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

66
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.

67
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

68
Modular Network Model of Aging
69
Modular Network Model of Aging
70
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

71
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.

72
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.

73
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)

74
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).

75
EXAMPLES OF BIOLOGICAL SIGNALS
76
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

77
MULTI-SINE SQUARE WAVEFORM
ABOVE COMPEX SQUARE WAVEFORM HANDMADE OUT OF
2,000 SINE WAVEFORMS (GERRYPOLLOCK 2008) LEFT
COMPUTER MADE SQUAREWAVEFORM
78
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.
79
(No Transcript)