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
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.
P-53 PROTEIN: A NATURAL SENTRY, STEM CELL PROTECTOR, TUMOR SUPRESSOR, and ANTI-AGING CHAMPION
Could an elephant hold some of the secrets of longevity? The elephant is an animal which has great longevity. Scientifically speaking, this bucks the trends of nature. Typically, the more cells an animal has the more likely that a cancer or some other serious medical problem will arise and thus shorten life span. Yet the opposite is true for elephants, certain species of whales, and a host of other animals that have extreme longevity. The common thread for these animals is improved DNA repair and cell cycle regulation mechanisms to prevent DNA damage. This damage accumulates during the life course of the animal. The secret may be that these animals have extra amounts of the P-53 protein. This protein controls repair which in turn promotes longevity and resistance to age-related diseases.
Certainly, there is not just one factor which will increase longevity in large animals but there are some common threads. However, one very important thread concerns Telomeres which are the ends of the DNA in all cells. Every time our cells reproduce the telomere gets shorter until a certain critical length is achieved. This certain critical length sets a number of reactions into place. This is very evident in the following diagram. This diagram speaks of the work of Dr. Ron DePinho. It is called the unified theory of aging. This diagram comes from an article about a good friend, Dr. William Andrews. Dr. Andrews has a quest to search for substances which seem to stimulate telomerase. If we can stimulate telomerase we might prevent short telomeres. Remember that telomeres are the ends of the DNA which shorten every time our cells undergo division. Short Telomeres will cause the cell to becomes a wayward cell involved in all types of mischief. These cells are called senescent cells.
There is protein called P-53 which is activated by cells with short telomeres. The short Telomeres cause the cells to enter a phase called cell senescence. The diagram below explains better what causes senescent cells to arise and subsequently what problems senescent cell cause in the body.
What few people understand is that as cells age, some of them degenerate into a population of poorly functioning senescent cells that accumulate throughout our body. There is no value to retaining these lingering senile cells. Their continued presence underlies a myriad of degenerative disorders. Senescent cells should be purged from the body. The buildup of these dysfunctional senile cells contributes to decay of individual organs and greater susceptibility to disorders related to chronic inflammation and thus disease of aging. I have written a blog already on senescent cells. In that blog I spoke about some supplements which seem to attack senescent cells. The body has a much better way of attacking these cells. This method is called the P-53 protein. This is one of the foundations of giving elephants and other large animals their advantage in anti-aging.
This blog will target a very intriguing aspect of senescent cells called the P-53 protein. In the first diagram above we see that the P-53 activation is awoken by critically short telomeres. When the p-53 is activated it is a very good guardian. We can see the P-53 helps in cellular repair.
One of the main purposes of P-53 is to have some control over the cell division. If the cell has significant damage especially to its DNA than that cell is flagged and the cell is programed for death. This programed death of a cell is called Apoptosis. When the damage to the cell’s DNA is not that great than the P-53 protein will direct the DNA to repair itself. The following diagram is a bit more technical. It shows us what happens when P-53 is working properly and when it is damaged.
What we can see in the above diagram is that an abnormal P-53 may lead to cancer. For this reason, the P-53 protein is also called the tumor suppressor gene.
P53 is a tumor suppressor involved in a wide variety of tumor types. At least 50% of known tumors contain mutations of P-53 in humans and animals. These mutations are found in different cell and tissue types. This has made P-53 the one of the targets in cancer research and therapy worldwide.
Main stream medicine targets this tumor suppressor in gene therapy and uses the protein extensively in cancer therapy. Just like recombinant cytokines growth factors, there is a recombinant P-53 protein. Recombinant DNA technology is when we join together of DNA molecules from two different species that are inserted into a host organism to produce new genetic combinations that are of value to science, medicine, agriculture, and industry. Typically, bacteria can be programed by the recombinant DNA technique to produce medicines proteins etc. Nowadays Insulin is produced in this fashion.
The vision of using P-53 comes from the work of Dr. Biava who isolated the P-53 protein from the zebra fish, creating a recombinant protein. This P-53 protein carries the signaling and the function of the P-53 tumor suppressor factor allowing the practitioner to program the microenvironment of the cancer patient or anti-aging patient.
P-53 is a transcription factor. Transcription factors are proteins involved in the process of converting, or transcribing, DNA into RNA. Regulation of transcription is the most common form of gene control. The action of transcription factors allows for unique expression of each gene in different cell types and during development. P-53 modulates gene expression and induces Cell Cycle arrest, senescence or apoptosis (cell death), thereby preventing tumor formation. P-53 is killing those bad senescent cells. So, it seems that P-53 is a smart protein able to detect and regulate oncogene (cancer causing genes) activity. When there is no risk, P-53 is flagged for inactivity and degradation which suppresses its expression so that it does not interfere with normal healthy cell proliferation.
P-53 IS A BIG PLAYER IN THE CELL CYCLE
Abnormalities in the Cell Cycle lead to tumors. The normal Cell Cycle has four phases: Synthesis of DNA
Mitosis (cell division), 2 gap phases; one before each active phase; that is, before Synthesis and before Mitosis (cell division) respectively. But regulation of the cycle is also dependent on tumor suppressor genes such as P-53.
Getting back to the reason why elephants seem to have excellent longevity is due to the fact that elephants have evolved unusual P-53 genes. While we only have one copy of the gene, elephants have 20 copies. Research teams have observed that the elephant’s swarm of P-53 genes responds aggressively to DNA damage. Like many things in life it is a numbers game.
If we were to recap the many facets of P-53 we would find the following:
MAIN PROPERTIES OF p53
Tumor suppression which can dramatically reduce the incidence of cancer.
Maintains genomic stability in somatic cells. This means that the cells will not develop mutations that leads to all kinds of problems.
Regulates transcription, especially in stress responsiveness. Remember transcription involves the production of messenger RNA which turns on or off a variety of genes.
Regulates genes that control Cell Cycle arrest and cell death
Regulates homeostasis in cellular metabolism and Cell Cycle
Regulates autophagy. Autophagy is the process where sub-cellular organelles are destroyed and new ones are rebuilt to replace it. Think of it as similar to replacing parts on a car. Instead of replacing the entire car you just replace the defective parts. In autophagy old cell membranes, organelles and other cellular debris can be removed. This is done by sending it to the lysosome which is a specialized organelle containing enzymes to degrade proteins.
Involved in metabolic maintenance
Involved in fertility
Involved in cellular reprogramming
We can see the P-53 protein has far reaching tentacles. The P-53 protein responds to cellular stress in general. Oxidative stress in aging or degenerative pathophysiology can trigger the sentry to duty, so a recombinant P-53 protein can ostensibly be used in anti-aging therapies, degenerative conditions and prevention of tumorigenesis. This is the seminal point to this entire blog.
Rather than depend entirely upon our own P-53 protein, which potentially may have some mutations and loss of effectiveness, we are able to supplement it with a recombinant form of the P-53 protein. Remember, just like the elephant, it is a numbers game with P-53. We will have available a recombinant form of P-53. This will be supplied in the form of a patch which contains the P-53 with penetrating molecules. The patch is kept on overnight and then discarded. We feel this will be another nail in the coffin of aging. We still have a way to go but it is certainly a step in the right direction.
- Dr. P