The Root cause and Culprit behind Chronic Diseases, Cancer and Aging is well recognized now by many authorities. It includes: 1- A state of chronic low grade inflammation. 2- Mitochondrial dysfunction.
In order for our organs to function properly, they require energy, and that energy is produced by the mitochondria (the power engine). Mitochondrial function is at the very heart of everything that occurs in our body. Mitochondria our body’s lifeline are tiny organelles in our cell, thousands of them comprising 15 to 50% of the cell volume. Red blood cells and skin cells have very little to none, while germ cells have 100,000, but most cells have one to 2,000 of them. They're the primary source of energy for our body. They supply over 90% of our body’s energy. Converting the food we eat and the air we breathe into usable energy. It have enormous potential to influence our health, specifically cancer. Optimizing mitochondrial function and preventing mitochondrial dysfunction is extremely important for health and disease prevention and may be at the core of effective cancer treatment. Important nutrients and co-factors for mitochondrial function include: all B vitamins, magnesium, omega-3 fat, CoQ10, acetyl L- carnitine, D-ribose, and alpha-lipoic acid. Exercise is also important for mitochondrial health and function
3. New Lifestyle diseases
Non-communicable diseases (NCDs)
• Obesity
• Metabolic syndrome
• Coronary artery disease
• Diabetes type 2
• Hypertension
• Arteriosclerosis
• Stroke
• Cancer
• Depression - anxiety
• Arthritis
• Osteomalacia
• Osteoporosis
• Swimmer's ear – loss of hearing
• Ch. obstructive pulmonary disease
• Liver Cirrhosis
• Nephritis
• Etc, etc, etc…
Emerged as bigger killers than infectious or hereditary ones.
The leading cause of death in the world.
63% of all annual deaths.
> 38 million people are killed /year.
1- Cardiovascular diseases (17.5 million)
Complications of hypertension (9.4 million)
2- Cancers (8.2 million)
3- Respiratory diseases (4 million)
5- Diabetes (1.5 million)
These 4 diseases account for 80 % of all NCDs deaths (> 38 million)
4- USA’s 4th Leading Cause of Death – Pharma’s Drugs
Posted on June 25, 2012 by Child Health Safety
Causes:
• Stress-Depression
• Diet
• Sleep-awake
• Lack of Exercise
• Sun avoidance
• Wireless WiFi devices
• Leaky gut syndrome
• Other pollutants
Including Medicines
4. Dr Josef mercola:
I never learned anything about the root cause of chronic
disease in med school
Surprisingly, my seven years of medical school and family
practice residency never addressed the root cause of common
chronic illness.
All I was taught was how to manage symptoms through the use
of pharmaceuticals and medical procedures.
Then, in 1995, my understanding of chronic disease took a
quantum leap. I was introduced to Dr. Ron Rosedale and his
breakthrough views on clinical metabolic biochemistry.
What I Learned in 1995 Forever Shaped My View on Cancer and
Chronic Disease
Cancer Is One of the Most Manageable Diseases “Once we
realize that cancer is a metabolic disease
The Root cause and Culprit behind Chronic Diseases, Cancer and Aging
Clinical metabolic biochemistry - breakthrough
6. In order for our organs to function
properly, they require energy, and that
energy is produced by the
mitochondria (the power engine).
Since mitochondrial function is at the
very heart of everything that occurs in
our body,
Optimizing mitochondrial function
and preventing mitochondrial
dysfunction is extremely important
for health and disease prevention
Important nutrients and co-factors for
mitochondrial function include:
all B vitamins, magnesium, omega-3 fat,
CoQ10, acetyl L- carnitine, D-ribose, and
alpha-lipoic acid. Exercise is also important
for mitochondrial health and function
7. 1- Mitochondria are tiny organelles in our cell
- Thousands comprising 15 to 50% of the cell volume
-Red blood cells and skin cells have very little to none
- Germ cells have 100,000
- Most cells have one to 2,000 of them
2- It is our body’s lifeline. It is a Power plant
3- They're the primary source of energy for our body.
They supply over 90% of our body’s energy
4- Converting the food we eat and the air we breathe
into usable energy
The Mitochondria
How Your Mitochondria Influence Your Health
January 24, 2016
5- It have enormous potential to influence our health, specifically cancer, and optimizing
mitochondrial metabolism may be at the core of effective cancer treatment
8. Acetic acid acetyl group, derived from acetic
acid, is fundamental to the biochemistry of
virtually all forms of life. When bound to
coenzyme A it forms acetyl-CoA
The citric acid cycle is a key metabolic pathway that unifies carbohydrate, fat, and protein metabolism. The reactions of
the cycle are carried out by 8 enzymes that completely oxidize acetate, in the form of acetyl-CoA
ِباَنأعَ أاْلَو ِلي ِخَّنال ِتاَرَمَث نِمَوُهأنِم َونُذ ِخَّتَت
اًَركَسََٰذ يِف َّنِإ ۗ اًنَسَح اًقأز ِرَوأعَي ٍم أوَقِِّل ًةَي َل َكِلَونُلِق
(67)النحل سورة
وسلم عليه هللا صلى قال:(َخال ُمداِاإل َمأعِنُّل)
مسلم رواه(2051)
الكحو ل ّتحو توضح التالية الكيميائية المعادلةإلى ل
األكسجين غاز مع بالتفاعل ّلخ:
CH3CH2OH + 2 O2 --- >
2 CH3COOH + 2 H2O
Alcohol + Oxygen ---->
Acetic Acid + Water
كحول+أوكسجين----->حمضالخل+ماء
Mitochondria
CoA
How the human life is maintained
9. AIR
O2
FUEL
Carb-Protein-Fat
How the human life is maintained
WATER
﴾ٍِّيَح ٍءأيَش َّلُك ِاءَمألا َنِم اَنألَعَجَ﴿و[اْلن سورةالية بياء:30]
And We have made from water every living thing.
ENERGY
Cell survival
Waste (ROS)
Free radicals
Cell apoptosis
Control system: (Signaling pathway - Feed back) -
Nervous – Hormonal – Enzymatic
Aged cells
Cancer cells
Mitochondria
10. Reactive Oxygen Species (ROS)
Possess multiple functions in cellular
biology, involving cell death, proliferation,
and differentiation.
Moderate Amount of (ROS)
Rgulates cell death (Apoptosis) ,
proliferation, and differentiation.
Too much (ROS)
Will harm the mitochondria itself
We adjust the dose of medicines to kill
pathogens not to harm the host
The free radicals - Reactive Oxygen Species
(ROS)
11. Cell commits suicide by apoptosis. Cellular homicide is
necrosis
Apoptosis (from Ancient Greek word “falling off”) is a
process of programmed cell death that occurs in
multicellular organisms. Biochemical events lead to
characteristic cell changes (morphology) and death.
Programmed cell death
(APOPTOSIS)
Dr. Anurag Jain
2) Hormone-dependent physiologic involution, such as involution of the endometrium during the menstrual
cycle.
3) Cell deletion in proliferating cell population, such as intestinal crypt epithelium
4) Death of cells that have served there useful purpose, such as neutrophils in an acute inflammatory
respone.
5) Elimination of potentially harmful self reactive lymphocytes.
Pathological causes :
1) Cell death produced by a variety of mild injurious stimuli like
– heat, radiation, cytotoxic cancer drugs, infection, etc.
that cause irreparable DNA damage that in turn triggers cell suicide pathways.
2) Cell injury in certain viral diseases such as viral hepatitis.
3) Cell death in tumors.
Physiologic causes:
1) The programmed destruction of cell during embryogenesis. It is
programmed because it is death of specific cell types at defined times
during development.
12. ketogenic diet, forces cancer cells to use its mitochondria (cut off sugar) with a burst of
reactive oxygen species ROS.
ketogenic diet which radically improves mitochondrial health, could help most cancers,
especially if used in conjunction with glucose fermentation poisons like 3-bromopyruvate.
One of the universal characteristics of cancer cells is they
have serious mitochondrial dysfunction with radically
decreased numbers of functional mitochondria. "The
mitochondria can still function in cancer cells
The metabolic switch:
Hypoxia in the presence of sugar cancer cells become
immediately dependent on glucose (Anaerobic glycolysis)
and not using their mitochondria (no reactive oxygen
species ROS any longer)
Forcing it to use its mitochondria (cut off sugar) we get a
burst of reactive oxygen species ROS that lead to death,
because that cancer cell is already primed for that death. It's
ready to die.
Mitochondria's Role in Cancer
The metabolic switch
13. Dr. Otto Warburg was a physician with a
Ph.D. in chemistry and was close friends
with Albert Einstein.
Most experts recognize Warburg as the
greatest biochemist of the 20th century.
He received a Nobel Prize in 1931
for his discovery that cancer cells use
glucose as a source of energy
production (anaerobic Glycolysis)
This is called the "Warburg Effect"
Sadly, to this day it is essentially ignored
by nearly every expert.
14. Some Features of Warburg Effect
Glucose uptake and glycolysis proceed
about ten times faster in most solid
tumours than in non- cancerous tissues.
Tumour cells commonly experience hypoxia
(limited oxygen supply), because
they initially lack an extensive capillary network
to supply the tumour with
oxygen.
The high glycolytic rate may also result in
part from smaller numbers of mitochondria
in tumour cells thus resulting in less ATP
generation and higher consumption of Energy
(ATP).
In some cases, tumour cells overproduce
several glycolytic enzymes, including an
isozyme of Hexokinase-II and it results in
committing the cell to continued
glycolysis.
HIF-1 (Hypoxia-Inducible Factor -1)
is a protein that stimulates the activity of eight
glycolytic enzymes and it gives tumour cell
capacity to survive Anaerobic conditions.
15. Causes of Warburg Effect
• Mitochondrial Defects: mtDNA mutations lead to malfunction in
respiration
and oxidative phosphorylation.
• Hypoxia : Possible adaptation owing to lack of Oxygen availability in
the Environment.
• Oncogenic Signals : Point Mutations in genes such as Ras family can
result in proliferation of cells and signal initiation.
• Altered Metabolic Enzymes: Overproduction and mimicking of
metabolic enzymes such as Hexokinase-II result in increased
Glycolytic activity
Significance of Warburg Effect
Scientists after extensive research came to the conclusion that most
Tumour cells exhibit high glycolytic uptake.
Taking cue from this mechanism, numerous Glycolytic Inhibitors
have been developed. These compounds are acting as potential anti-
canceragents.
Alpha-cyano-4-hydroxycinnamic acid is a glycolytic inhibitor that has
been successfully used in Brain Cancer.
Recently, a molecule named Di Chloro Acetic or DCA acid was devised
by University of Alberta, claiming that it’s introduction would result in
normal functioning of Mitochondria. The testing of this
compound’s claims are
underway.
16. Mitochondrial Fuel
Which Fuel You Burn In Your Mitochondria for Energy Determines How Long Your Mitochondria Last
and That Determines How Long You Live!
Just As Gasoline Engines Run Best With Gasoline and Not
Diesel or Aviation Fuel, So Too,
Our Mitochondrial Cellular Engines Run Best
With Fat As Fuel, Instead of Sugar!
According to Dr. Ron Rosedale - “If I were to summarize in a single sentence what practice
would best promote health, it would be this”:
“Health and life span are determined by the proportion of fat
versus sugar people burn throughout their lifetime
The more fat that one burns as fuel, the healthier a person will be,
and the more likely he or she will live a long time;
The more sugar a person burns, the more disease ridden and the
shorter a life span a person is likely to have.”
(The above sentence is perhaps the most IMPORTANT statement you will ever read in regard
to health and longevity).
The mitochondria can only burn fat or sugar for
energy.
Which fuel is burned in the mitochondria for energy
determines how long the mitochondria stay in good shape.
17. Creating energy, by burning fuel in the mitochondria, is necessary, but it is destructive to our
bodies, just like burning gasoline or diesel is necessary, but destructive to the engine of the
automobile.
•Burning fat in the mitochondria produces more energy than does burning sugar.
•Fewer free radicals are released when burning fat than when burning sugar
•However, burning sugar is very fast compared to burning fat, and so, sugar burning is very
USEFUL DURING TIMES OF EMERGENCY.
You could almost say that our cells were designed to burn sugar only temporarily in times of
great exigency, when the damage from free radicals is not as important as dealing with the
emergency
If our bodies had been designed to primarily burn sugar as a fuel, then we would store sugar
cubes within our bodies, but we don’t, we store fat. We store only minor amounts of sugar
(in the form of glycogen) — enough to last for 30 to 60 minutes of emergency exertion.
Main Mitochondrial Fuel Concept
Fat is the Best Fuel
18. The Hypothalamus Sends Signals to the Body
Instructing Fat Burning or Sugar Burning.
In Many People the Hypothalamus is
Erroneously Sending the ‘Burn Sugar Signal’
The hypothalamus is a gland in the brain that dictates to
the entire body which fuel the cells of the body are to use:
fat or sugar.
The hypothalamus decides which mode to put the body in
based on the amount of leptin it can measure in the body.
A great number of people’s bodies are being “forced,
unnecessarily” to burn sugar instead of fat because that
tiny hypothalamus gland believes the body is starving,
and, therefore, sends a signal to the cells of the body that
sugar should be burned instead of fat (in order to conserve
fat).
This is unnecessarily causing the mitochondria
to “deteriorate faster”.
Why Does the Hypothalamus Unnecessarily Force a Sugar
Burning Mode in Our Bodies?
One of the most important functions of the
hypothalamus is to link the nervous system to
the endocrine system via the pituitary gland.
Thehypothalamus is located below the
thalamus and is part of the limbic system. In
the terminology of neuroanatomy, it forms the
ventral part of the diencephalon.
19. •Too much stored fat (Obesity).
Too much stored fat produces large amounts of circulating leptin which desensitizes the hypothalamus’s ability
to detect leptin (Leptin resistance). When leptin levels are not able to be detected, because the receptors in the
hypothalamus have been desensitized, the hypothalamus believes the body is starving and instructs sugar
burning in order to conserve and build up fat stores. This is ironic because essential the body’s pantries are full
of fat, but these pantries are inaccessible and so the cells are instructed to ignore fat and look for sugar to burn
for energy ( Craving).
There are only three reasons for the body
to be in sugar burning mode:
•Too much stress.
Stress creates the adrenal gland to relase
adrenaline. Adrenaline overrides the
hypothalamus signal and instructs sugar
burning.
•Too much blood sugar.
Blood sugar (over time) damages receptors in the
hypothalamus. When these receptors are damaged
then the hypothalamus cannot correctly sense
leptin... and believe there is no fat (i.e. starvation is
occurring).
Why Does the Hypothalamus Unnecessarily Force a Sugar
Burning Mode in Our Bodies?
20. Mitochondrial fission, fusion, and stress
Youle RJ1, van der Bliek AM.
Mitochondrial fission and fusion play critical roles in
maintaining functional mitochondria when cells
experience metabolic or environmental stresses.
Fusion helps mitigate stress by mixing the contents
of partially damaged mitochondria as a form of
complementation.
Fission is needed to create new mitochondria, but
it also contributes to quality control by enabling the
removal of damaged mitochondria and can
facilitate apoptosis during high levels of cellular
stress.
Disruptions in these processes affect normal development, and they have been
implicated in neurodegenerative diseases, such as Parkinson's
22. Dr. Ron Rosedale : Defective metabolic processes in mitochondria, not the genetic make up That
cause cancer and nearly all other chronic diseases, including accelerated aging
What causes Mitochondrial dysfunction?
The causes of Defective metabolic processes in mitochondria ?
1- The Harmful Effects of too much Sugar
A- Diet (HCLF)
Insulin and leptin receptor resistance
Free radicals (ROS) 90% in Mitochondria
B- Stress.
Adrenaline – hypothalamus ->> sugar
C- Obesity
Leptin resistance - hypothalamus ->> sugar
2- The Harmful Effects of too much Protein
Activation of the mTOR metabolic signaling pathway
3- Lack of exercise and Physical activity
24. Sugar is a “dirty” fuel, excessive free radicals caused by
reactive oxygen species (ROS).
Wile fat burns much cleaner. So by replacing carbs with
healthy fats,’ mitochondria are less likely to suffer damage
90 % or more of the total ROS (Reactive oxygen species)
are produced within the mitochondria, causing devastating
damage.
It was thought excessive ROS could be addressed by taking
antioxidants, but we now know that this was a flawed
strategy and it is far better to prevent their production by
eating an optimal fuel mixture.
LCHF - MMT - KD can help our cells’ mitochondria reach
the “Goldilocks” zone for producing ROS — not too much
and not too little, but just the “right” amounts for healthy
cellular and mitochondrial function.
Harmful Effects of too much Sugar
Chronic low grade inflammation - Mitochondrial dysfunction
25. Harmful Effects of too much Sugar
Chronic low grade inflammation - Mitochondrial dysfunction
1- State of chronic inflammation
2- Lipoprotein Oxidation & Glycation
3- Hyper insulinemia syndrome - Metabolic syndrome
-> Insulin resistance (type 2 DM)
-> increased triglycerides VLDL (Very-low-density lipoprotein)
-> Cholesterol (small dense LDL type B particles)
4- HFCS (High-fructose corn syrup) is found in almost all
types of processed foods and drinks (Sugar: toxic,
addicting, and deadly)
5- feeds” the cancer cells fructose is readily used by cancer
cells (not using mitochondria – no ROS to kill it)
6- Gaining weight (insulin and leptin signaling resistance)
7- Increases uric acid levels - risk for heart & kidney
8- Overloads and damages the liver much sugar or fructose
likened the effects of alcohol
9- Other diseases linked to metabolic syndrome include:
Type 2 diabetes, Heart disease, Hypertension, Polycystic
ovarian syndrome, Lipid problems, Dementia and
Alzheimer's disease
27. Harmful Effects of too much Protein
Paleo diet
Activation of the The mammalian Target Of Rapamycin (mTOR) metabolic
signaling pathway by too much protein
The figure highlight and summarize the current
understanding of how mTOR nucleates distinct multi-
protein complexes, how intra- and extracellular
signals are processed by the mTOR complexes, and
how such signals affect cell metabolism, growth,
proliferation and survival.
mTOR function in skeletal muscle a focal point for overnutrition and exercise . A. Rivas,a Sarah J. Lessard,b Vernon G. Coffeya
aExercise Metabolism Group, School of Medical Sciences, RMIT University, Bundoora, Victoria 3083ailartsuA ,ز The. Research Division, Joslin Diabetes
Center and Department of Medicine, Harvard Medical School, Boston, MA 02215ASU ,.ز Corresponding author (email: vernon.coffey@rmit.edu.au) .
Published on the web 6 October 2009. . Received March 29,2009yaM detpeccA .26,2009.
28. Harmful Effects of too much Protein
Paleo diet
The mammalian target of rapamycin (mTOR) -
Discoveries that have been made over the last
decade
phosphatidylinositol 3-kinase-related kinase family of protein
kinases. signaling pathway integrates both intracellular and
extracellular signals
The mTOR pathway serves as a central regulator of cell
metabolism, growth, proliferation and survival.
The mTOR pathway is activated during:
1- Tumor formation, angiogenesis, insulin resistance,
adipogenesis and T-lymphocyte activation etc
2- Deregulated in diseases as cancer and type 2 diabetes.
Nutrients and Exercise modify mTOR function
Growing therapeutic use of mTOR inhibitors (rapamycin and
rapalogues) in solid tumors, organ transplantation, coronary
restenosis and rheumatoid arthritis.
The figure highlight and summarize the current
understanding of how mTOR nucleates distinct
multi-protein complexes, how intra- and
extracellular signals are processed by the
mTOR complexes, and how such signals affect
cell metabolism, growth, proliferation and
survival.
29. Hypoxia-inducible factor 1alpha (HIF-1)
is regulated by the mammalian target of
rapamycin (mTOR) via an mTOR signaling
motif.
J Biol Chem. 2007 Jul 13;282(28):20534-43. Epub 2007 May 14.
Land SC1, Tee AR.
1Institute of Medical Genetics, Wales College of Medicine, Cardiff
University, Heath Park, Cardiff, Wales, United Kingdom.
Abstract
Abstract
Tumors that form as a result of heightened mammalian target of rapamycin (mTOR) signaling are highly
vascularized. This process of angiogenesis is regulated through hypoxia-inducible factor (HIF)-mediated
transcription of angiogenic factors. It is recognized that inhibition of mTOR with rapamycin can diminish the
process of angiogenesis. Our work shows that activation of mTOR by Ras homologue enriched in brain (Rheb)
overexpression potently enhances the activity of HIF1alpha and vascular endothelial growth factor (VEGF)-A
secretion during hypoxia, which is reversed with rapamycin. Mutants of Rheb, which do not bind guanine
nucleotide (D60K, D60V, N119I, and D122N) and are unable to activate mTOR, inhibit the activity of HIF when
overexpressed. We show that regulatory associated protein of mTOR (Raptor) interacts with HIF1alpha and
requires an mTOR signaling (TOS) motif located in the N terminus of HIF1alpha. Furthermore, a mutant of
HIF1alpha lacking this TOS motif dominantly impaired HIF activity during hypoxia and was unable to bind to the
co-activator CBP/p300. Rapamycin treatments do not affect the stability of HIF1alpha and modulate HIF activity
via a Von Hippel-Lindau (VHL)-independent mechanism. We demonstrate that the high levels of HIF activity in
cells devoid of TSC2 can be reversed by treatments with rapamycin or the readdition of TSC2. Our work explains
why human cancers with aberrant mTOR signaling are prone to angiogenesis and suggests that inhibition of
mTOR with rapamycin might be a suitable therapeutic strategy.
30. Cancer is One of the Most Manageable Diseases
Once we realize that cancer is a metabolic disease
Dr Josef Mercola - 2016
We can take charge of those kinds of things , with Eating too many
sugars and carbs without fiber, along with too much protein, we
ignite a cascade of metabolic events that includes:
•Widespread inflammation and cellular damage, especially our
mitochondria, or cells’ power factories
•Faster aging and a greater risk of all cancers from the activation of
body’s most important signaling pathway mTOR from eating excess
protein
•An increase in insulin resistance that can progress to prediabetes or
Type 2 diabetes because cells have lost their ability to respond to
insulin effectively
•Overeating due to leptin resistance with loss of control over appetite
and knowing when you’re “full”
•An inability to lose weight because body is holding on to fat instead
of burning it for fuel
33. World Health Organization MONICA
study
(MONICA : multinational MONITORING
trends and determinants in
CADIOVASCULAR disease)
14 European countries
+ urban Australian Aborigines
10 years
7 million people
40 studies collected
The ten year data collection was
completed in the late 1990s,
A diet low in saturated fat 'will not prevent
heart disease or prolong life'
"The Great Cholesterol Myth". Dr. Malcolm Kendrick
MD . July 2011.
As any person (no medical experience needed) with eyes can
see, the Aborigines had the lowest cholesterol and the highest
death rate from heart disease.
34. 35
The typical atherosclerotic plaque comprises of the lipid
core and the fibrous cap, and is the most commonly
classified histologically by the American Heart Association
Atherosclerotic plaque
Causes:
1- Endothelial damage & permeability
2- Small dense particles LDL type B
3- Smooth muscle cells migration and proliferation
4- Monocyte adhesion, migration and foam cell
development.
Caused by:
1- State of chronic inflammation
->> Oxidative stress
2- Hyperglycemia
->> Lipoprotein Oxidation & Glycation
3- Hyper insulinemia – Hyper leptinemia
-> increased triglycerides VLDL
-> Cholesterol (small dense LDL type B particles)
Treat the cause is the logical thinking:
1- Anti-inflammatory lifestyle
2- Control Hyperglycemia-
3- Control Insulin - Leptin resistance
Hyper insulinemia – Hyper leptinemia
(Diet too high in sugars & Obesity)
35. Figure 1: Oxidative stress affects four fundamental mechanisms that contribute to
atherogenesis (i) oxidation of LDL to form ox –LDL (ii) endothelial cell dysfunction
(increased release of MCP-1, MMPs, increased expression of VCAM-1, ICAM-1 and LOX-1,
decreased activity of NO, platelet aggregation) (iii) vascular smooth muscle cells migration
and proliferation (iv) monocyte adhesion and migration and foam cell development. [15]
36. In Summary, Saturated Fats Are Healthy
•Increase your LDL levels, but they increase the
large fluffy particles that are not associated with
an increased risk of heart disease
•Increase your HDL levels. This more than
compensates for any increase in LDL
•Do NOT cause heart disease as made clear in all
the above-referenced studies
•Do not damage as easily as other fats because
they do not have any double bonds that can be
damaged through oxidation
•Serve to fuel mitochondria and produce far less
damaging free radicals than carbs
Could Eating the Right Fats Save 1 Million Lives per Year?
D. Mercola - March 06, 2016
37. In many epileptic patients, anticonvulsant drugs either fail adequately to control
seizures or they cause serious side effects.
An important adjunct to pharmacologic therapy is the ketogenic diet, which often
improves seizure control, even in patients who respond poorly to medications.
The mechanisms that explain the therapeutic effect are incompletely understood.
Evidence points to an effect on brain handling of amino acids, especially glutamic
acid, the major excitatory neurotransmitter of the central nervous system.
The diet may limit the availability of oxaloacetate to the aspartate aminotransferase
reaction, an important route of brain glutamate handling.
The ketogenic diet and brain metabolism of amino acids: relationship to
the anticonvulsant effect.
Yudkoff M1, Daikhin Y, Melø TM, Nissim I, Sonnewald U, Nissim I.
Annu Rev Nutr. 2007;27:415-30.
As a result, more glutamate becomes accessible to the glutamate decarboxylase reaction to yield gamma-
aminobutyric acid (GABA), the major inhibitory neurotransmitter and an important antiseizure agent.
In addition, the ketogenic diet appears to favor the synthesis of glutamine, an essential precursor to GABA.
This occurs both because ketone body carbon is metabolized to glutamine and because in ketosis there
is increased consumption of acetate, which astrocytes in the brain quickly convert to glutamine.
The ketogenic diet also may facilitate mechanisms by which the brain exports to blood compounds such as
glutamine and alanine, in the process favoring the removal of glutamate carbon and nitrogen.
38. Alterations in the metabolism of excitatory amino acids
and γ-aminobutyric acid (GABA) during the high-fat, low-
carbohydrate ketogenic diet. Metabolism of acetyl-CoA
generated from fats leads to high consumption of
oxaloacetate (see Fig. 1). L-Aspartate, a nonessential
amino acid, is formed by the transamination of
oxaloacetate with an amino group from glutamate.
Reduced availability of oxaloacetate along with robust
availability of αketoglutarate from high activity of the first
part of the Krebs cycle leads to low aspartate levels. It
has been hypothesized that more glutamate is thus
accessible to glutamic acid decarboxylase for production
of GABA [33]. Not all Krebs cycle intermediates are
shown in the schematic.
The brain, energy is everything. The brain needs a crapload of
energy to keep all those membrane potentials maintained - to
keep pushing sodium out of the cells and pulling potassium into
the cells.
In fact, the brain, which is only 2% of our body weight, uses 20%
of our oxygen and 10% of our glucose stores just to keep
running.
(Some cells in our brain are actually too small (or have tendrils
that are too small) to accommodate mitochondria (the power
plants). In those places, we must use glucose itself (via
glycolysis) to create ATP.)
When we change the main fuel of the brain from glucose to
ketones, we change amino acid handling. And that means
we change the ratios of glutamate and GABA.
The best responders to a ketogenic diet for epilepsy end up with
the highest amount of GABA in the central nervous system.
glutamine, an essential precursor for GABA.
If you recall, GABA is the major inhibitory neurotransmitter in the
mammalian nervous system. Turns out, GABA is made from
glutamate, which just happens to be the major excitatory
neurotransmitter. You need them both, but we seem to get into
trouble when have too much glutamate. Too much excitement in
the brain means neurotoxicity, the extreme manifestation of
which is seizures. But neurological diseases as varied
as depression, bipolar disorder, migraines, ALS, and dementia
have all been linked in some way to neurotoxicity.
42. Dr. Ron Rosedale : Defective metabolic processes in mitochondria, not the genetic make up That cause
cancer and nearly all other chronic diseases, including accelerated aging
What causes Mitochondrial dysfunction?
The causes of Defective metabolic processes in mitochondria ?
1- The Harmful Effects of too much Sugar
A- Diet (HCLF)
Insulin and leptin receptor resistance
Free radicals (ROS) 90% Mitochondria
B- Stress.
Adrenaline – hypothalamus ->> sugar
C- Obesity
Leptin resistance - hypothalamus ->> sugar
2- The Harmful Effects of too much Protein
Activation of the mTOR metabolic signaling pathway
3- Lack of exercise and Physical activity
43. 1- low carb High fat Diet Regime (LCHF) –
Mitochondrial Metabolic Therapy (MMT) 2017 -
Ketogenic diet (KD)
2- Mitochondrial Metabolic Therapy (MMT) 2017 is
Similar to a ketogenic diet (epilepsy 30-50%)
3-MMT is a high fat, moderate protein, low
carb eating plan
Unlike a ketogenic diet, it emphasizes on high-
quality, (unprocessed whole foods )
Unlike Paleo diet it does not consume far too
much protein (moderate protien)
Mitochondrial Biogenesis
Salvage 1- The Harmful Effects of too much Sugar
44. Intermittent fasting
Beside longevity and health issues, it also provide powerful cancer
prevention and treatment benefit. And the mechanism for that is related to
the effect fasting has on our mitochondria.
Reactive oxygen ROS. Some free radicals are actually good and your
body requires them to regulate cellular function (fat burning), but problems
develop when you have excessive free radical production (sugar burning) .
There are two possible solutions to this problem:
• Increase your antioxidants
• Reduce mitochondrial free radical production by calorie restriction .
This is one of the reasons why intermittent fasting works, as it limits the
window that you are eating and automatically reduces your calories.
It is particularly effective if you avoid eating several hours before going to
sleep as that is your most metabolically lowered state.
A review paper1 that provides much of the experimental work for the above explanation was published
in 2011, titled "Mitochondrial DNA Damage and Animal Longevity: Insights from Comparative Studies.”
Interventional strategy
where in individuals are
subjected to varying periods
of fasting.
Mitochondrial Biogenesis
Salvage 1- The Harmful Effects of too much Sugar
45. Mitochondrial Biogenesis
Salvage 1- The Harmful Effects of too much Sugar
Interventional strategy where in
individuals are subjected to varying
periods of fasting.
Fasting Promotes Healthy Mitochondrial Function, Our body has to rely
on lipids and stored fats for energy, which means our cells are forced
to use their mitochondria. mitochondria are the only mechanisms by which
our body can make energy from fat. So, fasting helps activate our
mitochondria.
Intermittent fasting, ketogenic diet and certain drugs can kill
cancer cells, by activating the mitochondria. It creates a burst of reactive
oxygen species ROS, the damage from which tips the scale and causes the
cancer cells to die.
Fasting clears away damaged cells through a process called autophagy, which basically
means when a cell that's damaged, it can die. But if it doesn't die, sometimes it becomes what's called
senescent and this happens a lot with aging. What that means is that the cell is not dead but it's not
really alive either. It's not doing its function.
It's just kind of sitting around in your body secreting pro-inflammatory molecules, things that are
damaging other nearby cells thereby accelerating the aging process because inflammation drives
aging in so many different ways.
Autophagy clears away those cells that are just sitting there creating damage and not doing much
else, which is nice because that's also a very important biological mechanism for staying healthy."
46. Mitochondrial Biogenesis
Salvage 1- The Harmful Effects of too much Sugar
Why Does the Hypothalamus Unnecessarily Force a Sugar
Burning Mode in Our Bodies?
Overcoming too much stress.
Reducing stress is the antidote to adrenaline causing sugar burning. To do so, one
must eliminate fear, anxiety, and/or sleep deprivation. Sleeping sufficiently,
meditation and eliminating causes of stress are the keys.
Reducing blood sugar.
The best way to reduce blood sugar is to drastically reduce one’s consumption of
foods that contain sugar and other carbohydrates. The absolute best way to prevent
sugar fluctuations is to eat 5 to 6 small meals per day (every 2 to 3 hours), of non
sugar/carbohydrate containing foods.
Overcoming Leptin Insensitivity.(Obesity)
Overcoming leptin insensitivity (i.e. repairing the hypothalamus) isn’t so easy. The
rather long explanation of why it isn’t so easily overcome is that the bodies of sugar
burning people (primarily fat people) have large pantries of stored fat which creates
large amounts of the messenger molecule leptin which will push the leptin levels
above 9.0 ng/ml and damage the receptors. After a while, the hypothalamus cannot
detect leptin at all and thinks that its level is zero, and therefore, instructs sugar
burning mode. In a sugar burning mode, it is difficult to entice the body to burn fat
stores and therefore very difficult to get rid of fat so that leptin levels will go down to
a “fat burning”range of between 4.0 and 9.0. For a fairly in-depth discussion about
doing this, please request our Becoming Leptin Sensitive Booklet.
47. Managing Your Mitochondria, By Mark Sisson October 20, 2011
The single most fundamental – and simple – way to
improve mitochondrial function
is to turn away from relying on sugar-burning and
transform yourself into a fat-burning beast.
See, mitochondria burn fatty acids cleaner than they burn carbohydrates. Generating ATP
via fats/ketones produces fewer free radicals, because it’s more efficient, whereas generating ATP via carbs
produces more. As a result, glutathione can do its job and our ketone-burning mitochondria have to divert less
attention to cleaning up free radicals. This doesn’t just make mitochondrial ATP production from ketones more
efficient; it has the potential to render it downright anti-inflammatory, too. When we dip into a full-fledged
ketogenic diet, cut back on bad carbs, or intermittently fast, we are switching over to fat-burning. When we
switch over to fat-burning, our mitochondria do the same. Heck, that’s what we mean by “fat-burning.” There’s
even evidence that ketosis can spur mitochondrial biogenesis, albeit thus far only in rats.
In my new book I present my Primal prescription for becoming a fat-burning beast. In fact, one of the reasons I
wrote the 21-Day Total Body Transformation is because untold millions of people are languishing in sugar-
burning land and their mitochondria aren’t burning quite as cleanly as they could. The “transformative” aspect of
the 21-Day Total Body Transformation is the epigenetic switch from sugar-burning to fat-burning. And improving
mitochondrial function and (if that rat study pans out in humans) increasing mitochondrial biogenesis are at the
heart of this switch.
Mitochondrial Biogenesis
Salvage 1- The Harmful Effects of too much Sugar
48. Mitochondrial Biogenesis
Salvage 2- The Harmful Effects of too much Protein
Mitochondrial Metabolic Therapy (MMT) 2017
is a high fat, moderate protein, low carb eating plan
Unlike a ketogenic diet, it emphasizes on high-quality,
unprocessed whole foods
Unlike Paleo diet which allow consumption of far too much
protein
The mammalian target of rapamycin (mTOR) pathway is Central
regulator of cell metabolism, growth, proliferation and survival.
49. Mitochondrial Biogenesis
Salvage 3- Lack of exercise and Physical activity
Exercise Helps Keep Our Mitochondria Young
Exercise
Promotes mitochondrial health, as it forces your mitochondria to work harder. one of
the side effects of mitochondria working harder is that they're making reactive oxygen
species ROS , which act as signaling molecules. One of the functions they signal is to
make more mitochondria (fission). So, when you exercise, your body will respond by
creating more mitochondria to keep up with the heightened energy requirement.
Aging
Is inevitable. But your biological age can be quite different from your
chronological age, and your mitochondrial health have a lot to do with your
biological aging.
As noted by Patrick, "youthfulness" is not so much about your chronological age, but rather how old you feel, and
how well your body works:
"I want to learn how to optimize my own cognitive performance and my athletic performance. I want to also
increase the youthful part of my life. I want to be 90. I want to be out there, surfing in San Diego just like I was
when I was 20. I would like to not degenerate as rapidly as some people do. I like to stave off that degeneration
and extend the youthful part of my life as long as I possibly can so I can enjoy life."
50. Role of Regular Physical Exercise
A- Burn of fat
(as MMT & Ketogenic diet)
B- Improve insulin sensitivity
(depleting glycogen & fat stores)
C- Peak rise of hormones
Human growth hormone(HGH-GH) – Endorphins ,
Dopamine, Norepinephrine, Serotonin) - exercise intensity
D- Mitochondrial Biogenesis
Mitochondrial Biogenesis
Salvage 3- Lack of exercise and Physical activity
51. Mitochondrial Biogenesis
Salvage 3- Lack of exercise and Physical activity
Mitochondrial Biogenesis:
Exercise is one of the most powerful signals for PGC
1-alpha
A protein encoded by PPARGC1A gene (Peroxisome proliferator-
activated receptor gamma coactivator 1-alpha (PGC-1α) )
PGC 1-alpha:
Is the primary signal for Mitochondria to Reproduce and
Multiply, a process called Mitochondrial biogenesis
PPARGC1A
(PGC-1α( is a protein encoded by the PPARGC1A gene. known as human accelerated
region 20 (HAR20).
PGC-1α is a transcriptional co activator that regulates the genes involved in energy
metabolism. It is the master regulator of mitochondrial biogenesis.
52. PPARGC1A
PGC-1α activating host factors
1- Free Radicals
Reactive oxygen species (ROS) and reactive nitrogen species (RNS),
both formed intracellularly as by-products of metabolism but
upregulated during times of cellular stress.
2- Cold Exposure
adaptive thermogenesis
3- Endurance Exercise
PGC-1α determines lactate metabolism, preventing high lactate levels
in endurance athletes & making lactate as an energy source
plays a central role in the regulation of cellular energy metabolism. It stimulates 1- mitochondrial biogenesis 2- promotes the
remodeling of muscle tissue to a fiber-type that is metabolically more oxidative and less glycolytic in nature
It participates in the regulation of both carbohydrate & lipid metabolism.
It is involved in obesity, diabetes, & cardiomyopathy.
Mitochondrial Biogenesis
Salvage 3- Lack of exercise and Physical activity
53. Mitochondrial Biogenesis
Salvage 3- Lack of exercise and Physical activity
Exercise (Mitochondrial Biogenesis) for
Cutting Cancer Risk:
The mammalian target of rapamycin (mTOR) -
Discoveries that have been made over the last decade
The mTOR pathway is Central regulator of cell
metabolism, growth, proliferation and survival.
Nutrients (less protein) and Exercise modify
mTOR function
1- Activated during tumor formation, angiogenesis, insulin resistance, adipogenesis and T-lymphocyte activation etc
2- Deregulated in diseases as cancer and type 2 diabetes.
3- Growing therapeutic use of mTOR inhibitors (rapamycin and rapalogues) in solid tumors, organ transplantation,
coronary restenosis and rheumatoid arthritis.
54. Mitochondrial Biogenesis
Salvage 3- Lack of exercise and Physical activity
Exercise slashed the risk of cancer in 13 out
of the 26 cancers
for example
Kidney cancer by (23 %)
Lung cancer by (26 %)
Liver cancer by (27 %)
Esophageal adenocarcinoma by (42 %)
Large Study 2016 Underscores Value of Exercise for Cutting Cancer Risk
Journal of the American Medical Association Internal Medicine 2016; 176(6): 816-
825=
The research involved a mega-pool of
1.44 million men and women from a dozen
large European and U.S.
prospective cohort studies (groups of
participants who’d been followed for
several years).
Participant age, body mass index, gender,
self-reported data on exercise, smoking
status and, if applicable, any cancer
diagnoses, were analyzed to determine
the effect exercise had on various
cancers.
A total of 186,932 primary cancers were
diagnosed during the follow-up period,
which had a median length of 11 years.
Regardless of the person’s weight or
smoking history, the data suggested
physical activity cut their risk of cancer.
55. Mitochondrial Biogenesis
Salvage 4- Feeding Your Mitochondria
The following nutrients; co-factors needed for mitochondrial
enzymes to function properly:
•CoQ10 or ubiquinol (the reduced form)
•L-Carnitine, which shuttles fatty acids to the mitochondria
•D-ribose, which is raw material for ATP molecule
•Magnesium
•Omega-3 fatty acids
•All B vitamins, including riboflavin, thiamine, and B6
•Alpha-lipoic acid (ALA) - Thiotacid
Get as many micronutrients as you can from whole foods
56. This slide offers a summary view of their various mechanisms of action:
Similar to a ketogenic diet (epilepsy 30-50%)
MMT is a high fat, moderate protein, low carb eating plan
Unlike a ketogenic diet,
MMT emphasizes on high-quality, unprocessed whole foods
Similar to a ketogenic diet (epilepsy 30-50%)
MMT is a high fat, moderate protein, low carb eating plan
Unlike a ketogenic diet,
MMT emphasizes on high-quality, unprocessed whole foods
1- With exercise the body Burn fat as its primary fuel, as with using a ketogenic diet and MMT (Mitochondria metabolic therapy)
2- Exercise is one of the most powerful signals for PGC 1-alpha, which is the primary signal for mitochondria to reproduce and multiply, a process called Mitochondrial biogenesis
1- With exercise the body Burn fat as its primary fuel, as with using a ketogenic diet and MMT (Mitochondria metabolic therapy)
2- Exercise is one of the most powerful signals for PGC 1-alpha, which is the primary signal for mitochondria to reproduce and multiply, a process called Mitochondrial biogenesis