Documente Academic
Documente Profesional
Documente Cultură
Key to Wellness
Private Practice
Mission, Kansas
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And All
of You!
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Disclosures
I work for NO special interest or
lobbying groups nor do I receive
stipends, consulting fees, gratuities
or honoraria from any
pharmaceutical or nutritional
companies.
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Rabindranath Tagore
1913 Nobel Laureate; Literature
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Objectives
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Seyfried, Thomas. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer (Kindle Locations 51065107). Wiley Publishing. Kindle Edition.
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Complexity is a strategy
used by professional elites
to maintain control.
Ian Roberts
The Energy Glut: The Politics of Fatness
in an Overheating World, 2010. p.90
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Nat Clin Pract Cardiovasc Med. 2007 February; 4(Suppl 1): S60S67.
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Crabtree Effect
Cancer cells have also been shown to be different from
normal cells by reversibly down-regulating their oxygen
consumption in response to increases in glucose: the
Crabtree effect. PLoS One. 2013; 8(2): e56884.
Increasing concentrations of glucose accelerates
glycolysis (the breakdown of glucose) which results in the
production of appreciable amounts of ATP through
substrate-level phosphorylation. This reduces the need of
oxidative phosphorylation done by the TCA cycle via the
electron transport chain and therefore decreases oxygen
consumption. http://en.wikipedia.org/wiki/Crabtree_effect
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Getting Reacquainted
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Endosymbiotic Theory
The mitochondria are the product of a symbiosis
between two micro-organisms that occurred
about two billion years ago.
The nature of the original partner organisms is
actively debated, but the progenitor of the
mitochondrion is thought to have been an alphaproteobacterium that harboured a complete
OxPhos system.
Philos Trans R Soc Lond B Biol Sci. 2013 July 19; 368(1622): 20120267.
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Benefits of Symbiosis
A single bacterial cell can generate only enough energy
to sustain about 10,000 genes.
When the host cell acquired multiple oxidative bacteria,
the bacterial energy could be pooled to provide the
required energy for adding more genes to the host cells
DNA to create more complex anatomical structures.
Philos Trans R Soc Lond B Biol Sci. 2013 July 19; 368(1622): 20120267.
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Genome Expansion
By enabling oxidative phosphorylation across a wide
area of internal membranes, mitochondrial genes
enabled a roughly 200,000-fold rise in genome size
compared with bacteria.
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Mitochondria are of
Female Origin
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Campbell, Joseph; Bill Moyers (2011-05-18). The Power of Myth (p. 211). Knopf Doubleday Publishing Group. Kindle Edition.
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Campbell, Joseph; Bill Moyers (2011-05-18). The Power of Myth (p. 226). Knopf Doubleday Publishing Group. Kindle Edition.
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15 Pounds of Mitochondria
Evans, Joseph (2013-02-28). The Secret Life of Mitochondria (Kindle Locations 138-139). Smashwords, Inc.. Kindle Edition.
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Mitochondrial Bioenergetics
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Mitochondrial Microanatomy
There are five distinct parts to a mitochondrion.
1. outer mitochondrial membrane
2. intermembrane space (the space between the outer
and inner membranes)
3. the inner mitochondrial membrane
4. the cristae space (formed by infoldings of the inner
membrane)
5. the matrix (space within the inner membrane)
Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, Peter Walter (1994). Molecular Biology of the Cell. New
York: Garland Publishing Inc. ISBN 0-8153-3218-1.
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Glycolysis
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Glycolysis Trivia
Glycolysis produces its energy 100 times faster than
aerobic respiration.
Glycolysis is the preferred energy source of rapidly
growing cell populations.
The early zygote becomes increasingly dependent on
glycolytic energy production as development progresses
to the blastocyst stage.
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Mitochondrial Matrix
The mitochondrial matrix contains enzyme
systems for the Krebs cycle and ketone
metabolism.
The matrix also anchors the mitochondrial DNA
(mtDNA).
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NAD+/NADH
The mitochondrial
NADH is oxidized by
the electron transport
chain, which pumps
protons across a
membrane and
generates ATP
through oxidative
phosphorylation.
Biochem Soc Trans. 2003 Dec;31(Pt 6):1095105.
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FAD/FADH2
The primary biochemical role
of FADH2 in eukaryotes is to
carry high-energy electrons
used for oxidative
phosphorylation.
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Coenzyme Q10
CoQ10 functions as an electron carrier from enzyme
complex I and enzyme complex II to complex III in
this process a process which also involves
menaquinones or Vitamin K2.
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Cytochrome C
Cytochrome c carries an
electron in the ETC and
is also an intermediate in
apoptosis, a controlled
form of cell death used to
kill cells in the process of
development or in
response to infection or
DNA damage.
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Seyfried, Thomas (2012-05-17T16:00:00+00:00). Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of
Cancer (Kindle Locations 2125-2129). Wiley Publishing. Kindle Edition.
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Cardiolipin:
ETC Caulking
Cardiolipin (CL) which represents 20% of membrane
phospholipids is necessary for maintaining coupled
mitochondria, and defects in CL can produce protein
independent uncoupling.
Hence, alterations in the content or composition of CL will
alter cellular respiration.
Seyfried, Thomas (2012-05-17T16:00:00+00:00). Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of
Cancer (Kindle Locations 2125-2129). Wiley Publishing. Kindle Edition.
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Mitochondrial Distribution
Mitochondria are distributed throughout the
cytoplasm in a nonrandom manner by
cytoskeleton motors.
Cells that are rapidly dividing have mitochondria
close to the nucleus and to ribosomes because
de novo protein synthesis is highly dependent on
the energy provided by ATP.
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Mitochondrial Genome
The mitochondrial genome contains 37 genes that
encode 13 proteins, 22 transfer RNAs, and 2 ribosomal
RNAs.
The 13 mitochondrial gene-encoded proteins all instruct
cells to produce protein subunits of the enzyme
complexes of the oxidative phosphorylation system,
which enables mitochondria to act as the powerhouses of
our cells.
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mtDNA Mutations
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http://en.wikipedia.org/wiki/Reactive_oxygen_species
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Antioxidant Defenses
Antioxidant defenses are also up-regulated in conjunction
with OxPhos to offset the effects of increased
mitochondrial ROS production. Mitochondrion. 10(1): 12-31.
Endogenous, genetically encoded antioxidant systems
linked to the Antioxidant Response Elements (AREs) will
be discussed in future slides.
Exogenous antioxidants will be given passing attention in
favor of the more powerful and evolutionary significant
endogenous antioxidants.
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Drug-induced
Mitochondrial Toxicity
Drugs that injure mitochondria usually do so by inhibiting
respiratory complexes of the electron chain; inhibiting or
uncoupling oxidative phosphorylation; inducing
mitochondrial oxidative stress; or inhibiting DNA
replication, transcription or translation.
It is important to test for mitochondrial toxicity early in
drug development as impairment of mitochondrial
function can induce various pathological conditions that
are life threatening or can increase the progression of
existing mitochondrial diseases.
Expert Opin Drug Metab Toxicol. 2005 Dec;1(4):655-69.
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NSAID Induced
Mitochondrial Toxicity
[Mitochondrial toxicity] involves specific biochemical
damage of mitochondria and uncoupling the oxidative
phosphorylation reaction.
Electron microscopic studies show vacuolisation and
ballooning of mitochondria within an hour of
indomethacin administration which is highly characteristic
of uncoupling of oxidative phosphorylation.
The consequence of uncoupling is diminished cellular
ATP, which alters the intercellular junction, increases
intestinal permeability, and releases calcium into cytosol
which in turn causes secondary biochemical damage.
Gut. 2001 February; 48(2): 163167.
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Mitochondrial Dysfunction
Injury to the mitochondrial electron transport chain (ETC)
or mutations of mtDNA leading to mitochondrial
dysfunction have recently been suggested as an
important factor in the pathogenesis of mitochondrial
cancer
a range
of other
diseases, aging,
and a range
of other human
disorders.
human disorders.
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Muscles
Common Symptoms:
Hypotonia, weakness, cramping,
muscle pain, ptosis, and
ophthalmoplegia.
Despite the subjective
weakness, many patients have
minimal objective findings,
possibly because fatigability is
difficult to quantify in a
physicians office.
Cleve Clin J Med. 2001 Jul;68(7):625-6, 629-42.
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Fibromyalgia?
The etiology is unknown; however, recent studies
suggest that mitochondrial dysfunction is involved in the
pathophysiology of fibromyalgia.
Mitochondrial DNA content (mtDNA/gDNA ratio) was
reduced in fibromyalgia patients versus healthy controls
(p<0.001).
Expression levels of peroxisome proliferator-activated
receptor gamma-coactivator 1-alpha was significantly
lower in fibromyalgia patients (p<0.001) compared with
healthy controls.
Antioxid Redox Signal. 2013 Nov 20;19(15):1855-60.
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Brain
Common Symptoms: Developmental delay, mental
retardation, autism, dementia, seizures, neuropsychiatric
disturbances, atypical cerebral palsy, atypical migraines,
stroke and stroke-like events.
Migraine, dementia, seizures, and strokelike episodes
can occur at any stage of the disease, but like myopathy,
brain involvement is not required for the diagnosis.
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Nerves
Common Symptoms: Neuropathic pain and weakness
(which may be intermittent), acute and chronic
inflammatory demyelinating polyneuropathy, absent deep
tendon reflexes, neuropathic gastrointestinal problems
(gastroesophageal reflux, constipation, bowel
pseudoobstruction), fainting, absent or excessive
sweating, and aberrant temperature regulation.
Nerve cells and Schwann cells are extremely active
metabolically: nerve cells require a tremendous amount
of energy to maintain the electrochemical gradient
necessary for nerve transmission.
Cleve Clin J Med. 2001 Jul;68(7):625-6, 629-42.
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Kidneys
Common Symptoms: Proximal renal tubular dysfunction,
may result in loss of protein (amino acids), magnesium,
phosphorous, calcium, and other electrolytes.
The proximal renal tubular cells require an abundant and
steady energy supply.
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Heart
Common Symptoms: Cardiac conduction defects (heart
blocks) and cardiomyopathy.
The sinoatrial and atrioventricular nodes are the most
metabolically active tissues in the body, and the muscular
activity of the heart never ceases. Therefore, cardiac
conduction defects and cardiomyopathy are
complications of mitochondrial dysfunction.
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Liver
Common Symptoms: Hypoglycemia, gluconeogenic
defects, and nonalcoholic liver failure.
Maintenance of glucose homeostasis is the most vital
moment-to-moment function of the liver.
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Lao Tzu
Tao Te Ching
Chapter 63
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Genome Instability
If damage to mitochondria is persistent and defective
mitochondria accumulate in the cell, it would lead to
instability of the nuclear genome.
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Genome Instability
Accumulated nuclear genome instability may help cells
acquire new functions such as resistance to apoptosis,
migration, and invasive characteristics which, in turn,
could induce tumorigenesis.
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Epigenetic Influences
Evidence that mitochondrial dysfunction is associated
with epigenomic changes can be found for a wide range
of classical epigenomic diseases.
In cancer, a genetic disease, changes in the epigenome
such as loss of Imprinting (phenomenon by which certain
genes can be expressed in a parent-of-origin-specific
manner is lost) and hypomethylation are common.
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Epigenetic Influences
The chromatin modifications of cancer cells can be
directly modulated by mitochondrial OxPhos.
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MtDNA Rehabilitation
When mtDNAs were reintroduced into the mtDNAdeficient cancer cells, 30% of the hypomethylated sites
become remethylated.
Thus, there is a direct cause and effect relationship
between mitochondrial function and epigenomic
methylation in cancer cells.
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OxPhos-p53 Connection
The p53 protein also regulates OxPhos and it has been
shown that mutational inactivation of p53 in cancer cells
suppresses OxPhos and induces glycolysis.
Science. 2006;312:16501653.
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Mitochondrial Biogenesis
Mitochondria cannot be generated de novo; instead, they
proliferate by growth and division of pre-existing
organelles. Nature Rev Mol Cell Biol. 2010;11:872884.
Mitochondria divide during mitosis, providing daughter
cells with a normal complement of mitochondria. Antioxid Redox
Signal. 2012 May 15;16(10):1150-80
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Mitochondrial Biogenesis
Nutrient excess stimulates mitochondrial fission,
fragmented mitochondrial morphology, and an arrest in
oxygen consumption, oxidative phosphorylation,
and
C
Crra
abbt
ATP synthesis. Front Aging Neurosci. 2013 Sep 6;5:48.
trreee
e EE
By contrast, nutrient deficiency triggers mitochondrial
ffffee
cctt
fusion, elongated mitochondrial morphology, and
an
acceleration of mitochondrial respiration and ATP
production. Front Aging Neurosci. 2013 Sep 6;5:48.
Thus, mitochondrial fission and fusion is a fine tuned
process that controls the switches of energy production
with energy demand, thereby maintaining homeostasis.
Commun Integr Biol. 2011 November 1; 4(6): 752754.
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Calorie
Restriction/
Fasting
SIRT1
Dietary
Polyphenols
Endurance
Exercise
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SIRT1
SIRT1 stands for silent information regulator type 1.
SIRT1 is an enzyme that deacetylates proteins that
contribute to cellular regulation (reaction to stressors,
longevity). http://www.scientificamerican.com/article.cfm?id=unlocking-the-secrets-of-2006-03&page=3
J Biol Chem. 2005 Apr 22;280(16):16456-60.
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Calorie
Restriction/
Fasting
SIRT1
Dietary
Polyphenols
PGC-1
Endurance
Exercise
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Calorie
Restriction/
Fasting
SIRT1
Dietary
Polyphenols
PGC-1
Endurance
Exercise
Mitochondrial
Biogenesis
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Benefits of
Mitochondrial Biogenesis
Increased
Decreased
OxPhos
ROS
Metabolic Efficiency
Oxidative Stress
Energy Level
Body Fat
Disease/Dysfunction
Exercise Performance
Age-related Deterioration
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Calorie Restriction
In 1935, nutritional scientist Professor Clive M. McCay
(Cornell University) published his seminal paper showing
that rats fed a diet with 30-40% fewer calories lived about
33% longer than rats fed ad libitum.
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CRON-diet
Calorie Restriction Optimal Nutrition
The CRON-diet involves calorie restriction while
still attempting to provide the recommended daily
amounts of various nutrients.
Proponents recommend a goal of restricting
intake by 20%.
The actual daily amount eaten depends on the
adherent's basal metabolic rate (BMR). A common
daily intake is 1800 calories per day.
http://en.wikipedia.org/wiki/CRON-diet
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CRON Weakness
Calorie restrictors are exquisitely aware of exactly how
many calories they are eating at all times.
CRON, in other words, falls prey to one of the biggest
stumbling blocks for any diet: It requires you to constantly
think about the one thing you dont want to be thinking
about: what you can and cant eat.
Johnson M.D., James B. (2008-04-10). The Alternate-Day Diet: Turn on Your "Skinny Gene," Shed the Pounds, and Live a Longer
and HealthierLife (Kindle Locations 242-244). Penguin Group US. Kindle Edition.
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Intermittent Fasting
Intermittent fasting (IF) is a pattern
of eating that alternates between
periods of fasting (usually meaning
consumption of water and
sometimes low-calorie drinks such
as black coffee) and non-fasting.
http://en.wikipedia.org/wiki/Intermittent_fasting
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Intermittent Fasting
Interestingly, intermittent fasting but
not caloric restriction for 20 weeks
increases hippocampal neuron
tolerance to excitotoxic stress in
mice, suggesting neuroprotective
effects of intermittent fasting.
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Mosley, Michael; Spencer, Mimi (2013-02-26). The FastDiet: Lose Weight, Stay Healthy, and Live Longer with the
Simple Secret of Intermittent Fasting (p. 14). Atria Books. Kindle Edition.
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Fasting is Evolutionary
For most animals out in the wild, periods of feast or
famine are the norm.
Our remote ancestors did not often eat four or five times
a day. Instead they would kill, gorge, lie around, and then
have to go for long periods of time without having
anything to eat.
Our bodies and our genes were forged in an environment
of scarcity, punctuated by the occasional massive
blowout.
Mosley, Michael; Spencer, Mimi (2013-02-26). The FastDiet: Lose Weight, Stay Healthy, and Live Longer with the Simple Secret of
Intermittent Fasting (p. 13). Atria Books. Kindle Edition.
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Seasonal Expressions
of Mitochondria
When carbohydrates were abundant to our ancestors,
such as during the plant growing season, consumption of
plant starch resulted in increased blood glucose levels.
When glucose is abundant PGC-1 is down-regulated,
mitochondrial OxPhos is depressed, and metabolism
shifts toward glycolysis.
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Insulin-Metabolism Response
A rise in serum glucose stimulates the pancreatic -cells
to release insulin.
Insulin signals the availability of carbohydrates to the rest
of the tissues in the body, shifting metabolism toward
glycolysis for ATP generation Mitochondrion. 10(1): 12-31., the storage of
excess calories as fat by activating lipoprotein lipase J Clin
Invest. 1982 May; 69(5): 11191125. and conservation of adipose tissue by
the suppression of cellular [hormone-sensitive] lipase Mol Cell
Biol. 2010 November; 30(21): 50095020. .
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Mitochondrial Response
to Glucagon
When carbohydrates are scarce, glucose becomes
limiting to animals, serum glucose levels fall, insulin
secretion declines, and the pancreatic -cells secrete
glucagon.
Glucagon then signals via cAMP to mobilize stored fat
and up-regulate mitochondrial OxPhos to burn fat and
generate energy to survive periods of glucose
deprivation.
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Beta-Hydroxybutyric Acid
Beta-hydroxybutyrate, the principal "ketone" body in
starving man, displaces glucose as the predominating
fuel for the brain, decreasing the need for glucose
synthesis in the liver (and kidney) and accordingly spares
its precursor, muscle-derived amino acids.
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Metabolic Efficiency
Decreasing food intake decreases the UCPs, coupling
is tighter, and metabolic efficiency is increased.
Increasing the UCPs increases the metabolic rate which
tends to reduce obesity, but it generates more free
radicals.
Walford R. Beyond the 120 Year Diet, 2000. ISBN-10: 1568581572. p. 63.
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Successful Fasting as
a Selective Pressure
A normal 70 kg man survives 2-3 months of starvation
[on ketones] instead of several weeks, and obese man
many months to over a year.
Without this metabolic adaptation, homo sapiens could
not have evolved such a large brain.
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Metabolic Efficiency
Take in fewer calories and your body increases its
metabolic efficiency; up your intake and your efficiency
decreases.
Walford R. Beyond the 120 Year Diet, 2000. ISBN-10: 1568581572. p. 63.
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Ketoacidosis
In the super-fasted state (the diabetic) where even basal
insulin levels are inadequate, excessive amino acids are
released from muscle, hepatic gluconeogenesis and
ketogenesis increase and levels of glucose and ketones
rise.
These result in progressive hyperglycemia, hyperketosis
and glucosuria and ketonuria.
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Ketosis v. Ketoacidosis
Benign dietary ketosis is a
controlled, insulin regulated
process which results in a
mild release of fatty acids
and ketone body production
in response to low
carbohydrate intake.
pH below 7.3
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Simple Starvation
Simple starvation and/or the ketogenic diet produce a
mild but closely regulated metabolic acidosis, compatible
with normal life as evidenced.
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CR/Fasting/Ketosis
Protective Effects
Animal models and isolated cells show that ketone
bodies, especially -hydroxybutyrate, confer
neuroprotection against diverse types of cellular injury.
Behav Pharmacol. 2006 September; 17(5-6): 431439.
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Nrf2 Triggers
During periods of oxidative stress, Nrf2 is released from
sequestration in the cytoplasm and translocates to the
nucleus. Nrf2 binds antioxidant response elements
(AREs) in the regulatory regions of target genes and
activates transcription. Toxicol Pathol. 2007 Jun;35(4):459-73.
The Nrf2 antioxidant response pathway is "the primary
cellular defense against the cytotoxic effects of oxidative
stress." N Engl J Med. 2012 Sep 20;367(12):1098-107. Integr Comp Biol. 2010 November; 50(5): 829843.
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Superoxide Dismutase
SODs are enzymes that
catalyze the breakdown
of the superoxide anion
into oxygen and
hydrogen peroxide.
Free Radic
Biol Med. 2002 Aug 1;33(3):337-49. CRC Crit Rev Biochem.
1987;22(2):111-80.
Mol Aspects
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Superoxide Dismutase
Superoxide dismutase enzymes contain metal ion
cofactors that can be copper, zinc, manganese or
iron.
In humans, the copper/zinc SOD is present in the
cytosol, while manganese SOD is present in the
mitochondrion.
CRC Crit Rev Biochem. 1987;22(2):111-80.
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Catalase
Catalases are enzymes
that catalyse the
conversion of hydrogen
peroxide to water and
oxygen, using either an
iron or manganese
cofactor.
13 (5): 55780.
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Glutathione Peroxidase
Glutathione peroxidase
is an enzyme containing
four selenium-cofactors
that catalyzes the
breakdown of hydrogen
peroxide and organic
hydroperoxides.
27 (910): 95165.
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Recommendations, or ...
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http://en.wikipedia.org/wiki/Single-subject_research
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http://en.wikipedia.org/wiki/Single-subject_research
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Dentition
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Which Supplements
Do You Need to Take?
Dark Berries
Resveratrol
Green Tea (ECGCs)
Turmeric
Vary them from time to time
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Thank You
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