Title: IONIC CURRENTS The Spark of Life
1IONIC CURRENTS The Spark of Life Directional
Force for Cellular Metabolism and Energetics
- Think Simplicity then Discard it... --Alfred
North Whitehead
2 ABSTRACT
-
- Aging is not only the sum total of shortened
telomeres, denatured proteins and DNA molecules,
or oxidative damage in the mitochondria. Aging
attacks key regulatory nodes crucial for the
biological network stability. It is the dynamic
process of increasing imbalances in the systemic
organization of degenerating biological
processes. The old, the ill, and the injured all
suffer from misarranged patterns of atoms. A
single substitution an A for a G in a DNA
molecule can cause a significant change in the
conductance of the molecule leading to cancer.
Such research findings demonstrate how the
sequence and interrelations of amino acids in a
protein, or the sequence of base pairs in a DNA
molecule can become determining factors between
health and disease, aging and youth.
3 WE ARE AGING. WHY?
- We used to think the answer is simple. We are
born fresh and young and eventually the system
breaks down and dies. But how about the bodys
immune defenses and self reparative mechanisms?
4Systemic Intelligence
ScienceDaily (Apr. 17, 2008) Protein
researchers at the Ruhr University on the team
from Junior Professors Dr. Clemens Steegborn and
Dr. Dirk Wolters have clarified a complex safety
mechanism that drives damaged cells to cell death
when they can no longer be rescued. They
identified on the one hand the part of Protein
p66Shc that is responsible for a cells suicide
and they additionally ascertained the precise
mechanism of its regulation. In order for the
self-destruction to be initiated, several protein
components must work together as a complex. The
complex can apparently be decomposed by the
cells repair mechanisms for precisely as long as
the cell damages are reparable. Only when the
cell is defective beyond repair does it perish.
5Systemic Memory
CELLULAR INTELLIGENCE IMMUNE ORGANIZATION
MEMORY DEVELOPMENT
After the initial infection, some of the
descendents of an immune cell reacting to a
microbe must become the soldiers that fight the
infection and die but some, instead, regenerate
to take the place of the mother cell, leaving an
immunologic memory to recognize the invading
microbe in the future. (J Chang, M.D., S. Reiner,
M.D. 2007,)
6Cellular Auto-Clean up
- Aging is accelerated by suppressing a cellular
cleanup-mechanism known as autophagy engulfing
damaged cellular proteins or molecules (research
started in 2003-2004). Autophagy is regulated by
Atg8a-- a protein essential in forming
autophagosomes, the direct cellular detox
mechanisms ) Salk Institute for Biological
Studies, Kim Finley, Ph.D Boosting autophagy in
the nervous system of fruit flies promoted
longevity. Regulating autophagy (cellular
clean-up or cell detoxification) may be the key
factor in controlling the aging process!
Above The image shows the brain of a normal,
15-day old fly. Bottom Autophagy Repressed.
Damaged proteins tagged for degradation (bright,
red stain) start to accumulate in the brains of
15-day old flies
7 IS AGING AN INEVITABLE PROCESS?
- A living organism is an intelligent entity that
even demonstrates cellular memory. - Most likely, it does not follow an objects
linear progression from new to old. - The cells in our bodies are not born to simply
march to their death. - Could then one dare to think that Aging is not
inevitable?
8MOLECULAR AGING REVERSAL
- Shanklin et al (2006) reported that a single
substitution in the amino acid sequence of an
enzyme changed its function into that of a
theoretical distant ancestor. Its as if we
turned back the clock nearly 2.5 billion years,
to the time when oxygen first appeared in Earths
atmosphere, to get a snapshot of how enzymes
evolved to deal with reactive oxygen species,
said Shanklin.
9What are the Components of Aging?
- The simple answer seems to be the sum total of
biological dysfunctions. - But how about the disruption caused by the
degeneration of any part of the organism within
the overall biological network? A disruption
analogous to that caused by a car accident in
rush hour traffic? - What about oxidative damage as a result of
energy production in the mitochondria or
environmental pollution, analogues to adverse
weather conditions in rush hour traffic? - What about inadequate cell energy (ATP),
analogous to an electrical power shortage,
shutting down traffic lights and central computer
networks?
10AGING GENES
David Sinclair Tapping into longevity genes may
protect us against the aging process without the
need for Caloric Restriction (CR)
Longevity genes are a bit like a 911 command
centerSinclair (Harvard University) and others
begun by working with simple bakers yeast and
isolated a gene called SPT1 which controls the
activity level of a second gene called SIR2.
They discovered that artificially stepping up
NPT1 activity stimulated SIR2, and caused yeast
cells on normal nutrients to live an average of
40 percent longer. Same results with flies and
mice.
So is SIR2 the key to aging??? Sinclair
(Harvard) Stephen Helfand (Stanford) also
identified Resveratrol, a chemical found in red
wine and peanuts which targets the aging genes
lengthening life span.
11AGING GENES
- An extra copy of the SIR2 PROMOTES LONGEVITY.
(yeast, worms, flies) - However! Longo et al (USC 2005) studied yeast
and human cells and found that SIR2 PROMOTES
AGING. They deleted SIR2 in yeast and observed a
dramatically increased lifespan on these cells.
BUT They also used CR and/or a mutation in one
or two genes, RAS2 and SCH9, that control the
storage of nutrients and resistance to cell
damage. They claim that human cells with reduced
SIR2 activity also appear to confirm that SIR2
has a pro-aging effect, but these results were
not included in their paper.
12From DNA to Chromosome
13What Happens During Aging?Telomere Shortening /
Attrition
- Telomere Attrition Telomeres are the ends of
chromosomes and consist of short, tandemly
repeated (TTAGGG)ngt DNA sequences. During cell
division telomeres lose TTAGGG repeats as a
result of the incomplete replication of linear
chromosomes by conventional DNA polymerases, the
so-called end-replication problem. This
progressive telomere shortening is proposed to be
one of the molecular mechanisms underlying the
organisms aging, since critically short
telomeres trigger chromosome instability and loss
of cell viability - Telomeres (yellow) are segments of DNA at the
ends of chromosomes
14What Happens During Aging?The Role of Telomeres
- Chromosomes that the cell is trying to pull
apart. They cannot be separated because they are
stuck together as a result of their telomeres
being damaged.
15What Makes Cancer Cells Immortal?The Role of
Telomerase
- Telomerase is a reverse transcriptase encoded by
the Tert (telomerase reverse transcriptase) and
Terc (telomerase RNA component) genes, which add
TTAGGG repeats (telomeric repeats) onto the
chromosome ends (Blackburn 2005)
Defective telomerase activity and short telomeres
have been implicated in the pathobiology of
several agerelated diseases and premature aging
syndromes (Collins and Mitchel, 2002). In
contrast, telomerase is abnormally up-regulated
in gt90 of human tumors, where it is though to
sustain tumor growth by maintaining telomeres
above a threshold length.
16What Happens During Aging?The Role of Telomerase
Flores et al (2006)
Telomerase The Stem Cell Factor
17Stem Cells Need Specific SignalsFor Correct
Differentiation
- Researchers from Johns Hopkins have discovered
the presence of functional ion channels (that act
like electrical wires) in human embryonic stem
cells (ESCs). Li's lab (John Hopkins University)
genetically engineered heart cells derived from
human ESCs, suggesting the possibility of
transplanting unlimited supplies of healthy,
specialized cells into damaged organs. A major
concern for human ESC-based therapies is the
potential for engineered grafts to go haywire
after transplantation and form tumors... We
therefore decided to explore the existence of ION
CHANNELS in pluripotent, or versatile, human ESCs
because ELECTRICAL ACTIVITY IS KNOWN TO REGULATE
CELL DIFFERENTIATION AND PROLIFERATION," says Li.
Ionic Currents increased by adrenaline, In
pacemaker cells Which generate the Cardiac
rhythmic activity
18STEM CELLS IONIC CURRENTSBiological Processes
Powered By Cellular Electricity
- "In a number of different cell types, from
cancer to T-lymphocytes, Potassium (K) channels
are responsible for altering the membrane voltage
of cells," says Li. "We found that blocking
potassium channels in ESCs also slowed their
growth," says Li. "Our findings may lead to
genetic strategies that suppress undesirable cell
division after transplantation, not only for ESCs
and their derivatives, but perhaps for adult stem
cells as well.
IONIC CURRENTS REGULATE STEM CELLS
DIFFERENTIATION
19DNA AGING
- Hutchinson-Gilford Progeria syndrome, a
devastating disease in which children age rapidly
and usually die between their 7th and 20th
birthdays. The Story of Zachary Moore is a
tribute to author Keith Moores son, Zachary, who
died of old age at the age of 3.
20DNA AGING
- Hoeijmakers et al (2008) Erasmus Medical Center,
Rotterdam, the Netherlands, studied a 15 year old
girl (XFE progeroid syndrome -- progeria and DNA
damage) aging xeroderma increased sun
sensitivity that is the hallmark of a DNA repair
defect. They previously found that mutation of
the DNA repair gene ERCC1 induced symptoms
associated with aging in mice. - (Yet if you knock off other genes associated with
DNA repair you get a cancer predisposition --
Niedemhofer, Pittsburgh Un)
21DNA AGING
- Hoeijmakers et al (2008) found
- Accumulation of unrepaired DNA molecules can
contribute to normal aging - Growth Hormone and IGF1 / insulin signaling may
also be associated with aging. - EXPLANATION
- If the system is very high in Growth Hormones and
insulin levels are also high, you grow rapidly.
If that system is tuned down with low levels of
Growth Hormones and insulin, then you don't grow
that abundantly, but you invest more in
maintenance and repair. We call this a 'survival
response," Hoeijmakers said. - They
22Chromatin the DNA ArchitectSinclair et al (2007)
- Chromatin is a complex packaging system to
maintain chromosome organization (which
experience thousands of chemical alterations in a
single day) and DNA breaks. - The long-term maintenance of the nuclear
architecture is vital for the normal functioning
of cells and tissues over a lifetime. - Hutchinson-Gilford progeria syndrome involved a
mutation that disrupts the nuclear architecture
(the work of chromatin) -- symptomes resembling
normal human ageing, such as loss of hair,
restricted joint mobility and atherosclerosis
23What Happens During Aging?Chromatin, the DNA
Architect
Senescence associated heterochromatin foci (SAHFs)
Senescence associated heterochromatin foci (SAHFs)
The more densely the nucleosomes are packed, the
more protected is the DNA from chromosomal
damage, but the less accessible it is for
transcription. Highly compacted,
transcriptionally silent chromatin is known as
heterochromatin, whereas more accessible
chromatin is known as euchromatin
24DNA The spark of Life
- Davidovitch et al (1980) has postulated that
cyclic nucleotides which are subunits of DNA and
RNA seem to be intimately involved in the
cellular response to the stream of electrons. - Innomata (2007) measured the electrical
conductivity of DNA
The Electric DNA
25DNA The spark of Life
- DNA has been shown to conduct an alternating
current, but not direct currents. - Armitage et al, UCLA (2003) are claiming that
since conductivity of DNA varies with humidity,
DNAs conductivity arises from water molecules on
the water layer which DNA has under practically
any conditions. - Bouchiat et al (2003) claim that DNA is a
semi-conductor - Dekker (2001) Since the phosphate groups on
the backbone are negatively charged, the DNA is
usually surrounded by positive "counterions". - CONSENSUS There is a transport of electrons
allowing DNA to deflect oxidative damage away
from important sections.
26DNA The spark of Life
Experimental Results Compromised by Methodology
limitations
- Brown (2008) - Nanotubes Measure DNA
Conductivity - DNA molecule is only 2 nm wide. A nanotube
is as thick as DNA. This allowed to confirm that
DNA is conductive. The null hypothesis was
tested by adding an enzyme to the surrounding
liquid that cuts DNA and as expected the
electrical circuit was broken. If one of the
bases in a pair is changed, the two strands will
still stick together, but with an altered
structure around the mismatched bases. - The team first measured the conductivity of a
well matched strand and then exchanged it for a
strand with a single mismatch. This single
mismatch boosted the resistance of the DNA by a
factor of 300 -- i.e. there is a need to make
measurements on duplex DNA that is well-matched,
undamaged, and in its native conformation.
27Gene Electrotrasfer to Treat Skin Disorders
- Kranjc et al (2006) Gene electrotransfer is a
promising nonviral method for transferring genes
into the cells. The method is based on
electroporation (applying electric pulses to
increase permeability of cellular membrane) and
it has been proven to be successful in both in
vivo and in vitro conditions. This phenomenon
occurs when cells are exposed to electric fields
established by high and low voltage pulses. The
first high voltage pulse (100V) results in a high
level of cell permeabilization, while the second
low voltage (5V) provides a driving force for DNA
into the cells. The efficiency and
successfulness of gene electro-transfer largely
depends on the specifications of the electrical
device. Skin is an attractive target tissue for
gene therapy because of its size and
accessibility for the in vivo gene transfer.
28DNA The spark of Life
ELECTRONIC CIRCUITS
- DNAs apparent metallic conductor properties
along with its ability to self-replicate has led
some researchers to suggest that it could be used
to create electronic circuits that assemble
themselves. - Research Question Research design to identify
and decode DNA ionic currents. Then use info to
develop an electronic device that resonates these
ionic currents serving as a DNA pacemaker for
damaged DNA?
29DNA MANIPULATION -- Caution
- Nanotechnology scientists (eg. Lee et al 2008,
Ohio State University) uncoil DNA and form them
into precise patterns to use them as wires in
biologically based electronics / medical devices.
- BUT... Tao and Zhang (2005) found was that
just a single base pair mutation in a DNA
molecule, such as substituting an A for a G, can
cause a significant change in the conductance of
the molecule. These researchers wired DNA to
identify mutations. e.g. track mutations for
cancer research. -
30DANGERS in using DNA as Part of an Electronic
Circuit
- In manipulating DNA, the slightest nucleotide
substitution or error, could lead to mutations
and disease such a cancer.
31PROTEINS CELLULAR INTELLIGENCE
32PROTEIN SYNTHESIS
33DNA -- mRNA-- Ribosomes -- tRNA
34THE FUNCTIONS OF PROTEINSThe Essence of Life
- Proteins serve as enzymatic catalysts, cellular
guardians, they are involved in DNA repair, are
used as transport molecules (hemoglobin
transports oxygen) and storage molecules (iron is
stored in the liver as a complex with the protein
ferritin) they are used in movement (proteins
are the major component of muscles) they are
needed for mechanical support (skin and bone
contain collagen-a fibrous protein) they mediate
cell responses (rhodopsin is a protein in the eye
which is used for vision) antibody proteins are
needed for immune protection control of growth
and cell differentiation uses proteins. These
are just a few examples of the many, many
functions of proteins. It takes over 100,000
proteins to run our bodies.
35Imaging Techniques to ObserveFunctions of Large
Proteins
- Strands of the protein fibronectin, illuminated
using a new imaging techique developed at the UW
to observer the functions of Proteins. - Protein Structure determines its function
36Aging Effects on ProteinsCollagen Decreases
- Collagens are the main component of skin,
accounting for around 60 of its dry substance
(1). procollagen type I, synthesis activity in
the older group has decreased by approx. 60 (2).
Not only is less collagen synthesized with
increasing age but the collagen that is present
is degraded more rapidly. As a consequence of
these two effects together, the collagen content
decreases on - average by 1 per year as we grow older.
-
37Collagen Increasing TreatmentsIs Collagen a
Crucial Factor in Longevity?
- A number of treatments increase Collagen Lasers,
Thermage, Microcurrent (Santos 2004 Cheng 1982 - Chi 1999, 2002)
38Proteins and Longevity
- Syntichaki and Tavernakis (2006) One of the
major hallmarks of ageing is the progressive
accumulation of molecular damage in nucleic
acids, proteins,lipids, etc. - Protein turnover determines the rate at which a
protein pool is getting refreshed with protein
synthesis providing fresh proteins - Protein degradation removing damaged proteins.
A decline in turnover rates would delay the
removal and replacement of damaged proteins. - Conditions, which favor maintenance of high
protein turnover rates, could have a beneficial
effect on longevity.
39Proteins and Longevity
- Protein synthesis is one of the most
energy-consuming cellular processes, devouring an
estimated 50 of the total cellular energy.
40Proteins and Longevity
- Syntichaki and Tavernakis (2006) Therefore,
reduction of protein synthesis rates under
unfavorable, stress conditions would result in
notable energy savings. This energy could then be
diverted to cellular repair and maintenance
processes, thus contributing to longevity. In
addition, the reduction in mRNA translation may
prevent the synthesis of unwanted proteins that
could interfere with the cellular stress
response. Remarkably, the stress-induced
attenuation of global translation is often
accompanied by a switch to the selective
translation of proteins that are required for
cell survival under stress.
41Proteins and Longevity
- Hansen et al (2007) Pan et al (2007) the
general reduction of protein synthesis, due to
the decreased frequency of mRNA translation, also
lowers the cellular load of erroneously
synthesized proteins. - Inhibition of mRNA translation due to loss of
the initiation factor IFE-2 enhances longevity.
42 Research Findings and their Interpretation
- Underlying Assumption 1. Limited reservoir
of energy / 2. Cellular repair and maintenance
processes do not involve proteins / 3. By
limiting protein synthesis we do not compromise
overall function of the biological organism. - Research such as Hansen et al (2007) and Pan et
al (2007) explains why there is an overall
reduction of protein synthesis with aging, i.e.
to protect the body from the deleterious effects
of erroneously synthesized proteins (damage
control). However, adopting such research
findings to form an anti-aging treatment could
lead to even greater adverse effects as a result
of protein shortage.
43Biological Tendency for Damage Control
- Lund et al (2000). Young red blood cells produced
13 times more heat shock protein 70 mRNA
following heat shock and four times more 70 kDa
protein after recovery. - Gonos (2002) Apolipoprotein, is over expressed
under a variety of stress conditions and confers
chemotherapeutic drug resistance. It may
therefore represent a novel 'survival factor'.
44Electrical Properties of Proteins
- Simoncini Moody (1991) -- University of
Washinghton showed that the development of
electrical properties in these cells involves RNA
and Protein Synthesis. When transcription (DNA
converted to RNA) is blocked the Ca2 and outward
K currents fail to appear. - Mc Leoh et al (1987) investigated the effect of
electric current on protein biosynthesis in
mammalian fibroblasts. Protein synthesis was (1)
orientation specific (only cells parallel to the
electric field responded) (2) frequency specific
-- around .5 Hz and (3) current density specific
-- around of .3 microamps. Results suggest
cell-mediated changes in tissue repair and
remodeling. Other cells such as ganglion cells
respond to 2 microamps/c2 and .5 Hz.
45Mild Stress Central Repair Mechanisms
- Syntichaki and Tavernakis (2006) hypothesized
that hormesis, a phenomenon where mild stress
stimulates maintenance and repair mechanisms, may
in part depend on lowering mRNA translation to
levels that increase energy availability but
allow essential protein production. Hormesis is
associated with reduced accumulation of damaged
proteins, stimulation of proteasomal activity,
increased cellular resistance to toxic agents and
often prolongs lifespan. (Cypser and Johnson,
2002 Rattan, 2004).
46IONIC CURRENTS IN EMBRYONIC DEVELOPMENT
- Functioning of Stem Cells is Regulated by Ionic
Currents (Li et al 2007) / All embryos drive
Ionic Currents through themselves (Nucciteli et
al 2003 etc) 100 microamps per square centimeter
47IONIC CURRENTS IN TISSUE HEALING
ION INTELLIGENCE SPATIAL ORIENTATION
- Endogenous Electric Fields are crucial in Wound
Healing (Nucciteli et al 2003, 2004, 2005, 2006
Zhiao 2004, 2005, 2006, 2007 etc) - NEURONAL SPROUT
- IS DIRECTED TOWARD THE WOUND
48ION INTELLIGENCE SPATIAL ORIENTATION
- Electrical activity is known to regulate cell
differentiation and proliferation. Min Zhao et al
(2004, 2006, 2007) Electric Fields regulate not
only cell movement but orientation of cells
during mitosis, an effect which may underlie
shaping of tissues and organs.
49ANTIOXIDANT EFFECT OF ELECTRON FLOW ON WOUND
HEALING
50(No Transcript)
51IN SEARCH OF THE ELECTRON
52Oxidative DamageAging as a State of Oxidative
Stress
- Barouki R. (2006) Oxygen metabolism leads to
reactive species, including free radicals, which
tend to oxidize / damage surrounding molecules
such as - DNA - leading to DNA instability / denaturation
(causing the paired strands of DNA to separate
into single strands)
53Oxidative DamageProtein Folding Determines
Biological Function
- Virtually every process in biology is affected or
controlled by proteins. Proteins are linear
polymers, built out of various combinations of
just 20 amino acids, joined together by so-called
peptide bonds in different sequences. Each
natural protein folds into precisely one specific
stable three-dimensional structure, which
determines its biological function. The
functional properties of proteins can thus only
be understood and predicted via knowledge and
prediction of their three-dimensional folded
structures.
54Oxidative DamageAging as a State of Oxidative
Stress
- Free radicals tend to damage Proteins leading
toprotein denaturation (causing tertiary
structure of protein to unfold diminishing or
eliminating proteins biological activity)
55Oxidative DamageGene Expression and Aging
- Similar gene expression patterns characterize
aging and oxidative stress (Landis et al, 2004,
Cambidge, UK)
Heat Shock Proteins- their expression is
increased when the cells are exposed to elevated
temperatures or other stress, eg toxins,
infection, inflamation etc
Defensin Immune peptide gene -- peptides are
small polymeres (proteins are polypeptides)
Low ap4 is associated with osteoporosisfound in
patients after chemotherapy Low concentrations of
Hydrogen / Phgt7
PM Perfect Match MM Mismatch
56Oxidative DamageMitochondria the Powerhouse of
the Cell
- Mitochondria of healthy young adults respond
differently to increased requirements for energy
than older folks. Mitochondria of youthful people
adapt to increased energy requirements by
replicating rapidly (fig 7). This results in more
mitochondria producing more ATP for energy.
However, as we age, our mitochondria replicate
less readily. That means there are fewer
mitochondria to produce the energy. These fewer
mitochondria attempt to respond to increased
demand by hypertrophying (increasing in size -
fig 8). Unfortunately these larger mitochondria
are less efficient and produce more damaging free
radicals than their more youthful, more numerous,
and smaller progenitors.
57 Oxidative Damage Mitochondria the Powerhouse of
the Cell
58Oxidative DamageMitochondria The Fountain of
Youth
- A recently discovered cell survival switch could
be key to increasing longevity (David Sinclair,
Harvard, 2007) The mitochondrion is a tiny
cellular structure that turns chemical fuel into
cellular energy. In the study, Sinclair and his
collaborators genetically engineered cells to
express higher levels of a mitochondrial enzyme
called NAMPT, and then subjected those cells to
toxic chemicals. They found that cells with
higher enzyme levels were better protected
against these chemicals and more resistant to
cell death. The researchers also found that as
long as the cells' mitochondria were healthy, the
cells could stay alive, regardless of the state
of the rest of the cell. "That means the
mitochondria are the gatekeepers of cell
survival," says Sinclair.
59Oxidative DamageMitochondria ATP The
Fountain of Youth
- Shigenaga (1994) Acetyl-L-carnitine, a
high-energy mitochondrial substrate, appears to
reverse many aspects of age acociated decay in
cellular function, in part by increasing cellular
ATP production.
60 ENERGY LIFE AND ATP
- Imbalance between Na (sodium ions) and K
(potasium ions) within and outside the cell. - Within the cell Low Na high K / Outside
the cell High Na low K - Na rushes inside the cell triggering the next
gate to change -- impulse travels down the cell
(action potential 50 mvs) -- K rushes outside
the cell (resting potential - 70 mvs) The ATPase
Na/K pump that catalyses the decomposition of
ATP into ADP plus a phosphate (P). - Ca gates open causing neurotransmitter to be
released and enter the synapse of another neuron
leading to neuronal communication. - Na / K involved in membrane potentials and Ca
involved in neuronal communication. -
61 The Structure of ATP Synthase
- The structure of ATP synthase consists of two
rotary motors, labeled F1 and Fo. The presence of
Na leads to phosphorylation adding a Phosphate
to ADP to produce ATP the following reaction
with K leads to a dephosphorylation.
62 The Structure of ATP Synthase
- The pumping of protons across a membrane
generates a proton motive force, which can be
exploited by an ATPase running 'in reverse' to
generate ATP.
63Molecules on Wheels
- Proton-driven F0 rotates F1 in a clockwise
direction for ATP synthesis. - By itself, F1 only hydrolyses ATP, and hence is
called F1-ATPase. - ATP hydrolysis occurs sequentially on the three
beta-subunits, which generate power strokes
driving the anticlockwise rotation of gamma
subunit. - Rodelez et al (2005) forced the ATP synthesis of
F1 against the chemical potential - ATP synthesis was detectable via the enzyme
itself after the magnetic field was released,
the enzyme resumed its ATP-hydrolysing
anticlockwise rotation at a speed proportional to
the ATP concentration in the chamber.
64Molecules on Wheels
- Reed et al at Burnham Institute in La Jolla
(2008) has identified a fragment of a protein
that senses chemicals that induce a cell to move
into the right direction. This protein is
involved in the choreography of cell migration
that is vital in the development and survival of
the organism. This can help us address a host of
diseases that result from too little or too much
cell movement, or from cells moving in the wrong
direction and to the wrong place.
65Nuclear Architecture / Spatial Organization
- Zhao et als (2006) demonstrated that electric
currents can act as directional cues in cell
movement and wound healing. These cues activate
signaling pathways similar to those reported for
chemotaxis. Two specific genes PI(3)Kg and PTEN
were identifies as the genes essential for
electrical-signal-induced wound healing,
demonstrating that PI(3)Kg and PTEN genes control
electrotaxis -
66Nuclear Architecture / Spatial Organization
- Taddei et al (2008) and Gasser et al (2008)
found that gene expression is stronger when the
gene is attached to the nuclear envelope (the
membrane that surrounds the nucleus) than when it
moves away from the nuclear envelope (see image).
In other words, cells make use of the nuclear
architecture to code epigenetic information. The
DNA sequence alone doesn't determine everything.
67Modular Network Model of Aging
- Xia et al (2006) The aging process cannot be
conceptualized by examining a single gene or a
single pathway, but can best be addressed at the
systems level. - Xia et al (2006) studied modular structure of the
proteinprotein interaction (PPI) networks during
fruitfly and human brain aging. These network
modules and their relationships demonstrate (1)
Aging is largely associated with a small number,
instead of many network modules, (2) Some
modular changes might be reversible -- aging
changes may be reversible (3) Genes connecting
different modules through PPIs are more likely to
affect aging/longevity. - Aging might preferentially attack key regulatory
nodes that are important for the network stability
68Modular Network Model of Aging
69Modular Network Model of Aging
70Modular Network Model of Aging Cell
Proliferation Differentiation
- Xia et al, (2006) found that the gene expression
related to cellular differentiation decreases
with age. On the other hand, gene expression
related to cellular proliferation increases with
age. - This is inconsistent with
- the Hayflick Limit Theory
71Modular Network Model of Aging Cell
Proliferation, Differentiation, PP Interactions
- The expression of D decreases and that of P
increases with age in the human brain (both
significant when only samples of age less than or
equal to 85 years are included. Such a trend
stops and even reverses in the longest-lived
people (agesgt85), which suggests that their
expression levels might also be related to
longevity. Due to the small sample size this is
only marginally significant These changes also
suggest that the relationship of P and D module
expression with age might be reversible. - The expression levels of Protein to Protein
interactions do not have a significant
association with age unless the longest-lived
samples (85) are included.
72Modular Network Model of Aging
- The expression of the Immunity module increases
steadily in the aging brains, consistent with the
previous findings of increased inflammation
responses in the aging brain. - Calorie Restriction (CR) delays the onset of
increased Proliferation decreased
Differentiation aging pattern. Therefore P-D
relationship is reversible under (CR)! - The modular aging networks uncovered by Xia et
al (2006) provides an entry point to address many
fundamental questions on aging at the systems
level. The answers to these questions will
provide guidance for finding preventive and
interference strategies for the aging process and
its associated diseases. For example, as the
coordination and regulation of the modules have
strong impact on aging, we may want to design
drugs to target the regulatory circuitry. Also,
as some changes are more reversible than others,
we should make them high-priority drug targets.
73Newtonian vs Quantum Physics
- 1. Focusing on specific components of aging,
such a aging genes is equivalent to focusing on
the atom -- A Newtonian research method that does
not fully appreciate the extensive
interconnectivity among the cells biological
information network or cellular communication or
intertwined energy (chemical / electrical)
signals which is the Quantum Physics approach . - 2. Functionality is not specific. Biological
systems are redundant. The same proteins may be
simultaneously used in different organs and
tissues where they provide for different
behavioral functions. (e.g. Contradictory
findings of the SIR2 gene that was found to
prolong longevity and aging)
74FUTURE RESEARCH
- Perhaps the simplest way of focusing on the
dynamic processes of cellular life is by decoding
endogenous electrical signals that map biological
interactions and their outcomes. Biological
signals must be first analyzed in terms of their
amperage, frequency, voltage, spatial
organization then translated into electronic
signals that comply with the biological
specifications. Electronic signals will then be
intertwined to orchestrate a Gestalt waveform
built on the basis of information attained from
observations of biological interactions and
architecture a process similar to that done in
Pollocks lab (1990-2004).
75EXAMPLES OF BIOLOGICAL SIGNALS
76HOW CAN ELECTRICITY MAKE MUSIC
- It needs a large number of sine waveforms, the
way a large jazz band needs a lot of instruments - These sine waveforms must be combined in an
organized fashion that follows the parameters of
biological signals, the way the instruments of
the jazz band needs to obey certain music rules
in order to be harmonious rather than make noise
77MULTI-SINE SQUARE WAVEFORM
ABOVE COMPEX SQUARE WAVEFORM HANDMADE OUT OF
2,000 SINE WAVEFORMS (GERRYPOLLOCK 2008) LEFT
COMPUTER MADE SQUAREWAVEFORM
78CONCLUSION
MULTIDISCIPLINARY EXAMINATION OF AGING PROCESS
Diverse research evidence has been integrated to
illustrate the need for a multidisciplinary
examination of the aging process that may
ultimately elucidate the dynamic organization of
the biological system in its entirety. We rely
on Genetic research for information on genes
associated with the aging process Molecular
Biology for a more detailed analysis of the
structure and multifunctions of the cells
Quantum Physics to delineate interrelationships
between ionic particles Mathematics to organize
data and give us insight of vector theory and
dynamic fields Systems theory to simplify
information processing by categorizing details
into systems the Gestalt principle to identify
processes composed by other underlying
sub-processes Architecture to identify the
design and spatial organization of the biological
system Electronics and computer programming to
reconstruct or resonate organic functions aiming
towards an enhancement of reparative mechanisms
and extended longevity. No science is irrelevant
in grasping the grand scheme that sustains life.
We need all other disciplines to elevate science
to the level of Proactive Anti-aging Medicine.
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