Major Diseases of Aging Unified by a Global Theory: Easy,

Simple Practices Let You Live Longer and Better.

Gregory S. Bambeck Ph.D. and Michael Wolfson J.D., M.B.A.

Kent, Ohio U.S.A. 44240

INTRODUCTION

Even before The Human Genome Project, scientists have predicted a new
age of biomedicine. Myriad small improvements continued to accumulate,
but no great fulfilling promises have arrived. For nearly thirty very exciting
years we have anxiously awaited some Great Breakthrough. Now, the
waiting is over. This century, with good reason, has been labeled the
Century of Bio-Technology and early fruits are finally ripening on the
vine.

One major genetic control system has been found that manipulates several
thousand genes which regulate metabolism from the fetus all the way
through the aging process, and even in the cancer cell, albeit with a special
caveat. From this regulatory control system, we have gained a much better
understanding of the aging process, its natural consequences and the things
that go wrong, and even more importantly, how to correct many of them.

For the past several decades, most of what we knew about the diseases of
aging was disjointed, disconnected pieces-parts full of potentials and
enticements, but lacking a glue, a central unifying singularity. We now
have that glue--a global hypothesis that knits these unconnected cuttings
into a whole cloth that is mechanically definable. We have moved from
correlation to causation; from best guesses to workable applications. As
incredible as it may seem, our greatest killers, such as heart disease, cancer,
type II diabetes, neuromuscular/vascular wasting and even aging itself is a
single entity with many negative facets, each with its unique features. This
even includes the extension of human life length beyond the normal
maximum. Of course, we dont know everything yet, just as we will never
know everything about anything, but we finally know enough about this to
call it a system. Once you have a system, you can lay intelligent plans.
Prior to that, we are stuck with best guesstimates.

We will provide a brief outline of the theory here, but this document is
primarily devoted to the practical applications of that theoryWhat YOU
can do. These are the things you deploy to avoid these diseases while
maximizing the potential to live longer than natures plan originally built
into you. You will be pleasantly surprised by how simple it really can be. A
lot of the complexities of the past go away because much of the voodoo
and confusion go away.

A central theory of the diseases of aging does for biomedicine what E=mc
squared did for physics. It allows the scales to fall from our eyes, and it
permits us to peer through the halls of mirrors to the window overlooking
the garden of understanding. These two authors have studied thousands of
scientific papers from the last couple of decades, paying particular scrutiny
to those of the last half dozen years, and again and again we find the global
metabolic theory making sense of our perplexities. It is a most refreshing
epiphany, because a dark and tortuous path has become straight and true in
the dappled sunshine. That which was obfuscated is now perfectly clear.

Scientific papers written within the last few years are much more
interpretable within this unifying framework. Very soon, these
understandings will be known by legions of scientists and soon thereafter,
by the world. This document and other documents we have recently
published herald the coming of this new age of extended youth and vitality.

Before we launch into practical applications, lets take a brief perusal of the
theory. Aside from water and minerals, 95% of the flesh of all animal
organisms, from single cell organisms, to sponges, to worms, to insects, to
mice, and even to humans, is composed of four basic bio-chemicals:
carbohydrates, fats, amino acids and nucleotides, all of which can be used
either as fuel or as cell building materials. They can either be burned as fuel
to obtain energy or knitted together in combination to make huge molecules
that form the structures and functions of a new cell. The universal
regulatory pathway manipulates the flow of these four main constituents
and the energy balance of the cell to control the maintenance of the
housekeeping functions in non-dividing cells and to provide energy and
material flow into the building processes to make new cells. In the past, we
knew much about the flow patterns but we didnt know how the component
systems were managed. Now we do know, and we are discovering how the
regulatory pathway works to control the length of our lives through its
rejuvenative, regenerative and degenerative processes.

The core of the regulatory pathway sequence is called the AMPK to TOR
to PGC-1alpha to ROS to SESN and back to AMPK, feedback loop. Dont
be afraid of the science jargon, its a simple five item list. Just think of
them as the names of five people you havent met yet, and are just about to
begin to know. Write this five-item loop down on a notepad and refer to it
as you read this paper, so as to remain grounded in the discussion. A much
more in depth description is provided in The Life Extension Pathway,
Resveratrol, etc. and Cancer Control: Mitochondrial Biogenesis Duality,
the Metabolic Mechanism and Practical Applications, which can be found
via search engine under Bambeck Wolfson Life Extension.

Caloric restriction (CR) is the gold standard of life extension. CR

activates AMPK to inhibit TOR and the rest of the control elements in this
pathway, all the way back to AMPK. Put simply, an upward arrow next to
AMPK results in a downward arrow next to everything else. Got that
notepad? Install arrows, now. Conversely, inhibition of AMPK shortens
life, and all the arrows point in the opposite direction. Quite simple, isnt
it? Well, yes and no, because the devil is in the details, and each
component can be activated individually or in combination. So keep that
notepad at the ready. For instance, there are pharmaceuticals, such as
metformin and rapamycin, nutriceuticals such as resveratrol, and hormones
like growth hormone and thyroxine, which can act singly or in combination
on different parts of the pathway to either mimic or contradict CR. Among
other things, this pathway controls the building (neogenesis) and efficiency
(regenesis) of the mitochondrion, the major oxygen using fuel burning unit
in all animal cells. The mitochondrion sits between PGC-1alpha and ROS.
Cancer cells suffer from mutational derangements that alter non-oxygen
fuel burning in a process we call forced hyper-glycolysis. New medicines
are being found which disrupt these derangements, and yield beneficial
outcomes. So, as you can see, on the one hand it is quite simple, but on the
other hand it can get a little hairy.

This should be enough for the reader to basically understand the practical
applications section, below. If you need more information to supplement
your understanding, please feel free to consult the aforementioned
publication. And so, folks, lets go take a look at some practical
applications. Now, dont forget to drag that notepad along with you. We
dont want anybody getting lost.

PRACTICAL APPLICATIONS: EASY THINGS YOU CAN DO

One might consider this to be the wild hypothesis part of the document, but
based upon the aforementioned findings, the proposals might actually be
more sound than a lot of the health stuff that peppers the grocery store
checkout stands. However we remind everyone that we are not medical
doctors, and therefore, not licensed to practice medicine. Nor is it our
intention to do so. Any use of the information contained in same is at the
readers discretion. We specifically disclaim any and all liability arising
directly or indirectly from the use or application of any information
contained in any of these articles. What we write herein is more a free
speculation of ideas engaging over the counter phytonutrients and life style
choices.

Recent longitudinal studies show us that dietary sugar is killing us more

resolutely than either saturated fat or high protein content, as found in
animal products. The diseases of aging, such as diabetes, heart disease and
cancer, kill the vast majority of us and excess dietary (extracellular) sugar
is a main and growing culprit. However, the previously outlined AMPK,
TOR, PGC-1alpha, ROS, SESN cycle shows that the system yields to the
relentless decay-diseases of aging, in spite of dietary sugar, due to
intracellular metabolic shifts over time. In other words, even though sugar
powered the creation of our lives from inception to birth, it will eventually
kill us even if we dont eat it. This is natural aging, and the data clearly
shows that unnatural or supra-natural efforts must be made to obtain the
unnatural or supra-natural state called life extension beyond the natural or
normally expected limit. Face it, caloric restriction (CR) is draconian and is
only natural in the sense that, in nature, food sometimes runs out. No
organism exists that will naturally CR itself in the presence of adequate
food. Mega doses of anti-oxidants or a hundred bottles of wine worth of
resveratrol a day is, decidedly, unnatural. In a related vein, amino acid
restriction, in the form of a dietary reduction of methionine, seems to act in
synergy as a CR mimetic. However, such a dietary regimen seems far too
complex, restricted and unnatural to be practical in a preliminary review
such as this one. We will leave such things for future consideration in an
expanded applications document, later.

That being said, such things have been found to stand the test of time. For
instance, the Chinese have been drinking a high resveratrol Japanese
knotweed root extract, called itadoli tea, for millennia with claimed
beneficial results and no known ill effects save for some occasional
intestinal discomfort, found to be mostly due to emodin, a co extract, which
incidentally, is not found in modern concoctions. The remainder of this
brief discussion is mostly devoted to some unnaturally natural stuff that
folks might do without having to live a supplement menagerie supported
life in near anorexia with its attendant impediments to muscularity, wound
healing, immune function, fecundity and others. The focus, here will be on
forcing a default state to mitochondrial regenesis, which is the heart and
soul of life extension and the inhibition of cancer cell induction and
maintenance. Thus, the discussion will completely avoid the well worn
schoolmarm admonitions such as eat your vegetables, take your
vitamins, exercise regularly, drink plenty of water, keep your weight
down, dont eat between meals, brush your teeth after every meal,
dont eat anything that you cant fit into your mouth, dont ingest it if
you cant pronounce i, holy cow, that sure is a big fish and other
common sense standard fare that we wont even mention, here.

It is difficult to tell how much of dietary resveratrol is neogenic and how

much is regenic. It cannot be heavily neogenic due to its TOR bypass,
catabolic and anti-oxidant functions plus its average life expectancy
increasing and rejuvenative outcomes in the absence of increased cancer
induction or any true life length reduction. Standard dietary resveratrol also
cannot be very strongly regenic because there is no appreciable up
regulation in AMPK, no real reduction in cancer incidence, no increase in
cancer cell apoptosis and no true life extension. However, much
mitochondrial biogenesis is observed, but how much of this is neogenesis
converted to regenesis is unknown because most investigators were
unaware of the difference.

Progressive nutriceutical supply companies recognize this and are actively

pursuing remedies. The essential problem is simple. When resveratrol is
eaten, well over 90% of it is sulfonated and glucuronidated in the intestines
and in the liver via the hepatic portal system, rendering it water soluble
while targeting it for kidney removal to the urinary tract. Free, unmodified
dietary resveratrol is typically less than 2 uM during its one and a half hour
elevated blood plasma phase following ingestion. Glucuronate and sulfate
derivatized resveratrol do not cross interstitial cell membranes and the low
free resveratrol in cell microsomal fractions indicate that the interstitial cell
extracellular sulfatases and glucuronidases have no general impact. This
may not be true at sites of inflammation, but the desired whole body effect
appears not to be there. Although we have no retention or turnover numbers
on free intracellular resveratrol, it does not appear to accumulate over time.
Experiments have shown that serum soluble free resveratrol concentration
in the 20 uM range definitely impact the CR/AMPK pathway. For instance,
DMSO solubilized resveratrol, when injected into mice, causes all the
desired AMPK and downstream effects in brain tissue.

As mentioned earlier, nutraceutical suppliers are being very ingenious in

their attempts to get serum resveratrol concentrations up to the CR mimetic
range. One supplier shows, graphically, how micronization of resveratrol
dramatically increases free resveratrol up to and well beyond the minimal
required AMPK activating range. Other suppliers are creating encapsulated,
solubilized and time released formats. One supplier provides lozenges for
sublingual delivery. Resveratrol mixed with synergizers such as quercetin
and co enzyme Q, are also offered. We eagerly await their time based
serum data, and even more so, their intracellular AMPK up regulation data.

Heres a quick and dirty home remedy. You can dissolve up to about 500
mg of resveratrol in a shot of 86 proof booze, or flavored schnaaps, for the
more faint of heart. Solubility is mostly dependant upon alcohol content, so
the same should hold for a glass of wine, but it may take a while to
dissolve. Besides, the smaller the volume, the better it is for non-intestinal
absorption. Take a slug, swirl it around in your mouth for a full minute
before swallowing, kick back, and enjoy. Dissolving is what you might call
the nanonization technique. It has been shown to enhance buccal and
aerodigestive absorption by as much as 800% above dietary methods, and it
does not increase the kidney metabolite load one whit. Anyway, many of
the medical gurus out there tell us that 10-20 grams of ethanol a day, is
good for us.

Then, theres the stretch (or even strain) of your imagination beyond the
orbit of Pluto, plan. Human beings have daily circadian and monthly lunar
cycles for a reason. Anyone who has read about the circadian melatonin
cycle knows what were talking about. The fact that human females have a
lunar cycle length receptivity cycle, and that in small, tight knit groups,
cycle together, is no accident. The seasonal based cycle was replaced by
the lunar cycle because conditions made it happen. What made it happen,
you query? We thought you would never ask.
The mutational force is the primary evolutionary driver, but it is accidental,
generational and is usually a losing proposition, with rare selective
advantage. But, the winners support population survival in the form of
multi-generational adaptation. The selection advantage of a switch from a
seasonal to lunar cycle must have been powerful, simply because it was
forced into existence. Consider the following. Over 99% of the last two
million years, or so, of human evolution, has been devoted to the slow
steady conversion from gathering, to scavenger gathering, to hunter
gathering, while the remaining less than 1% is called civilization. Having
excellent 3-D color vision, but poor night vision, the night light of the full
moon became a great advantage as it advanced geographical food acquiring
range and easier pickings. Being bipedal and having prehensile dexterity in
a shrinking dryas ecosystem were great evolutionary pre-adaptations and
opportunity vs. death drivers for proto-humans.

This dynamic food energy switch created full moon super-nutrition for
several days to a week, followed by a remaining month of being trapped in
standard fare. This tuned up a monthly cycle of high, then haphazard
nutrition, which caused elevated body fat that could conveniently support
endometrial growth and fecundity, two weeks after the full moon, during
the pitch black nights of the new moon. Since nobody looks ugly in the
dark, alcohol not yet being invented, and besides, there being nothing else
to do but stumble around like blind idiots, a nutritional match was made in
heaven. In addition, sexual glue is social glue. This was already operating
in the context of a proto-hominid large brained noisy critter, with its
ecological niche pushing a movement toward even more brain growth,
symbolic representation as language and a pre-civilization social tool kit
simply awaiting large enough population numbers to invent neat stuff like
cities, war and jacuzzies. Thus, the African stage was set, and fortunately
for us, all four acts played out before we, as the genetic evidence shows,
almost became extinct.

This pattern would also be reflected as a natural nutrient driven monthly

cycle of low and high AMPK activity and a regular neogenesis and
regenesis cycle, which may have assisted us in becoming the longest living
primate. The long parturition period, the interminable time stretch from
birth to sexual maturity and the creation of history, in the need for elders to
pass all that big brained accumulation to the next generational batch of
incomprehensibles that seem to arise for the first time in memory with each
succeeding generation, could have helped to assist this life lengthening
admixture. In the context of this paper, that is, if there still is any context,
this kind of long-winded speculative wannabe has just got to be followed
with a circadian/lunar cycle recipe format.

The advent of commercially available high concentration bioavilable

resveratrol would open the door to possibilities that will really bring the
troops home. At full dose, it would bias the system toward true CR
mimicry of AMPK driven mitochondrial regenesis, while at one tenth full
dose, it would bias the system toward the neogenic meta-mimicry we
described in detail, before. Since neogenesis takes several days to
complete, while regenesis is much quicker, a circadian/lunar cycle plan that
forces the system into lengthy defaults to life extending regenesis, might
look something like this: Low dose neogenic resveratrol could be
coordinated with anti-oxidants, dietary nutrient loading and/or power based
exercise for five to seven days, or so, then followed by high dose
resveratrol coordinated with daily food avoidance between dinner and
breakfast and/or high oxygen utilizing endurance exercise prior to breakfast
in a more extended time frame, say about three weeks, to entrench
mitochondrial efficiency, cellular house cleaning and a shift away from
glucose toward fat burning. Here we have something for everybody.
Lounge lizards could reap the benefits of the phytonutrient pattern only
effect, while the more restless spirits among us could enhance those effects
by dietary and exercise regimens. Either way, organs and tissues other than
cardiovascular and skeletal muscle could become larger recipients of
resveratrols benefits. Numerous daily, weekly and monthly variations of
the theme could be envisioned. One plan might be to include one meal a
day to cause chronic fasting default to regenesis and/or with exercise to
assist regenesis with glucose nutrient debt and/or a CR mimetic to activate
the AMPK life extension loop.
A very interesting rat study of intermittent CR has put the world of CR
afficionados on its ear. Using alternate days of ad libitum food supply and
total fasting, in rats, results in no long term CR, as the rats make up for
fasting by feasting between fast days, while ending up with life extension
comparable to CR. This more or less jives with the down regulation of
PGC-1alpha to regenesis turn on time frame. In fact, this study is the actual
proof of principle, since life extension by CR cant happen without it. This
also jives with our notion that, at least partial neogenesis followed by
regenesis, wont hurt life extension, and you can avoid the misery and
downside risks of genuine CR.

An interesting question emerges here. Since regenesis is a CR long term

life extension holding pattern, how long is it good for? By this, we mean:
Once mitochondria become efficient, how long do they stay efficient before
they need restimulated to become efficient again? In other words, how
many days of feast can one get away with before each day of fasting? If
regenesis is good for a week, then a one day a week fast is a small price to
pay. Not only that, if 18 hours of fasting works as well as 24, then all one
would needs do is miss breakfast once a week. Can this be supplemented
with a low or high dose resveratrol regimen that would accentuate the
effect?

We need experiments and we need them earlier rather than later. But rats
live five or more years, and rats are not people, (as opposed, oft-times, to
the other way around). Over the counter metformin is over a decade away,
if ever, and rapamycin is too dangerous to become street legal in any time,
dimension or reality. Metformin, when used with growth hormone to
mechanistically force the system to toggle back and forth between
neogenesis and regenesis could ultimately turn out to be the greatest anti-
aging plus rejuvenation achievement of all time. This could truly cause
cells to behave more like they do in the juvenile stage. The timing, dosage
and testing required in such a scenario would be critical. This is playing
with some real big mojo, here, and it would be illegal without a
prescription under a doctors care. Only people, at least in their early
middle years, say past thirty, could participate in such a program, safely.
Fortunately, at present, we have resveratrol, which is freely obtainable and
we know enough about CR and mitochondrial neogenesis and regenesis, to
get answers, fast, and in humans instead of rats. Human volunteers and
tissue biopsies that measure CR via AMPK activity and mitochondrial
biogenic state from krebs cycle enzymes vs. cytochrome content, can allow
us to follow the system status through time. The system is well enough
defined, by now that the meanings of these assays point to causation rather
than correlation. A wide array of experiments could be rapidly conducted,
and could pinpoint which timings, conditions and regimens are optimal,
whether there are any down sides and what other items might be included.
Ideally, we may find a CR mimetic dose schedule of resveratrol, a better
mimetic or a mixture of synergistic components that require no life style
changes outside of normal prudent health practices except for that magic
pill, of course.

AFTERWORD

About a week after we completed our first draft of the practical applications
section, we read in the newspaper that exercise physiologists had
discovered that carbohydrate loading, health-wise, was far inferior to
fasting prior to and during a work-out. The carb loading thing may work
if youre training for the Tour de France, but it isnt for the average Joe.
Fasting caused non-oxygen sugar burning to shift over to oxygen fat
burning and inefficient white muscle to shift into efficient red muscle,
simultaneous with advantageous cardiovascular effects, weight loss and
reduction in diabetes-causing insulin resistance. Quizzically, they
hypothesized that hunger induced adrenaline was instituting the changes.
Perhaps there is a better hypothesis, and you can probably guess what we
think it is. Several months after we published our first paper on cancer
metabolism, which describes a thirty year old hypothesis, researchers
announced a newly discovered cancer growth stopping hyperglycolysis
blocking concept therapy that reawakened (their words) mitochondrial
regenesis (our words). Then they fumble around for the concept of a
mechanism. We are pretty firm on what we think the mechanism is.
Diabetic lung cancer victims live longer with metformin, but the
researchers do not make the CR connection. Dietary resveratrol with
exercise increases mitochondrial muscle volume more than exercise alone
or resveratrol alone and slows ventricular hypertrophy. What is the
connection? Mitochondrial biogenesis measurements sometimes show one
thing and sometimes show another, and scientists are befuddled because
they dont know the difference between neogenesis and regenesis.
Arguments erupt in kingpin pharmaceutical companies over whether
resveratrol is a CR mimetic, or not, because researchers havent separated
CR meta-mimicry from CR mimicry. Everywhere we look, we see
examples like this, where specialists understand one or two trees so well
and the forest so poorly that the conclusions become almost strange,
contradictory and surreal. Many scientists, in the fields we have visited,
wouldnt be so surprised or perplexed, if they only had a single unifying
global hypothesis to make their results coherent. We have such a theory,
and all these conundrums make sense to us. Prudent applications of such a
theory can have breathtaking impacts upon the nations medical bill and the
aggregate number of years added to human life; in the first case, measured
in the trillions of dollars, and in the second case, measured in the billions of
years. This is big stuff really big stuff.

Gregory S. Bambeck Ph.D. e-mail: gregorybambeck@yahoo.com

Michael Wolfson J.D., M.B.A. e-mail: mwolfson@stanfordalumni.org

Copyright by Gregory Bambeck and Michael Wolfson June 19, 2010.