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IONIC CURRENTS The Spark of Life

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Title: IONIC CURRENTS The Spark of Life


1
IONIC 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?

4
Systemic 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.
5
Systemic 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,)
6
Cellular 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?

8
MOLECULAR 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.

9
What 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?

10
AGING 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.
11
AGING 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.

12
From DNA to Chromosome

13
What 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

14
What 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.

15
What 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.
16
What Happens During Aging?The Role of Telomerase
Flores et al (2006)
Telomerase The Stem Cell Factor
17
Stem 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
18
STEM 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
19
DNA 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.

20
DNA 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)

21
DNA 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

22
Chromatin 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

23

What 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
24
DNA 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
25
DNA 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.

26
DNA 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.

27
Gene 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.

28
DNA 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?

29
DNA 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.

30
DANGERS 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.

31
PROTEINS CELLULAR INTELLIGENCE
32
PROTEIN SYNTHESIS
33
DNA -- mRNA-- Ribosomes -- tRNA
34
THE 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.

35
Imaging 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

36
Aging 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.

37
Collagen Increasing TreatmentsIs Collagen a
Crucial Factor in Longevity?
  • A number of treatments increase Collagen Lasers,
    Thermage, Microcurrent (Santos 2004 Cheng 1982
  • Chi 1999, 2002)

38
Proteins 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.

39
Proteins and Longevity
  • Protein synthesis is one of the most
    energy-consuming cellular processes, devouring an
    estimated 50 of the total cellular energy.

40
Proteins 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.

41
Proteins 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.

43
Biological 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'.

44
Electrical 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.

45
Mild 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).

46
IONIC 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

47
IONIC 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

48
ION 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.

49
ANTIOXIDANT EFFECT OF ELECTRON FLOW ON WOUND
HEALING
50
(No Transcript)
51
IN SEARCH OF THE ELECTRON
52
Oxidative 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)

53
Oxidative 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.

54
Oxidative 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)

55
Oxidative 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
56
Oxidative 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
  • Mitochondria

58
Oxidative 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.

59
Oxidative 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.

63
Molecules 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.

64
Molecules 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.

65
Nuclear 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

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Nuclear 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.

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Modular 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

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Modular Network Model of Aging
69
Modular Network Model of Aging
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Modular 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

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Modular 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.

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Modular 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.

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Newtonian 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)

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FUTURE 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).

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EXAMPLES OF BIOLOGICAL SIGNALS
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HOW 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

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MULTI-SINE SQUARE WAVEFORM
ABOVE COMPEX SQUARE WAVEFORM HANDMADE OUT OF
2,000 SINE WAVEFORMS (GERRYPOLLOCK 2008) LEFT
COMPUTER MADE SQUAREWAVEFORM
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CONCLUSION
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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