The importance of Nrf2 in obesity and insulin resistance is clearly evident and the potential use of an Nrf2 activator as a treatment method will continue to be an exciting area to advance. Nrf2 ACTIVATION AND PAINNrf2 activation is thought to reduce pain related to many conditions. The muscle pain and fatigue associated with fibromyalgia is believed to respond to NRF2 activation. Nrf2 activation may reduce the central sensitivity associated with many chronic pain conditions including chronic headaches, chronic back pain, and fibromyalgia etc. Nrf2 ACTIVATION AND ADDICTIONMany of the brain’s neurotransmitters and neurochemical processes are impaired in conditions of chemical and behavioral addiction. NRT2 activation may play a role in facilitating restoration of these neurochemical processes and facilitate addiction recovery. Nrf2 ACTIVATION AND STEM CELLS ACTIVATION AND SURVIVALAs a cellular metabolic and stress sensor, Nrf2 is a pivotal regulator of stem cell self-renewal, proliferation, and differentiation. Nrf2 displays cell type-specific and/or stage-dependent impact on stem cell biology in response to various environmental cues. Nrf2 maintain ASCs self-renewal, quiescence, and regenerative capacity while protecting against ASC depletion in response to stress and aging.I suspect this will take on increasing importance in Regenerative Medicine stem cell procedures. We have seen this concept already in organ transplants and rejection. As time goes on, we may depend more on allogeneic sources of stem cells which exhibit immune evasive rather than privileged responses to the immune system.Thanks,Dr. P
The journey to cultivating and maintaining wellness truly begins inside. For me, wellness began in 2013 when I was just 19 years old. I was a very stressed college student who was eating, breathing, and sleeping nursing studies. Studying at all hours of the day and night came with the development of some unhealthy habits. Most days I would skip exercise in fear of losing study time, and I was definitely not taking the time to cook healthy meals. By the time that I had reached my second year of nursing school, I had enough with feeling helpless to my stressors. That’s when I decided to take things into my own hands.As a new year’s resolution, I went to my first yoga class and it changed my life forever. After just one class I found myself breathing deeper, retaining more information when I studied, and craving healthier foods. During this transitional period, I found myself having more energy and a new zest for life. I found new ways to move my body and making healthy versions of my favorite foods became exciting and delicious. Later, I even went on to become a yoga instructor.I had never really enjoyed eating meat, and actually began a slow transition to a plant-based diet at the age of 10. Contrary to popular belief, vegetarianism is absolutely not synonymous with healthy, and there are many processed unhealthy foods that do not contain animal products. I also don’t believe that there is a “one-size-fits-all” solution when it comes to dietary intake. Just because eating plant-based works for me, does not mean that it will for you.When it comes to cultivating positive habits and longevity, I do not believe that the body benefits from “cold-turkey” methods of diet change. As I stated earlier, I transitioned to a plant-based diet over a number of years beginning with eliminating red meats, then poultry, then seafood. This allowed my body to adjust over time, and now I no longer crave any animal products at all.Here Are My Three Rules of Healthy Living:Find joy in living healthfully, so you don’t fall into old habits.Find your favorite way to move your body and do it daily.It doesn’t have to be long or strenuous, just keep putting one foot in front of the other. Set the tone for the day with your morning routine.I begin my day with 32 ounces of water with lemon, and follow it up with fresh pressed celery juice.Pro tip: you must press the celery fresh each morning or it will lose its benefits.If i’m in a hurry and cannot press the celery fresh, I substitute it with some warm water and apple cider vinegar. A teaspoon of honey helps to tone the bitterness down while you’re getting used to the flavor.Take a moment to breathe.Meditation isn’t for everyone, and I’m not saying that you need to do some sort of extensive breathwork. All I want you to do is wake up, sit on the side of your bed, close your eyes, and take a few deep breaths to acknowledge the start of the day. Use this time for positive affirmations. Tell yourself that it will be a great day!Eat mindfully.This is the best tip that I have ever received. Someone once told me that we must be thankful for our food, enjoy every bite, and be in the moment with it. This may sound a bit odd, but think about how many times we find ourselves in front of the TV or computer mindlessly shoveling food into our mouths.Even if your goal isn’t to eat entirely plant based, we can all benefit from decreasing our intake of red meat. Maybe you try saving it for a “treat” once per week and see how you feel?By eating with intention, I found myself enjoying my food more, and even eating less.At the end of the day, I believe our happiness is of the utmost importance. I’ve found that the degree of health I feel directly affects how happy I feel.Live well, eat well, and be well;Bella Sannasardo, RN, BSN
constantly pushing the envelope to come up with methods to improve our results
clinically. We think that our new cytokine formula may be such a game changer.
Our new formula makes use of Velvet Deer Antler. But the formula is much
different from those formulas out there both in strength and the formula
itself. It is a proprietary mix.
illustration represents the growing portion of the antler. Deer Antler Velvet
has been used in traditional Chinese medicine for thousands of years but has recently
gained popularity in Western medicine. Deer antler can enhance immune system
function, improving athletic performance, increasing muscle recovery, enhance
sexual function, improve disease recovery, enhance cardiovascular function, and
a host of other conditions.
Antler Velvet covers the growing bone and cartilage that develops into deer
antlers. The growing antler
contains a number of necessary cells, including fibroblasts, chondroblasts,
chondrocytes and osteocytes. The tips of the antlers begin as undifferentiated
mesenchymal stem cells which are transformed into cartilage. Later, the
cartilage is turned to bone, due to the effects of testosterone. Deer antler
velvet is antler that is still in its cartilaginous stage.
of the problems with Velvet Deer Antler is the purity and concentration of the
product. Our antler product is sourced from a very reliable source. Typically,
there is a concentration of 1500 mg of velvet extract per bottle. Honestly,
that will have some effects but it is not exactly what we are looking for. We
have sourced a concentration of 4500 mg of Velvet Deer Antler per bottle. This
concentration would not be legal for any professional athlete and thus we would
not use it on them. Typically, these higher concentrations will help balance
hormones and promote tissue repair. In addition to this we have actually added
certain supplements to this very potent formula. These supplements will
increase stem cell efficiency and output from the bone marrow. This combination
is totally unique to our practice and network and it is proprietary in
WHAT ARE THE MAIN COMPONENTS OF
above diagram gives some idea of the many benefits of deer extract. An
important concept that is a common theme of many research papers is that the
combination of all components of velvet antler provides a synergistic effect
that is greater than the total effect that would be achieved by the separate
use of each of its individual constituents. That means that if velvet antler is
broken down into its constituents that are used separately, their combined
effect is significantly less than the effect realized when the nutrients are
provided in the naturally combined form of velvet antler. In summary, the
effect of the complete product is greater than the summed effect of all
Let us take a
better look at exactly what is found in the antler products. Most of the antler
product consists of protein. The active ingredients include collagen, lipids,
glycosaminoglycans, minerals, and various growth factors. We will take a look at the major subgroups of
components. The first component to take a look at are the glycosaminoglycans
are complex carbohydrates.
Glycosaminoglycans (GAGs), have widespread functions
within the body. GAGs play a critical role in Regenerative Medicine. They play
a crucial role in the cell signaling
process, including regulation of cell growth, proliferation, promotion of cell adhesion,
anticoagulation, and wound repair. They are an integral component of what is
called the extracellular matrix. The extracellular matrix (ECM) is the non-cellular
component present within all tissues and organs, and provides not only
essential physical scaffolding for the cellular constituents but also initiates
crucial biochemical and biomechanical cues that are required for tissue
morphogenesis, differentiation and homeostasis.
shown GAGs exist in velvet antler in several forms including:
Chondroitin Sulphate a carbohydrate that
helps protect and rebuild degenerating cartilage and is regarded as a potent
Glycosphingolipids are compounds
involved with growth and metabolism of cells and with memory and learning
Glucosamine Sulphate is a component of
Chondroitin Sulphate and is a major component of cartilage and synovial fluid
Hyaluronic acid a substance that binds
cartilage cells together and lubricates joints. It also acts as a signaling
molecule in many biological processes.
Phospholipids the major structural lipid
of most cell membranes
Here is a good illustration of the ExtraCellular Matrix. It is the substance between the cells.
Antlers grow by endochondral
ossification, the same way that long bones do. A major non-collagenous protein,
proteoglycan, a protein substituted with glycosaminoglycan chains, occurs in
the cartilaginous tissue of antler. While its use in the antler is not
understood, it has been shown that proteoglycan in cartilage, also called
aggrecan, regulates differentiation of chondrocytes and may control calcium
concentration in the growth plates where endochondral ossification occurs. This
may have important implications when we are treating joints with regenerative
the next two illustrations show the ramifications of the ExtraCellular
Matrix and repair of various tissues. We can see why enhancing the ExtraCellular Matrix is so important in Regenerative Medicine. We can
see that these represent the pillars of regenerative cell therapy. There are
few if any other products which have these effects on the extracellular matrix.
This is certainly a huge benefit that comes with the Velvet Deer Antler
Glycosaminoglycans have a hand in all of the above repair processes. Most
products are only addressing the cellular portions of repair while the antler
products are more comprehensive in their approach.
next illustration shows how the Glycosaminoglycans are involved in the new
field of tissue engineering. In the case of tissue engineering we call the
synthetic ECM a scaffold.
GROWTH FACTORS: THE CLONES OF WHAT STEM CELLS PRODUCE
we look at velvet antler growth factors, we see a list of whos who in
the growth factor universe. Growth factors, which are generally considered
as a subset of cytokines, refer to the diffusible signaling proteins that
stimulate cell growth, differentiation, survival, inflammation, and tissue repair. The major
growth factors which are found in deer antler include Insulin Like growth
factors (IGF-1), Bone morphogenetic growth factors (BMPs), Transforming growth
factor family (TGF), Fibroblast growth factor (FGF), Platelet derived growth
factor (PDGF), Vascular endothelial growth factor (VEGF), Epidermal growth
factor (EGF), Interleukins, and a variety of other factors. When looking at the
various growth factors we realize that this appears to be similar to what is
found in a Platelet Rich Plasma (PRP) product, and for that matter stem cells
Another aspect of deer antler deals with
its Amino acid contents. Remember that amino acids are natures building blocks. Amino acids, often referred to as the
building blocks of proteins, are compounds that play many critical roles in
your body. They're needed for vital processes like the building of proteins and
synthesis of hormones and neurotransmitters. These are broken down to essential and
non-essential amino acids. Another type of amino acid is the free form amino acid. These
amino acids aren't joined together with any other amino acids in a
protein 'string'. This allows the individual amino acids to be
instantly absorbed and used by the body without digestion. All of o
Of all the growth factors the most
consequential might be IGF-1. IGF-1 is a banned substance in the world of
professional sports. The precursor of IGF-1 is Human Growth Hormone (HGH).
IGF-1 is actually the active form of HGH. It is considered performance
enhancing. In the smaller doses this is typically not an issue but in the higher
doses we are using this is a problem and across the board we will not give this
formula to any athlete in the high school, college, or the professional sports
arena. Putting this aside, why do we like IGF-1? We can see some of the
Perhaps more importantly, we need to look at
IGF-1 on the basis of cell biology. IGF-1 has been shown to enhance
the migratory response of stem cells. We must realize that the IGF-1 supplied
by deer antler is a natural form. It seems to be safer than taking the
synthetic anabolic agents which can have disastrous consequences to ones
health. The following diagram is somewhat complicated but we see the importance
of IGF-1. It will interact with the stem cell and cause the cell to go on to
repair tissue or differentiate into that tissue.
and the other growth factors can also result in a number of other health
benefits. These extra health benefits may include preservation of a persons
muscle mass, improving the functioning of the immune system, increasing bone
density thus helping to improve Osteoporosis, a valid treatment for
fibromyalgia conditions, and lastly it may help in weight loss. The bottom line
is that these growth factors are all very important in treating damaged tissue.
This tissue could be a tendon, a joint, or muscle. Remember, with the antler we
are complimenting the growth factors that are supplied by the stem cells and
the Platelet Rich Plasma. Also, by taking these supplements on a daily basis we
continue the repair process. The one small caveat that we follow is that in
those patients who have a history of certain cancers we will typically
recommend a lower dose of the antler product. We should also keep in mind that
antler products also contain small amounts of the sex hormones testosterone and
estrogen. In the right doses these are also important for regeneration.
Another related factor found in
the antler is Prostaglandins.
They are substances with varying physiologic effects, acting as a
vasodepressor, smooth muscle contraction or relaxation, inflammation and
uterine stimulation. As components of deer antler velvet, prostaglandins may
assist in the capacity of the extract to reduce the swelling associated with
arthritis and injury. They also have physiological responses in lipid
metabolism, as seen in the cholesterol-lowering effects of deer antler velvet
on laboratory animals.
antler contains many different types of amino acids. Amino acids, often
referred to as the building blocks of proteins, are compounds that play many
critical roles in your body. Amino acids are organic compounds composed of
nitrogen, carbon, hydrogen and oxygen, along with a variable side chain group.
Your body needs 20 different amino acids to grow and function properly. Though
all 20 of these are important for your health, only nine amino acids are
classified as essential. These are histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, threonine, tryptophan, and valine. Unlike
nonessential amino acids, essential amino acids are those that cant be made by
your body and must be obtained through your diet. Another type of amino acid is
a Free-form amino acid. This
refers to single amino acid that is already in a pre-digested form and ready to
be used by your body. Some nutritional products, especially amino acid blends,
contain whole proteins and large peptides (chains of amino acids), which the
body must first break down into smaller peptides and individual amino acids
before use. For faster utilization and better bioavailability, look for
free-form amino acids. We can see that all the various different types of amino
acids work synergistically. They all have their purpose.
WHAT SUPPLEMENTS ARE ADDED TO THE FORMULA TO ENHANCE THE EFFECTS?
In addition to the Velvet Deer
Antler which provides all the aforementioned compounds. There are a host of
other compounds which enhance the efficacy of the product. These include a natural matrix of herbs bounded by research and science
to help ones stem cells become more active and body supportive. The following
compounds highlight these ingredients.
found in the cell walls of certain seaweed species that is has been used
medicinally for a wide variety of health purposes. Okinawa inhabitants have a diet rich in Wakame seaweed,
which contains the highest concentrations of Fucoidan. Okinawa is also known
for its high concentration of centenarians (people who are at least a century
old), which researchers believe is linked to their fucoidan-rich diet. The
anti-aging effects are associated with Fucoidan's remarkable ability to
facilitate tissue regeneration, immune function as well as improving cell-to-
cell communication. Not only is fucoidan known for its anti-aging effects, it
is also believed to combat cancer, metabolic syndrome and other degenerative
disorders. With stem cell therapy, there is always the risk that the adult stem
cells could migrate to other areas of the body unintentionally. However, the
daily use of fucoidan has been proven to increase mobilization of stem cells to
the appropriate area/ site of injury. Not only can fucoidan point the stem
cells in the proper direction, it has also shown to improve the stem cells'
survival during the differentiation process.
PTEROSTILBENE is a stilbene molecule and demethylated
derivative of resveratrol ( it is more bioavailable than resveratrol) that is
found in antioxidant-rich foods like blueberries, cranberries and grapes. These all help to slow down
the aging process. It is an antioxidant that helps fight free
It is known to stimulate a series of pathways in the body called Sirtuin gene
pathways. The sirtuin genes have effects on a variety of other pathways in the
body. Ultimately, the Sirtuins are involved in the regulation of the
mitochondria and subsequent ATP production. Research has shown Pterostilbene
protects against memory loss, high cholesterol, high blood
and even certain types of cancer.
CARNOSINE is an important nonessential amino acid
that helps support brain, heart, and eye health. It offers antioxidant
protection from free radicals and oxidative stress, boosts endurance, aids in
the recovery process, and offers electrolyte support.
BLACK RASPBERRY EXTRACT, one of
the least known, but yet strongest anti-oxidants that insures chromosomes
retain their health and rebuild themselves to optimum health.
RHODIOLA an adaptogenic herb that can elevate your mood and
mental stamina, reduce the stress hormone, cortisol and fight
depression due to its protective effects on key mood
neurotransmitters. Rhodiola rosea extracts have recently demonstrated its anti-aging,
anti-inflammation, immuno-stimulating, DNA repair and anti-cancer effects in
different model systems. An adaptogenic herb helps the body adapt
to and resist physical, chemical, and environmental stress.
ASTRAGIN is a 100%
natural compound which is patented and promotes a healthy gut lining reducing
inflammation in the intestinal lining and increasing absorption of nutrients. AstraGin has the ability to increase the assimilation of
important amino acids which increase nitric oxide levels in the human body,
making it the perfect performance enhancer when taken
pre-workout. Higher levels of nitric oxide result in enhanced blood
flow to the muscle which leads to better pumps, muscular contraction, and
improved nutrient transportation. AstraGin also aids in glucose absorption so
having this pre-workout ensures that you have sufficient energy levels whilst
THE FINAL QUESTION HOW DOES THE ANTLER PRODUCT GET TO
WHERE IT IS NEEDED?
have the absolute best formula on paper but the question is will it work? When
we evaluate medications and supplements a very important aspect to consider is
what we call the pharmacokinetics of the product. This concerns the science of
how the drug moves around in the body. Unfortunately, on paper many compounds
seem very promising but in real life are a failure. The main reason for this is
that they cannot be absorbed by the body.
The mode of
absorption of the antler product is what is referred to as sublingual. This
means it is absorbed under the tongue. This is many times a very effective mode
of absorption. It bypasses the gut and goes directly into the bloodstream where it is needed. The components are not broken down.
Also, in the saliva are very small particles called exosomes which can be
considered a rising star in drug delivery. Saliva is a very rich source of
exosomes. Thus, we have a very efficient method of delivering the velvet
components in a safe and reliable manner.
If we were to
undertake the task of trying to design a complete supplement to utilize in
Regenerative Medicine and Stem Cell therapy, Velvet Deer Antler would be at the
top of our list. It has most of the ingredients needed for success.
Furthermore, there is a very efficient way to deliver the goods to the cell
where they are needed. Deer antler will not be the only modality we will use,
but it certainly has an important place on our mantle. We are constantly
working to push the envelope and I suspect more advances will come.
This is a question that, when I give a lecture to either doctors or the lay public, most everyone gets it wrong. I am not talking about the chocolate one finds in a Hershey’s kiss or chocolate bar, because the problem with these is that they contain too much sugar. I would consider them a very unhealthy food. Ah, but chocolate with no sugar, that is a whole different story. What I would like to do is introduce everyone to the science of chocolate. First off, where does chocolate come from? It comes from the tropical Cacao tree, where it is found in pods. Here we see a picture of the beans that are found in the pod. They are roasted and ground up, then turned into chocolate: When one adds the sugar to these products, that is when the damage occurs. Dark chocolate has both cocoa butter and cacao fiber, both of which science has proven to have health benefits. The cacao fiber is the part of the cocoa bean where most antioxidants are found. This is why dark chocolate with high cocoa solids, and thus more cacao fiber, is considered healthy chocolate. So, now let us get to the science.Dark chocolate is rich in minerals, such as iron, magnesium, and zinc (think anti-viral). The cocoa in the dark chocolate contains some amazing compounds called flavonoids and antioxidants, which have many health benefits. Chocolate is considered one of the best antioxidant foods known to man. The following chart clearly shows this:Antioxidants will neutralize free radicals. Free radicals are highly unstable molecules that are naturally formed when you exercise and when your body converts food into energy. Your body can also be exposed to free radicals from a variety of environmental sources, such as cigarette smoke, air pollution, and sunlight. Free radicals can cause “oxidative stress,” a process that can trigger cell damage. Oxidative stress is thought to play a role in a variety of diseases including cancer, cardiovascular diseases, diabetes, Alzheimer’s disease, Parkinson’s disease, and eye diseases, such as cataracts and age-related macular degeneration. Remember that oxidative stress is one of the major causes of the failure of the immune system (again think virus infections). There is no question that dark chocolate is a superb antioxidant. In a study published in the October 2017 Journal of Community and Hospital Internal Medicine Perspectives, the antioxidants in dark chocolate were found to reduce oxidative stress, which scientists think is the primary cause of insulin resistance and subsequently diabetes. By improving your body’s sensitivity to insulin, resistance is reduced and, in turn, the risk of diseases like diabetes decreases.Also, at the center of chocolate’s health benefits are flavonoids. Most dark chocolate is high in flavonoids, particularly a subtype called flavanols, which are associated with a lower risk of heart disease and a variety of other conditions. As I have already said, some studies suggest chocolate or cocoa consumption is associated with a lower risk of both insulin resistance and high blood pressure in adults. These plant pigments are responsible for many of the health benefits of many fruits and medicinal plants, but chocolate may be a much more sensually pleasing vehicle. In addition, there is evidence that not only is chocolate rich in flavonoids, but that factors in chocolate somehow dramatically increase absorption of these compounds. The key flavonoids are procyanidins, which are similar to those found in grape seed extract, apples, berries, and pine bark extract. There are a few of these flavonoids that garner attention, such as PQQ.PQQ (pyrroloquinoline quinone) restores youthful cellular function and can extend the lifespan. PQQ helps generate and restore mitochondria, especially in aging cells. It allows the mitochondria powerhouses to work more efficiently. Dysfunctional mitochondria contribute to body-wide degeneration. Many of the diseases of aging have one thing in common; namely, they involve mitochondrial degeneration. Remember that mitochondrial degeneration leads to shortening of our telomeres. Shorter telomeres lead to aging. But it turns out PQQ has many other beneficial aspects.A team of researchers from China and Italy found that when PQQ was applied to human cells in culture, it delayed cellular senescence. A growing body of research suggests that reducing cellular senescence may lead to increased health and lifespan. Remember that a senescent cell is a cell that should have died but did not. These cells are like zombies, in that they attack normal cells. A senescent cell will increase inflammatory factors in various areas of the body. There is now a new name for this inflammation; it is called inflammaging. ‘Inflammaging’ refers to the chronic, low-grade inflammation that characterizes aging. We see that inflammation and aging are more or less synonymous. One causes the other to take hold. Recent studies have shown a way that PQQ may be able to slow aging even more, by reducing the activity of certain age-accelerating signaling pathways. The following is a chart shows different foods and the amounts of PQQ they have:Another important bioactive compound found in chocolate is Epicatechin, which is classed as a flavanol. Epicatechin is a natural flavonoid. It has been reported to possess an immense antioxidant effect, which contributes to its therapeutic effect against a handful of ailments. Epicatechin has many different functions. It will increase Nitric Oxide for increased vascularity and blood flow. It will lower cholesterol levels due to its natural antioxidant properties, while improving endurance and insulin sensitivity, regulating blood sugar levels, and stimulating muscle protein synthesis. A very fascinating property of Epicatechin is that it is a myostatin blocker.Myostatin is a type of protein called a myokine, which limits the level of muscle growth. Animals lacking myostatin, either due to a defective gene or because they have been treated with compounds that inhibit production, show huge increases in muscularity. In other words, the brakes on muscle growth are removed by the inhibition or absence of myostatin.Myostatin became famous within the bodybuilding community. It has been considered the holy grail of muscle building. Below is an example of a cow which has a gene that blocks myostatin. If you block myostatin in a human, a similar result will be obtained:A number of supplements have been designed to inhibit myostatin production over the past 20 years, but these have all been discarded as not working well. What is the exact epicatechin/myostatin connection? Research with epicatechin indicates that it increases levels of Follistatin, a special type of protein found in the muscles. Follistatin binds to and thereby inhibits the actions of myostatin in the body. In a nutshell, more Follistatin equals less myostatin, which in turn means more muscle mass and less fatty tissue.A study conducted on males of an average age of 40 showed that approximately 170mg of epicatechin per day, dosed at 2mg per kg of bodyweight, resulted in almost a 50% increase in Follistatin and a 16.6% decrease in myostatin, alongside a strength increase of 7%. In a second study, researchers provided participants with 50-200mg of epicatechin a day and were amazed to find that their Follistatin levels were 250% higher after just 5 days! In a study performed on mice, researchers found increases in nitric oxide and endurance that persisted even in the absence of exercise. In other words, epicatechin supplementation offers bodybuilders the potential for better muscle pumps and endurance even when they are not training. The same may hold true for the average person.As one can see, chocolate is one of the best health foods one can eat. Just remember to leave the sugar out. Do as I do, buy unsweetened chocolate and melt it in the microwave. When it is melted, then add some cinnamon (another great supplement) and Stevia as a sweetener. Sometimes we will add a bit of rum to spice up the flavor. I will typically buy my chocolate in bulk. Also remember that chocolate is much like wine; it can vary in taste by where it is grown and the growing conditions.Thanks,– Dr. P
At one time it was thought that there was little if any relationship between Senescent Cells and NAD supplements. We now know that this is far from the truth. Remember that the senescent cells are cells that should have died but continue to survive. By surviving they cause a multitude of problems. Senescent cells are believed to contribute to numerous age-associated diseases. Senescent cells are becoming a hot topic in the field of Regenerative Medicine. We now know they may be responsible for many of the failures in cellular therapy. Senescent cells are believed to contribute to numerous age-associated diseases. By the same token we now know that NAD, the supplement, is extremely important in general well-being and success in cellular therapy. Below we see diagrams concerning Senescent cells. The two above diagrams represent the essence of Senescent cells (Please see some of my previous blogs concerning Senescent cells).Unfortunately, many of the effects of the Senescent cells are found in the dark side of the first diagram. The elimination of Senescent cells by senolytic regimens (programs designed to kill senescent cells) appears to help in numerous aging-associated diseases including atherosclerosis, pulmonary problems, diabetes, neurological problems, cancer and osteoarthritis. Senescent cells secrete pro-inflammatory factors which are called Senescence-Associated Secretory Phenotype (SASP). These are essentially the “bad growth factors”. By the mechanism of the inflammatory growth factors, the Senescent cells are believed to contribute to numerous age-associated diseases. The second diagram shows the causes of cell senescence. These causes of cell senescence are essentially the causes of aging. We can see that the causes are multiple. The causes involve the usual suspects including DNA damage, mitochondrial damage, damage to the ends of the DNA called the telomeres, and finally what we call epigenetic factors.Epigenetic factors have far reaching effects. They involve changes to gene expression that our cells experience as we get older. These are commonly called epigenetic alterations. The following diagram demonstrates these facts.There are many factors that can affect the genes. The diagram shows some of the examples. These genetic alterations harm the fundamental functions of our cells and can increase the risk of cancer and other age-related diseases. The DNA is affected by the inflammatory cytokines secreted by the Senescent cells. These secretions are modifying gene expression in a cell, suppressing or enhancing the expression of certain genes in a cell as the situation demands. The genes which are turned on the cell can either be a friend or a foe. It can help prevent a cancer or help cause it. Here are two recent articles from two reliable sources concerning senolytic agents. As you can see Senescent cells are not some esoteric idea. They are becoming mainstream medicine. We are acutely aware of the importance of senolytic agents for overall health. They seem to be very important in NAD therapy also. Here are the articles: There is one other article which I will share with you which is more scientific discussing the Senescent cell problem.So, the real question is what do Senescent cells and NAD have to do with each other? Furthermore, are their paths on a collision course?Now I would like to discuss the collision course that NAD and Senescent cells are on. Recently I read a scientific article that was quite fascinating and thought provoking. The article discussed the ramifications of taking NAD+ supplements and their effect on Senescent cells. Let us do a quick review of NAD. NAD+ is a potent stimulator of the SIRT-1 gene pathway. This pathway is thought to be one of the major anti-aging pathways. This is the pathway that many people are familiar with by the effects of the compound Resveratrol which is found in red wine. Other methods of stimulating this pathway include calorie restriction, intermittent fasting, keto diet, high intensity exercise training, and perhaps most importantly NAD. When all is said and done the Sirtuin pathway stimulates the production and efficiency of the mitochondria which provide the cells with energy. Typically, the more mitochondria the healthier the cell and for that matter the healthier the person.From the point of view of anti-aging, NAD has tremendous potential. However, it seems that NAD may act as a double edge sword as we get older. There is no doubt that we become deficient in NAD as we age. The reason for this is multifocal. One important reason is that certain enzymes in our body become large consumers of NAD. Some of these enzymes are involved in the process of repairing DNA damage. If there is not enough NAD to go around than the NAD gets shuffled to the cells where it is an absolute necessity or the cells die. However, the consuming enzymes continue to try to utilize NAD but they will unfortunately not be able to accomplish DNA repair. If we are able to consume adequate amounts of NAD these enzymes get turned back on and do their important repair work. We are able to increase the amount of NAD available to the body by a variety of methods. One of the secret weapons we utilize is an NAD kinase patch. The NAD kinase patch contains an enzyme, NAD kinase, and penetrating molecules. This combination will dramatically increase the amount of NAD that enters the cell. As we age, we become deficient in the NAD kinase enzyme. This enzyme is the cutting edge of the cutting-edge technology especially when it pertains to NAD administration. It allows greater amounts of NAD to enter the cell. So far all seem good except for one detail. Both myself and my wife take NAD on a daily basis. We occasionally use the Kinase patches. We are doing this to hopefully “slow down” our aging. On the surface this makes perfect sense, yet some of the newest thinking demonstrates some potential problems when dealing with NAD administration. There is no doubt that I have Senescent cells in my body (recently I did a once a week x 2 regimen of Senolytic agents which has had some surprising beneficial effects). In the article I was referring to, on one hand it stated that the NAD+ levels decrease as we age leading to degenerative conditions. While at the same time, the number of senescent cells will increase with aging. The article states that decreased NAD+ levels that are associated with aging may actually decrease the effects of the senescent cells on the body. Conversely increasing NAD+ levels by supplementation either orally or intravenously or both methods may benefit tissue homeostasis, but also may worsen SASP and make the make the Senescent cells more aggressively inflammatory. This is certainly not a good thing. TAKEN TOGETHER THESE FINDINGS SUGGEST A FUNDAMENTAL TRADE-OFF IN TREATING AGING RELATED DISEASES WITH DRUGS OR SUPPLEMENTS THAT INCREASE NAD+. So, the bottom line is that we are increasing NAD levels which is a good thing but at the same time we are also making the Senescent cells increase the secretion of the inflammatory growth factors which is a bad thing.Another concern is a report that senescent cells can induce a cell surface protein called CD-38 on macrophages (a type of white blood cell in the immune system) and endothelial cells (Endothelium refers to cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall). CD-38 is a molecule important for many different cellular processes, including calcium signaling, which regulates basic cell functions. CD-38 is the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, CD-38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases. However, too much CD-38 is a sign of inflammation. Research has linked overexpression of CD-38 to obesity, cancer, and infectious diseases, like HIV. Both the decline in NAD+ and the presence of Senescent cells are hallmarks of aging. We are aware that a supplement called Apigenin seems to help block the effects of CD-38. (Apigenin is found in many fruits and vegetables, but parsley, celery, celeriac, and chamomile tea. Apigenin is particularly abundant in the flowers of chamomile plants). Apigenin may eventually be part of a regimen when administering NAD.Until recently, it was unclear exactly how rising CD-38, declining NAD+, and the presence of senescent cells were all related. Scientists also know that the presence of CD-38 levels increase with age, and that CD-38 is involved in lowering NAD+ levels. It is a major consumer of NAD. In turn increased CD-38 expression is believed to be the key modulator of lowered NAD+ levels with aging in mammals. CD-38 is intimately related to our immune system but unfortunately not in a good way. In the following diagram, we see that the inflammatory growth factors from Senescent cells have a direct effect on what is called an M-1 macrophage. This is a type of white blood cell which is many times associated with inflammation in the body. Not a big problem when we are dealing with bacteria but not good for anti-aging.The accumulation of Senescent cells may itself be an important safeguard causing decreased NAD+ levels which in turn could promote a multitude of problems. On the other hand, the lower NAD+ levels may diminish the influence of Senescent cells which is the safeguard. What the scientists found was two-fold: First, they observed that inducing senescence did not lead the senescent cells themselves to produce more CD38. But, the senescent cells did, as expected, begin secreting a cascade of inflammatory chemicals that in turn, up-regulated CD38 in surrounding non-senescent cells. In other words, they infected normal cells much like a zombie infects normal people. Interestingly, they found that different inflammatory factors did not individually increase CD-38, but when combined led to a strong increase in CD-38 activity. In the end, the scientists observed this affect in all the types of cells tested. We are aware that Quercetin and Apigenin are two supplements that can diminish CD-38 effects. These also act as senolytic agents. As a matter of fact, Quercetin is found as a senolytic agent in many University studies. In these studies, Quercetin is combined with Dasatinib to act as a super senolytic agent. Dasatinib is a Leukemia medication that is being used “off-label”. Because the dosages are extremely small the side effects are minimal. The elimination of most senescent cells by senolysis (the killing of senescent cells) before initiating NAD+ therapies may be beneficial and increase safety. There is the possibility that it may eventually allow for need for little IV therapy and mainly rely on oral medication. I think to treat the patient with some form of senolytic agent prior to NAD therapy may possibly the new standard of care for patients receiving NAD therapy. Unless we address the Senescent cell/CD-38 problem, trying to raise NAD+ levels with precursors may come with too many downsides, preventing us from both having our cake and eating it too. So, what is the real bottom line? We strongly feel that Senolytic agents are imperative when using NAD+ intravenously or orally. Actually, I think they have a place in almost everyone. We want to diminish Senescent cells and their inflammatory growth factors and at the same time increase cellular NAD levels. Luckily, we have been aware of the Senescent cell problem some time now. We have been treating our patients with a number of different senolytic agents for some time. Some of these have included a P-53 patch, certain supplements such as Quercetin, even utilizing Quercetin and Dasatinib together. We have worked out very specific regimens for this. If a physician is not taking steps to deal with Senescent cells his overall chance of success will be much lower in Regenerative procedures and overall patient health. Furthermore, there is the possibility that the patient’s overall health may take a turn for the worse in the long run by increasing the effects of the senescent cells. Here is the bottom line from an article I read “reducing the senescent cell burden in persons around age 60 and middle-aged obese individuals may become a critical step in restoring youthful NAD+ cellular levels in a way that maximizes benefit.Younger, non-obese individuals may not have a significant senescent cell burden and thus may not need aggressive senolytic therapy before contemplating NAD+ restoration”. These are excellent recommendations. IF A PHYSICIAN WHO IS ADMINISTERING NAD+ IS NOT ADDRESSING THE SENESCENT CELLS PROBLEM THAN I SUGGEST THE PATIENT SEEK TREATMENT ELSEWHERE. YOUR HEALTH IS AT STAKE!!!Thanks,Dr. P
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