THE EVOLUTION
OF AGING:
A NEW APPROACH
TO AN OLD PROBLEM
OF
BIOLOGY
Bowles, J. T.
January 1, 1998
contact information:
Jeff T. Bowles 60 E. Chestnut #395 Chicago, Illinois 60611,
e-mail JeffBo@aol.com
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 1
Abstract: Many gerontologists believe aging did not evolve, is accidental, and is unrelated to development.
The opposite viewpoint is most likely correct. Genetic drift occurs in finite populations and leads to
homozygosity in multiple-alleled traits. Episodic selection events will alter random drift towards
homozygosity in alleles that increase fitness with respect to the selection event. Aging increases population
turnover which accelerates the benefit of genetic drift. This advantage of aging led to the evolution of aging
systems (AS). Periodic predation was the most prevalent episodic selection pressure in evolution. Effective
defenses to predation that allow exceptionally long life spans to evolve are shells, extreme intelligence,
isolation, and flight. Without episodic predation, aging provides no advantage and aging systems will be
deactivated to increase reproductive potential in unrestricted environments. The periodic advantage of aging
led to the periodic evolution of aging systems. Newer aging systems co-opted and added to prior aging
systems. Aging organisms should have one dominant aging system that co-opts vestiges of earlier-evolved
systems as well as vestiges of prior systems. In human evolution , aging systems chronologically emerged as
follows: telomere shortening, mitochondrial aging, mutation accumulation, senescent gene expression
(AS#4), targeted somatic tissue apoptotic-atrophy (AS#5), and female reproductive tissue apoptotic-atrophy
(AS#6). During famine or drought, to avoid extinction, reproduction is curtailed and aging is slowed or
somewhat reversed to postpone or reverse reproductive senescence. AS#4-AS#6 are gradual and reversible
aging systems. The life extending/ rejuvenating effects of caloric restriction support the idea of aging
reversibility. Development and aging are timed by the gradual loss of cytosine methylation in the genome.
Methylated cytosines (5mC) inhibit gene transcription, and DNA cleavage by restriction enzymes. Cleavage
inhibition prevents apoptosis which requires DNA fragmentation. Free radicals catalyze the demethylation
of 5mC while antioxidants catalyze the remethylation of cytosine by altering the activity of DNA
methyltransferases. Hormones act as either surrogate free radicals by stimulating the cAMP pathway which
alters free radical levels within cells, or as surrogate antioxidants through cGMP pathway stimulation.
Access to DNA containing 5mC-inhibited developmental and aging genes and restriction sites is allowed
by DNA helicase strand separation. Tightly wound DNA does not allow this access. The DNA helicase
likely generates free radicals during strand separation; hormonal stimulation may either amplify or
counteract this effect. Caloric restriction slows or reverses the aging process by dramatically increasing
melatonin levels which suppresses reproductive and surrogate free radical hormones, while increasing
antioxidant hormone levels. Cell apoptosis during CR leads to somatic wasting and a release of DNA which
may increase bioavailable cGMP. The rapid aging syndrome of Progeria, and the set of three syndromes:
(Xeroderma Pigmentosum (XP), Cockayne Syndrome(CS), and Ataxia Telangiectasia (AT)), and the
Werner’s Syndrome are related to or caused by defective activity of three separate DNA helicases. The rapid
aging syndromes caused by mitochondrial DNA deletions or malfunctions mirror those seen in XP, CS, and
AT. Comparing these diseases allows for assignment of the different symptoms of aging to their respective
aging systems. FSH and DHT may promote the demethylation of the genes and restriction sites of AS#4,
LH and hCG of AS#5, and estradiol/DHT of AS#6 while cortisol may act cooperatively with FSH and LH,
hCG and DHT and in these roles. The Werner’s DNA helicase may control expression of a gene set that
links timing of the age of puberty, menopause, and maximum life span in one mechanism. Telomerase is
under hormonal control. Most cancers likely result from malfunctions in the programmed apoptosis of
AS#5 and AS#6. The Hayflick limit is likely reached primarily through loss of cytosine methylation of genes
that inhibit replication rather than telomere shortening. Men suffer the diseases of AS#4 which include
athersclerosis, hair loss/graying, alopecia, stroke at a higher rate than women who suffer from AS#5, which
include the atrophic diseases of osteporosis, Alzheimer’s, nerve and muscle wasting, arthritis, diabetes,
cataracts more often. Adult mammal cloning suggests aging-related cellular demethylation, and thus aging,
is reversible. This theory suggests that the protective effect of smoking and ibuprofen for Alzheimer’s
disease is due to LH suppression. End abstract.
Introduction:
Current viable theories of aging include theories regarding free radicals and antioxidants, replicative
senescence, telomeres, hormones, senescent gene expression, immunology, mitochondria, and others.
These theories for the most part, are not challenged , but rather, united in this unified theory of aging.
Since accepting Medawar’s hypothesis in the 1950’s that animals do not age in the wild (1), most
gerontologists generally believe that aging is accidental , has no purpose, and that only longevity evolves.
They believe that aging does not occur in the wild so therefore could not have been selected for or
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 2
against. Implied by these arguments is that development and aging are two separate processes; an animal
develops to sexual maturity; the process stops, then accidental processes lead to aging. [A summary of
this viewpoint can be found in “How and Why We Age”, by Leonard Hayflick, Ballantine Books, 1994.]
In the theory proposed herein, however, aging confers an advantage to a species subject to episodic
selection pressures based on the following logic:
1. Genetic drift is a random process that leads to a single phenotype in a finite population.
2. Aging greatly accelerates genetic drift in finite populations through population turnover.
3. Single episodes of selection push genetic drift towards the more adaptive trait with respect to the
selection episode.
4. Aging species are more likely to avoid extinction or gain population share than non-aging species when
both are subjected to periodic encounters with a similar episodic selection pressure in an environment
that can support only a finite number of individuals. This will happen because aging populations will be
more likely than non-aging populations to become homozygous for a trait that increases fitness prior to
subsequent encounters with the selection pressure.
[AUTHOR’S UNPUBLISHED NOTE ADDED SUBSEQUENT TO PUBLICATION: THE ABOVE
LOGIC IS INCOMPLETE, BUT PROVIDES THE CRUCIAL FIRST STEP REQUIRED TO
DEVELOP THE EVOLUTIONARY LOGIC THAT SHOWS HOW AGING CAN BE SELECTED
FOR AT THE GROUP LEVEL EVEN THOUGH IT IS DETRIMENTAL TO THE INDIVIDUAL.
THE AUTHOR HAS PUBLISHED A SUBSEQUENT PAPER TITLED “SHATTERED:
MEDAWAR’S TEST TUBES AND THEIR ENDURING LEGACY OF CHAOS”-MEDICAL
HYPOTHESES FEB 2000. THIS SUBSEQUENT PAPER CLEARLY OUTLINES THE
PROBLEMS WITH MEDWAR’S HYPOTHESIS THAT AGING COULD NOT HAVE BEEN
SELECTED FOR, CORRECTS THEM , AND SHOWS THAT GROUP SELECTION PROBABLY
OCCURS UNIVERSALLY IN BOTH TIME AND PLACE TO SELECT FOR SEX AND AGING.
THE ONLY PROBLEM WITH THE EXAMPLE PROVIDED IN THE FOLLOWING PAGES IS
THAT IT COMPARES TWO GROUPS OF AGING AND NON-AGING RABBITS THAT MUST
BE SEPARATED TO PREVENT INTERBREEDING AND THUS THE LOSS OF DIFFERENCES
IN AGING SYSTEMS. BY REPLACING ONE GROUP OF RABBITS WITH A GROIUP OF A
DIFFERENT SPECIES THAT COMPETES WITH THE RABBITS FOR THE SAME HABITAT,
THEN THE ANALYSIS BECOMES COMPLETE. BY COMPARING TWO LOCALLY
COMPETING, NON-INTERBREEDING SPECIES OF PREY, THEN THE TWO GROUPS CAN
OCCUPY THE SAME HABITAT WITHOUT INTERBREEDING. IN THIS CASE, THE AGING
SPECIES MAY SURVIVE WHILE THE NON-AGING SPECIES BECOMES EXTINCT AT THE
LOCAL LEVEL WHEN EXPOSED TO PERIODIC NOVEL PFREDATION. WHEN THIS
ADJUSTMENT IS MADE, THEN COMPETITION BETWEEN ALL SPECIES OCCUPYING
VARIOUS LOCALES WHICH ARE SUBJECTED TO PERIODIC, NOVEL PREDATION,
BECOMES THE UNIVERSAL FORCE THAT SELECTS FOR AGING (AND SEX) AMONGST
VIRTUALLY ALL SPECIES].
Also, this theory suggests that development and aging are timed by the same mechanisms, and evidence is
presented to suggest that the timing mechanisms in humans are primarily three separate DNA helicases
(or the replisomes that they are a part of) that allow access to developmental and aging genes. (In the
context of this theory, the gerontology community’s definition of aging and development is technically
incorrect but will be retained to avoid confusion.) Also, during the course of evolution, there were likely
many times where aging occurred in feral animals.
Do animals age in the wild?
It is generally believed by gerontologists that wild animals that lose vigor due to the first signs of aging
are quickly culled from the population by predation, disease, accident, starvation or drought, and that
populations are always subject to enough risks of death that aging rarely or never occurred.
Should we ask if predation, starvation and drought were removed as risk factors from a population, would
the risks of death from accidents and disease be enough to make aging a rare phenomenon in the wild? A
quick look at humans can shed light on this question. Humans age in the absence of predators, famine,
and drought. Accidents and disease do not halt the progression to senescence in most of the population.
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 3
Therefore, if predation, famine, and drought are removed as risk factors in the wild, as they are in human
society, aging should occur in the wild.
Wild animals (past and present) do not have medical care, but this factor should be offset by their
likelihood of having fewer fatal accidents than occur in modern human society. Also, it is likely rare to
find post-menopausal aged humans alive today only because health care prevented their deaths in their
younger years. Lack of health care is a weak argument to suggest that animals do not age in the wild.
So, if feral animals can age in the face of disease and accidents, then if predation, famine, and drought
are removed as risk factors aging should occur. Because drought and famine are periodic phenomena ,
there will be regular periods that lack these risk factors. Thus, predation is the sole environmental force
that can inhibit aging in the wild on a permanent basis. (The term predator can actually be thought of as a
metaphor for any force that leads to the death of an organism (or inhibition of its reproduction) before the
end of its natural reproductive life span at a constant enough rate to not allow aging to occur (or
menopause to be reached) in the wild. In this sense, parasites or chronic, contagious reproductive-life-
shortening diseases, or frequent and regularly occurring natural disasters could also have the same effect
on the evolution of aging as a predator does).
If predator/prey separation can occur for extended periods of time, then aging should occur in the wild
and can be selected for or against. Today’s diversity of species provides the proof that separation events
were common throughout evolution. Long periods of separation are required to create two species from
one. Therefore, every species that ever existed (estimated to be 200 million of which 180-190 million
species are now extinct) represents a separation event. These events occurred at random as there could be
no compelling reason for an original group to favor separation into two groups. However, a prey species
has a compelling reason to attempt separation from its predator and would likely separate from them with
a similar or higher frequency than that of separation events that lead to speciation.
A report from an Australian government agency [ANCA publication-Environment Australia ~
Biodiversity Group, 1996] about feral goats states “It appears that the feral goat’s prime predator- the
dingo- can adequately control feral goats where it is common, but the dingo is not effective in all areas. In
the eastern rangelands, goats can shelter around steep rocky outcrops and rock faces.” If predator/prey
separation exists today, it also surely existed in the past. Also, a Medline/Biosys search revealed many
studies where wild animals were captured and ages determined; animals near the limit of their estimated
maximum life spans were reported in many (i.e. 2). A report evidencing that aging does not occur in the
wild has yet to be found by the author.
When does aging begin?
Many gerontologists believe that development and aging are independent processes, and that evolution
selects for animals with enough “vital capacity” to reach sexual maturity. After maturation, accidental
aging processes, which are mere side effects of selecting for greater reproductive succes purportedly
impair vital capacity enough so that environmental risks lead to a swift demise. These beliefs imply that
the precisely timed mechanism that drives development from infancy to adulthood ceases its proper
functioning soon after sexual maturity is reached and then “accidentaly goes out of control and causes
random damage that leads to aging and death.
In this unified theory, development and aging are caused and timed by the same mechanisms. This idea is
supported by the recent discovery that the defective mechanisms behind the rapid adolescent/adult aging
disease of Werner’s Syndrome is found to be a DNA helciase , and that the defective mechanism behind the
childhood-aging disease of Progeria is suspected to also be a DNA helicase. Additionally, a third DNA
helicase has been implicated in the childhood diseases of Xeroderma Pigmentosum (XS) and Cockayne
Syndrome (CS); This third helicase is also likely affiliated with a defective topoisomerase involved in
Ataxia Telangiectasia (AT). Two DNA helicases ( the putative Progeria helicase and the XP /CS helicase)
likely time the development from infancy to pre-puberty (about age 12), and the Werner’s DNA helicase
times development from age 12 to completion of puberty. Later it will be proposed that these helicases allow
access to normally sequestered developmental, as well as aging genes. After the developmental changes of
puberty are complete, the Werner’s DNA helicase likely does not disappear, but continues to remain active,
with the Progeria and XS/CS helicases, and initiates gene expression that leads to the deleterious age
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 4
changes such as menopause and those that eventually cause death. Werner’s disease likely begins at
puberty initiation while symptoms generally appear around the age of 20; those with the disease show
almost all the different symptoms of aging with a few differences (such as unusual forms of cancer) as well
as some symptoms of aging that are normally thought of as isolated diseases (i.e. diabetes) at a more rapid
pace than normal individuals (3). (It will be posited that these “isolated” diseases are indeed symptoms of
aging that have just not yet drifted to homozygosity in the human population). Typically Werner’s patients
die in their fifties while appearing to be in their eighties. The existence of the Werner’s helicase suggests
that 1. the age of reaching puberty (menarche), 2. menopause, and 3. maximum life span (death) are all
linked together by one mechanism that times sequential gene expression. A shift in one of the three age
variables (for example: selection for an earlier age of reaching puberty) requires, because they are linked, a
shift in the others as well. In other words, by selecting for an earlier puberty, one is actually selecting for an
increase in the speed of the mechanism which triggers sequential pro-developmental, and pro-aging gene
expression. In support of this idea, a recent study has found a positive correlation between late menopause
(as evidenced by late births) and long maximum life spans in women. (4). Additionally, another report has
noted an almost linear relationship between age of onset of reproduction (including gestation) and the
maximum life span of various primates (5).
This theory suggests that aging begins at birth, but the deleterious changes associated with aging begin,
from an evolutionary perspective, with the onset of menopause. After menopause is complete, evolution is
proposed to no longer have a purpose for the female except as a reservoir of potential reproduction
capacity in the event of famine or drought ( as will be discussed later, in some species it has been shown
that hormone alterations do lead to what coujld be considered menopause reversal.The author believes
these hormone changes should also be inducible by non-lethal starvation or dehydration). The age
changes seen after menopause are not accidental, but appear to be just a continuation of the same process
that initiated menopause combined with effects generated from the remnants of previously evolved aging
systems that still exist in the genome but are no longer dominant. With these thoughts in mind, the
reconstruction of the evolution of purposeful, rather than accidental aging , can commence.
The Advantage of Aging: .
[AUTHOR’S UNPUBLISHED NOTE ADDED SUBSEQUENT TO PUBLICATION: THE
FOLLOWING LOGIC IS INCOMPLETE, BUT PROVIDES THE CRUCIAL FIRST STEP
REQUIRED TO DEVELOP THE EVOLUTIONARY LOGIC THAT SHOWS HOW AGING CAN
BE SELECTED FOR AT THE GROUP LEVEL EVEN THOUGH IT IS DETRIMENTAL TO
THE INDIVIDUAL. THE AUTHOR HAS PUBLISHED A SUBSEQUENT PAPER TITLED
“SHATTERD: MEDAWAR’S TEST TUBES AND THEIR ENDURING LEGACY OF CHAOS”-
MEDICAL HYPOTHESES FEB 2000. THIS SUBSEQUENT PAPER CLEARLY OUTLINES THE
PROBLEMS WITH MEDWAR’S HYPOTHESIS THAT AGING COULD NOT HAVE BEEN
SELECTED FOR, CORRECTS THEM , AND SHOWS THAT GROUP SELECTION PROBABLY
OCCURS UNIVERSALLY IN BOTH TIME AND PLACE TO SELECT FOR BOTH SEX AND
AGING. THE ONLY PROBLEM WITH THE FOLLWING EXAMPLE IS THAT IT
COMPARES TWO GROUPS OF AGING AND NON-AGING RABBITS THAT MUST BE
SEPARATED TO PREVENT INTERBREEDING WHICH WOULD CAUSDE THE LOSS OF
DIFFERENCES IN AGING. BY REPLACING ONE GROUP OF RABBITS WITH A GROUP OF
A DIFFERENT SPECIES (SAY GROUND SQUIRRELS) THAT COMPETES WITH THE
RABBITS FOR THE SAME HABITAT, THEN THE ANALYSIS BECOMES COMPLETE. BY
COMPARING TWO LOCALLY COMPETING, NON-INTERBREEDING SPECIES OF PREY,
THEN THE TWO GROUPS CAN OCCUPY THE SAME HABITAT WITHOUT
INTERBREEDING. IN THIS CASE, THE AGING SPECIES MAY SURVIVE WHILE THE NON-
AGING SPECIES BECOMES EXTINCT AT THE LOCAL LEVEL WHEN EXPOSED TO
PERIODIC, NOVEL, PREDATION. WHEN THIS ADJUSTMENT IS MADE, THEN
COMPETITION BETWEEN ALL SPECIES OCCUPYING VARIOUS LOCALES OR “DEMES”
WHICH ARE SUBJECTED TO PERIODIC, NOVEL PREDATION, BECOMES THE
UNIVERSAL FORCE THAT SELECTS FOR AGING (AND SEX) AMONGST VIRTUALLY ALL
SPECIES].
A thought experiment will demonstrate the evolutionary advantage of aging. Assume the following:
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part, without the prior, express, written consent of the author. 5
-2 groups of 4 rabbits live on an isolated island free of predation.
-Within each group are 2 fast and 2 slow rabbits.
-The rabbits are sexless and each can reproduce by budding (assumed for simplification)
-Each group is confined to one half of the island and they do not intermingle (assumed for
simplification) .
-The island can only support 4 rabbits in each separate area.
-Any young rabbits born, die unless the population is less than 4.
-One group ages and the other group does not.
-There are no disease, accidents, famine, or drought on the island (assumed for simplification).
In the non-aging group, the gene pool would not change until one of the members died from a cause other
than aging. In the aging group, members are dying and being replaced continually. When a rabbit dies,
there is a 50% chance that it is replaced by either a slow or fast rabbit in the aging group. Due to sampling
error (or genetic drift), over time, with no other influences, the population will have an equal chance of
becoming all fast or all slow rabbits.
Now, assume an old, slow fox washes up on shore that can freely roam the island; the fox catches and
eats only one slow rabbit from each group and then dies. Both populations now consist of 2 fast rabbits
and 1 slow rabbit. Now, a randomly selected rabbit is able to reproduce in each group. Because the new
ratio of fast to slow is 2 to 1, the new rabbit born will have a 2 to 1 chance of being fast to slow. So
after the population returns to 4 in each population, it is more likely that both groups will now be
3 fast /1 slow as opposed to 2 fast/2 slow.
In the non-aging population the rabbits will not die and the new ratio will remain constant. However, in
the aging 3/1 population, there would likely be a 3 to 1 chance of fast rabbits dying and/or being born vs.
slow ones. Over time, random deviations from this ratio in either births, deaths or both will cause the
population to become either 100% fast or 100% slow rabbits. There is however, a 3 to 1 chance that the
drift will be towards all fast rabbits. This drift will not occur in the 3/1 or 2/2 non-aging population.
Genetic drift occurs quickly in smaller populations. It will also occur in larger populations, but requires
more generations to increase its likelihood of leading to homozygosity in a trait. (In addition to the 3 fast
to 1 slow rabbit ratio, both or either population could have become 2 fast /2 slow rabbits. The following
summary ties it all together):
Both populations begin as:
4 rabbits: 2 fast and 2 slow
fox eats 1 slow rabbit from each population and then dies:
In both populations the new ratio is
2 fast to 1 slow
In either population there is a 67% chance that a new member will be born fast, and a 33% chance that it
will be born slow.
So after replacement of the eaten slow rabbit, either population will become:
3 fast /1 slow- a 67% chance (or)
2 fast / 2 slow- a 33% chance.
The non-aging population will remain in one of these states until the next predator arrives.
The aging population will, however, drift to 100% fast or 100% slow within just a few generations. If a 2
fast/2 slow population results after the predation (a 33% chance) and undergoes genetic drift there is a
50% chance of it drifting in either direction. However, in the event of a 3 fast to 1 slow population (a
67% chance), there would be a 75% chance of the population drifting to all fast and 25% to all slow.
So the final totals for the aging population are as follows:
Chance of a 100% fast population = 33% x 50% + 67% x 75% = 67%
Chance of a 100% slow population = 33% x 50% + 67% x 25%= 33%
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 6
In the most likely case, there will be two populations of 4 rabbits each. One is aging and 100% fast; the
other is non-aging with either 3/1 or 2/2 fast to slow ratios. Now if another fox washes up on shore that
will eat all the slow rabbits and then up to three fast rabbits from each population and then dies , the non-
aging rabbits will become extinct while the aging rabbits will leave one survivor to continue the species.
This scenario will occur with a 67% frequency with the given predation pattern.
On the other hand if the aging rabbits drifted to 100% slow rabbits, then they will become extinct when
the fox returns and the non-aging rabbits may survive (but will likely become extinct also). This however,
will occur with only a 33% frequency. So in this particular example, the aging rabbits have a 2 to 1
chance of becoming 100% fast and thus being the only surviving species under the above predation
pattern, whereas the non-aging species would likely become extinct in all scenarios.
In addition to protecting against extinction, other scenarios can be created where if the predation is not
intense enough to drive one species to extinction, then the aging population will gain population share at
the expense of the non-aging population if the populations occupy the same territory.
In a small sample size we can see a great advantage conferred by aging, however, as the population size
increases so do the number of patterns of possible sampling error. Larger populations will require longer
time frames for genetic drift to cause homozygosity in a trait. It is not unreasonable to suggest that many
prey species in their evolutionary past became reduced to very small numbers for a period before
rebounding. This is known in evolutionary terms as a bottleneck. Bottlenecks exist in many species today
that are on the brink of extinction, and likely occurred many times in the past as well.
Finally, even if population bottlenecks were infrequent, aging should still have become widespread among
species. If aging increased the rate of survival of aging over non-aging species to just a tiny fraction
above 50% (rather than by 2 to 1 in our example) , the immense number of generations during evolution
would have eventually compounded the slight advantage of aging species (at the expense of non-aging
species) to encompass virtually 100% of all species subjected to periodic predation.
Implications of aging systems:
If aging systems arose periodically in different species when it was evolutionarily advantageous, then
there should exist many different types of aging systems. This would be true because if the purpose of
aging is to cause an organism’s death at a particular time, then loss of teeth that would lead to starvation
in an elephant would be just as effective as cancer in a chicken, or insulin resistance in a nematode.
Therefore, most organisms should share the vestiges of the earliest aging systems to evolve in our single
cell ancestors such as telomeres. However, the longer two species have been separated on the evolutionary
tree, the less likely that it is that their most recently evolved aging systems will have much in common.
This suggests for example, that the study of aging systems in a Drosophila is less likely to have relevance
to human aging than studying those of a mammal or primate. In some cases, there may be almost no
relevance at all other than how the aging systems react to universally encountered environmental
conditions. This can also likely be said for the study of “anti-aging” through caloric restriction (CR).
While CR should work in all organisms that evolved a defense to famine in the past, the mechanisms of
action could be completely different between species. Therefore, to study aging in humans, it might be
more fruitful to concentrate on the symptoms and causes of the diseases that accelerate the various aging
systems such as Progeria and Werner’s Syndrome than to hope to gain much knowledge from studying
evolutionarily distant species.
The natural drift to longevity:
Aging, at times, provides a survival advantage in environments that can only support finite populations.
However, aging serves no purpose and is selected against in unrestricted environments. Why?
A non-aging organism will have a longer potential reproductive life span and thus will be able to have
more offspring. Those with shorter lives less. Over time, evolution will select for the members of a species
with the greatest reproductive potential, and therefore the greatest life span. Increasing the incidence of
longer-reproductive-life span genes in the population would eventually dilute the genes associated with
shorter-reproductive-life spans out of the population. By taking 3 to the 10th power = (about 60,000) and
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part, without the prior, express, written consent of the author. 7
comparing it to 2 to the 10th power (about 1,000), one will see the miracle of compound reproduction
(where 3 and 2 are the number of offspring per lifetime of an individual in one generation). This, of
course, assumes a constant litter size among individuals in the population as seen in humans. Litter size
will be addressed later.
So, all aging mechanisms should eventually be overcome by the natural drift towards longevity in the
absence of any constraining environmental or selection factors. Mutations that deactivate any earlier-
evolved aging systems are all that are needed for this to occur.
Aging provides an advantage to a species when it is encountering a periodic selection pressure. The
advantage of aging, however, would probably dissipate quickly if the selection pressure is absent for
too long a period and the species then enters an unrestricted environment. With no predation and
unlimited energy and water sources, the longest-living, maximally-reproducing organisms would be
favored to provide the greatest contribution to the gene pool. Aging systems that interfered with
increasing reproductive life span would eventually be diluted out of the population . If a species drifted to
longevity too quickly, a later encounter with a selection pressure could lead to the species’ extinction if it
is in competition with an aging species for the same habitat. Aging systems that postponed the drift
towards longevity would then be selected for so that the advantage of aging could be retained for longer
periods even if periodic selection pressure became less frequent.
The evolution of six aging systems:
Let us develop a rough blueprint for the evolution of life, from its beginnings to its current forms, with
the intent of focusing on what might have been important with respect to the evolution of aging:
First, life may have evolved at underwater thermal vents in a form similar to what are known today as
Archaea. Archaea have been accepted as a third branch of life that might have been the precursor to the
eukaryotes, a group to which humans belong. High temperatures at these vents might have lead to the
many, rapid chemical reactions necessary to originate the first life form. Intermittent heat surges at these
vents could have provided the periodic selection pressure necessary to lead to the first proposed aging
system of telomere shortening. An aging Archaea would have been likely to drift more quickly to a
population that had 100% heat shock gene-protected members. Heat shock genes might have allowed
these organisms to survive heat surges by allowing them to quickly repair proteins damaged by excess
heat. Some modern day Archaea have evolved the ability to survive at temperatures as high as 130° C (6).
(Given that heat shock genes are found in virtually all forms of life, including Archaea and mitochondria,
it suggests a common ancestor for all these life forms). We also know that modern day Archaea have
circular chromosomes. A simple way to create an aging system from a circular chromosome would be to
simply cut it in a stretch of non-coding DNA and cause it to retain a linear shape. Due to a DNA copying
anomaly where one strand of the DNA cannot be copied all the way to the end in linear chromosomes, the
DNA would shorten at each round of replication, and eventually the non-coding DNA would be lost and
coding portions would then become damaged. When this happened the organism would die or be unable
to replicate. This was likely the precursor to the modern day telomeres found in eukaryotes which consist
of non-coding DNA and typically shorten with each round of cell division in cells not protected by
telomerase, an enzyme that rebuilds the ends of chromosomes. Because a telomeric aging system would
have been the easiest for evolution to create, it likely evolved first and it will be referred to as Aging
System #1 or (AS#1).
The next step in the evolution of aging was likely the movement of Archaea to the oceans and the
emergence of photosynthesis. Strains of Archaea that were able to evolve the telomeric aging system,
would be expected to be able to evolve adaptations more rapidly than non-aging Archaea. Some of these
Archaea must have drifted off from the thermal vents and developed the ability to engage in
photosynthesis. What drifted off with them, however, were likely some other mitochondria-like creatures
that also evolved at the same thermal vent. (It is generally believed that mitochondria were originally
separate organisms from the cells they are found in and at one point in evolution merged with the larger
cells in a symbiotic union. This is evidenced by the fact that mitochondria exist outside of the cell nucleus
yet have their own separate DNA as well as heat shock genes).
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part, without the prior, express, written consent of the author. 8
So, if mitochondria existed as separate organisms prior to their merging with the drifting Archaea, then it
might be expected that they had evolved their own separate aging system. Once the two life forms merged
and the larger, combined, life form was completely dependent on the mitochondrial energy source,
whenever enough mitochondria in the cell had died, the cell itself would also die. If the mitochondrial
imposed death occurred before death caused by telomeric shortening, two aging systems could exist in the
same organism, one dominant and one vestigial. Mitochondrial aging will be referred to as Aging System
#2 or (AS#2).
The next step in evolution would likely have been the vast colonization of the oceans by these
photosynthetic Archaea. (We will now refer to them as algae). With the sun providing unlimited energy
and the ocean an unrestricted habitat, evolution would select for maximal reproductive potential and
therefore maximal life spans. The first two aging systems, therefore were likely deactivated. The symbiotic
mitochondria could simply evolve longer life spans, and the telomeric aging system could be deactivated
by the creation of telomerase which rebuilds the ends of the chromosomes after each round of replication.
Also, to counter the effect of the sun’s deadly mutating UV, Gamma, and X rays ( referred to herein as
solar radiation) a DNA repair system had to evolve that could excise damaged base pairs and replace
them with the proper ones. Additionally, to protect against the free radicals generated by the oxygen
produced from photosynthesis and solar radiation, an antioxidant protective system had to evolve as well.
After a billion years of this selection pressure it could be expected that the algae evolved into non-aging,
rapidly-reproducing organisms with perfect DNA repair and free radical defense systems. Is there any
evidence that single cell organisms were once immortal? Many cell-types with the proper manipulations
can become immortalized cancer strains and reproduce indefinitely as a culture. Cancer, in a broad sense,
may simply be a cell returning to its earlier, primitive, immortalized, state. It should not be very
surprising that a mortal life form that evolved from a previously immortalized life form could
spontaneously become immortalized through loss of some type of control. However, if the mortal life form
had evolved from mortal ancestors, spontaneous immortalization would seem to be quite a miracle indeed.
Immortalized algae would reproduce until a deep layer (the primordial ooze) formed on the oceans. Algae
in the topmost layers may have initially received too much solar radiation to survive. Eventually this
limitation had to be overcome through the evolution of solar radiation damage repair systems. However,
large amounts of unrepaired DNA damage that might accumulate in the genome while an algae resided in
the topmost layer might make reproduction, or cell division, an unwise decision. Logically, we would
expect the evolution of a mechanism that would inhibit cell division during periods where excess
radiation-induced free radical levels were encountered, and we find that many studies show that free-
radical induced DNA damage leads to inhibition of cell division (i.e. 7). This inhibition of mitosis in the
presence of DNA damage would be important in that it would prevent the copying and transmission of
DNA errors (prior to correction) to future generations. This early function likely is what evolved into the
elaborate checkpoint control mechanisms seen in the cell cycle today. So the first control on cell division
to evolve may have been a free radical-inhibited (or antioxidant-promoted) cell doubling system. Some
algae, however, residing at lower layers, wouldn’t receive enough sunlight to survive. They either died, or
evolved into predators that fed on the algae above them. (Note that this theory suggests that predators
evolved as single celled organisms. This assumption will be retained and does not negatively affect the
unified aging theory created herein. However, as the author is working on another paper concerning the
evolution of metamorphosis, apoptosis, and cancer, it has become apparent that the more likely course of
evolution was from single-celled algae to multi-celled aquatic plant life and then to predators. )
An immortalized predator evolves.
Evolution would select for immortalized predator strains because of unrestricted algae as a food source ,
and the vast ocean habitat. Eventually some strains of the predator would become so successful at
reproduction and preying on the algae that almost all of the algae would eventually be consumed and then
extinction of the predator would become possible due to its inability to engage in photosynthesis. (Overly-
efficient predators that lead to extinction of their prey and thus cause their own extinction will be referred
to in this theory as “super-predators”). A few isolated pockets of algae and predators must have remained,
however, or life, would not have continued to evolve.
Pockets of algae that were able to survive predation likely had avoided extinction by reacquiring the
advantage of aging. Aging would allow defenses to predation to quickly drift to 100% of the population
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in the event that episodic selection pressure was encountered. Although the telomeric and mitochondrial
aging systems could be reactivated to cause aging if necessary, other scenarios could also unfold; the
continual pressure of predation by itself would be enough to induce an aging system of mutation
accumulation in the algae. This would occur if predation was intense enough to cut short the
reproductive life spans of most members of the prey species. Spontaneous mutations are always occurring
and are usually deleterious and selected against. Neutral mutations, however, harmlessly accumulate in
the genome. If a mutation is neutral to the younger organism but deleterious to reproducing at older
ages, it would remain in a population of individuals that never reached ages where the gene became
harmful.
Expected life spans would be reduced by predation and the effects of the deleterious mutation would not
be apparent; however, if predation abated, then the expression of the deleterious mutations would occur
at the older ages. Also, eventually, genetic drift, may eventually cause this aging mutation to fixate at
either 100% or 0% of the population. Because mutations are always occurring, eventually, some of them
will accumulate in the prey species’ genome and drift to a 100% level while some will be lost. Mutation
accumulation was the third aging system expected to have evolved and will be referred to as( AS#3).
(Possibly induction of AS#3 could be experimentally demonstrated by exposing two groups of organisms
to mutating X-rays and culling individuals from the experimental group prior to the end of their
reproductive lives. After enough generations, symptoms of an AS#3 should become apparent in the
experimental group after the age of culling was surpassed while not being seen in the control group).
Until genetic drift had run its course, not all members of a species whose life spans are limited by AS#3
would harbor all the deleterious mutations possible; so wide variability in life spans should be seen. The
mortality curve law, or Gompertz equation, which states that each day one lives increases the chances of
one’s dying would not hold in this aging system. Why? Because once an individual made it past the point
where deleterious mutations became active and killed most others, one more hurdle to longevity would
have been cleared; in this case, the longer one lived the longer one would be expected to live. Eventually,
however, if left without predation long enough, the deleterious mutations of AS#3 should work their way
out of the population. Once gone, they might be gone forever and a new aging system of mutation
accumulation would have to await creation by a subsequent encounter with predation. It is possible that
all aging systems to have ever evolved after AS#3 were first generated by deleterious mutations and then
later co-opted and retained by subsequently evolved aging systems.
Meanwhile, while most of the predators likely starved , some escaped this fate by evolving an ability to
survive famine. Caloric restriction (CR) has been shown to slow the aging process and extend both mean
and maximum life spans in all organisms studied (8) (with the exception of the purportedly immortal
amoebae). Less widely mentioned is that CR can inhibit the reproduction function; for example, quite a
few studies have shown that female rodents undergoing CR lose their estrous cycles (i.e. 9), and it is well-
known that human females that reach too low a body fat level often cease menstruating. During famine,
curtailing reproduction avoids consumption of a limited food supply at a faster rate. If aging is also
inhibited, then the population will remain young enough to reproduce when the famine has abated.
Evolution was at a crossroads, if the algae evolved a perfect defense to predation, then the predators would
starve, and life would not have evolved further. If the predator had evolved the perfect offense , all the
algae would be consumed and all life (other than Archaea) would become extinct as the predators would
then starve. This likely lead to an arms race between the predator and the prey that had to remain in
balance for evolution to continue while avoiding predator extinction.
(A digression is in order: in single cell organisms, with functional telomeric aging systems, the act of
reproduction (cell division) also drove the process of aging (telomere shortening), so by inhibiting
reproduction, aging is also inhibited. This is a simple concept that the author expects will apply to all
aging organisms, no matter how complex. In humans, reproduction is controlled by hormones and the
case will be made that these same hormones control the aging process. Also, given that a DNA helicase
would be expected to be involved in duplicating the DNA during the cell division (aging) process, does it
not seem logical that diseases of rapid aging are also linked to DNA helicase defects? Finally, in multi-
celled organisms, cell division is also tantamount to growth and differentiation, thus growth and/or
differentiation should also lead to aging. This may help to explain the shorter life spans seen in the
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males of most species (due to their typically larger sizes), and why, as will be discussed , growth-
inhibiting regimens, other than caloric restriction, also lead to slowed aging ).
Multi-celled organisms control development through the methylation and demethylation of cytosine.
In response to an increasingly competitive predator-prey arms race, multi-celled organisms likely evolved
that were more efficient predators or better-defended prey. The quickest and easiest way that cellular
differentiation could have evolved was likely through the methylation of cytosine in the genome.
Many studies suggest that transcription of genes is suppressed by cytosine methylation (5mC)
(presumably by inhibiting the attachment of polymerase), and activated when the cytosines are
demethylated (10). Two critical but not well-known facts that lead to the generation of this unified theory
are that 5mC in DNA has been shown to be demethylated by free radicals (11) and remethylated by
antioxidants (12). This will be addressed later.
It has also been shown that after an egg is fertilized, there is almost a complete demethylation of the
genomic 5mC followed by a rapid, large-scale remethylation of the genomic 5mC prior to the
commencement of development (13). This would logically appear to be an error correction process to
ensure that the developing genome begins with a full complement of methylated cytosines. This large
scale remethylation is then followed by a programmed, and more gradual demethylation during
development (14). This gradual developmental demethylation proceeds more rapidly in the embryo, but
then decreases to a much slower rate as development nears completion, and then slows down to a
relatively constant rate for the remainder of the organism’s life (15).
Evolution’s need for hormones:
More complex organisms had more genes, cells, and cell types requiring differentiation and control by
extra-cellular signals. Different antioxidant and free radical combinations likely served as a means to
signal the expanding numbers of genes and cell types by causing various patterns of methylation and
gene expression. Antioxidants likely were the preferred form of signal messenger in that they lacked free
radicals’ negative side effects of causing damage and oxidization in tissues. It is expected that antioxidant
hormones were the first circulating hormones to evolve in photosynthetic organisms. Free radicals
involved in gene signaling likely remained confined to the inside of the cell.
The more complex organisms likely began experiencing a shortage of different antioxidants with which
to signal, and this may have proved to be an impediment to continued evolution of the organism
especially when the evolution of metamorphosis (discussed later) added additional complexity. More
hormones were likely required as predators and prey competed to avoid extinction. More signals meant
more potential complexity which meant the evolution of superior offense or defense and thus survival.
Also, while antioxidants were growth promoting in plants, predators likely also evolved a cell doubling
system that was promoted by free radical hormones that evolved from free radicals generated by the
metabolism of food. This allowed the predator to reproduce or grow only during periods of food
availability. Likewise, antioxidants became primarily growth-inhibiting in predators.
Evolution likely solved the hormone shortage problem by creating free radical surrogate hormones that
could circulate without causing damage, and then trigger a release of stored free radicals within the
targeted cell. It is expected that all hormones will be found to act as either antioxidants or free radicals in
their ultimate effect on activating or deactivating genes. Hormones such as LH and cortisol (16) , FSH
(17), and the many other hormones that stimulate the cAMP pathway are expected to be the proposed
free radical surrogates (estrogen, however, enters the nucleus (18) and likely is converted directly into a
free radical (19)). A much smaller group of hormones such as GH, insulin (20), DHEA (21), melatonin
(22) and other antioxidants or antioxidant surrogates act by stimulating the cGMP pathway , (or possibly
inhibiting the cAMP pathway). Testosterone enters the cell directly (23) and has been associated with
increasing cGMP levels in some studies (i.e. 24) and will be proposed to be converted into an antioxidant
during nuclear entry. There are a few hormones, however, such as prolactin which can stimulate either
pathway depending on which type of receptor they bind, as well as some hormones that stimulate the
cGMP pathway (like testosterone) that can be enzymatically converted into a cAMP stimulating hormone
(like DHT).
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By methylating certain genes and not others, evolution had found a way to create different cell types from
a single genome. This method of switching genes on and off was used not only as a way to regulate
development and differentiation , but was likely co-opted as a new and superior method by which the
organism could maintain an advantageous aging rate by timing the demethylation of deleterious genes.
Typically referred to as the Senescent Gene Expression model (SGE) of aging it will be designated here as
(AS#4). An aging system could have been created by simply co-opting the deleterious genes of AS#3 and
allowing them to be expressed at the proper time through demethylation. If the deleterious mutations of
AS#3 were not co-opted by methylation by AS#4, it is likely that AS#3 would never gain a foothold and
would be selected against when it interfered with reproduction at ages earlier than the age of predator-
imposed death. Thus, one might say that AS#3 and AS#4 are really inseparable in the long run.
An example of SGE (but not necessarily of AS#4) occurring with age was demonstrated in a study that
showed that the production of the metalloproteinases stromelysin and collagenase (which are implicated
in the breakdown of the body’s collagen) were increased in cells of both the aged and of those persons
suffering from the rapid aging diseases of Werner’s Syndrome, and AT & XP (25, 26).
Cytosine-demethylation relates to aging in several ways. In the genome, cytosine demethylation has been
shown to occur at an accelerated rate in shorter-lived animals and at a slower rate in longer-lived animals
(27). By the end of most organisms’ lives, cytosine demethylation in the genome is virtually complete
(28). Additionally, the maximum number of cell doublings (the Hayflick limit) has been shown to be
inversely proportional to the rate of demethylation of the genomic 5mC (29). The case will later be made
that cytosine demethylation likely plays the primary controlling role in aging in humans.
Methylated cytosines (5mC) allow the rate of aging to be accurately controlled through timing changes in
gene expression. The methylation status of a gene can be controlled through alterations in the level of
antioxidant and free radical hormones. SGE also has the added benefit of being somewhat reversible by
simply increasing the appropriate antioxidant to free radical hormone ratios to favor remethylation (and
therefore senescent gene silencing) over demethylation and SGE. Reversing the aging process could be
advantageous to a species’ survival during a severe famine or drought where almost the entire population
would perish save a few survivors. Rejuvenation of the reproductive fitness of each member of the
population would be of paramount importance, for if only several individuals survived to repopulate the
species, then restoration of fertility in even menopausal members could mean the difference between
extinction and survival. Reproductive rejuvenation is discussed later.
This new aging system was not yet perfect, however, as generalized genomic demethylation would affect
all the cells in the organism. A fairly large repair (methylation) process would be required to restore the
individual during a famine. More easily reversible aging systems to evolve subsequently would increase
the odds of a species’ survival during these periods.
As will be discussed later, an accelerated version of AS#4 is expected to be seen in the rapid aging
childhood disease of Progeria. It is expected that a DNA helicase malfunctions and causes the accelerated
demethylation and thus expression of a set of genes that cause part of the symptoms of aging which
include hair graying, alopecia, hypertension, and atherosclerosis among other things. These are, for the
most part, thought to be diseases that occur at a higher rate, or appear sooner in men than in women.
Evidence will also be examined that suggests FSH is the free radical surrogate hormone (or cAMP-
stimulating) that induces these demethylations. It is important to note that cancer is not reported to occur
in persons with Progeria. Also significant is that after a Medline search for cancers associated with FSH,
none could be found, while various cancers were associated with almost all other proposed free radical
surrogate hormones including LH and estrogen. Because of these facts, we can speculate that cancer is not
an aging symptom that belongs to AS#4.
Some hormone levels change significantly in humans with age.
Several hormones that are proposed free radical surrogates increase with age, and in some cases
dramatically-In human males:
-Estradiol increases from about 125 pmol/liter at age 45 to about 265 pmol per liter by age 80, more than
a 200% increase (30).
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-LH starts in a range of about 1.0 to 2.8 mI.U./mL at age 40 and increases to a range of 2.1 to 11 mI.
U./mL by age 80: anywhere from a 60% to 1100% increase (31).
-FSH at age 50 begins at about 2.5 mI.U./mL and increases to a range of 6 to 50 mI.U./mL by age 80: a
140% to 2000% increase. (the maximum % increase in range from baseline exceeds that in females)
(32).
In human females,
-LH increases from a range of 5 to 45 mU/mL at age 40 to a range of 40 to 130 mU/mL by age 55, a
change of anywhere from flat to +2600%. (the maximum % increase in range from baseline exceeds
that in males) (33)
-FSH increases in women from about 20 mI.U./mL at the age of 40 to anywhere from 40 to 200 mI. U./mL
by age 75.....a 100% to 1000% percent increase (combined values from 31, 33).
-Estrogen and its related hormones increase quite significantly around the time of menopause and then,
unlike the males’ sustained rise, crash precipitously when menopause is complete.(34).
Likewise, we see many antioxidant surrogate hormones declining dramatically with age
In human males:
-Testosterone typically ranges in males from about 3.5 to 10.5 ng/mL at age 40 and declines to a range of .
4 to 4 ng/mL by age 80 (35).
-DHEA declines from about 3600 ng/mL at age 20 to about 800 ng/mL by age 70 (36)
In human females:
-Testosterone levels are reported to decline by 50% from age 21 to age 40 (37).
-DHEA declines from about 2600 ng/mL a age 20 to about 800 ng/mL by age 70 (38)
In both sexes:
-Peak melatonin levels (which occur at night) in the elderly are 50% less than those of young adults
while basal melatonin levels remain constant. (39).
-Peak growth hormone levels (which occur at night) are reported to be diminished or completely absent in
some subjects over 50 years of age and decline from as high as 2.9 ng/mL to 1.1 ng/mL (40).
The Status of Telomeres
During development and normal life processes in multi-celled organisms, different cells require different
doubling capacities. For example, brain cells, are thought not to divide while cells involved in the
production of red blood cells, skin, hair, endometrium, or spermatids divide many times. Therefore
reactivation of telomerase in certain somatic cells would be necessary to allow varied rates of cell
doubling without triggering cell death due to telomere shortening. If telomerase is not activated in cells
that undergo significant amounts of division, a lethal aging system may be created, and in fact, if tissue
types exist that lack telomerase expression, these tissues might be the factor that limits the maximum life
span in humans to about 120 years.
However, one would expect that after many years of evolution that all the aging systems should
eventually be integrated and cooperative. One study suggests that telomeres may be co-opted by other
aging systems as telomerase activation has been shown to be under hormonal control. A drop in
testosterone levels (a proposed antioxidant) caused by castration of rats was shown to activate telomerase
in their prostate and seminal vesicles (41). Other studies show that telomerase activity in the
endometrium rise and fall with the menstrual cycle in a hormone-dependent manner, and that telomerase
activity was absent or reduced in post-menopausal women (42, 43). This suggests that increased estradiol
levels , (a proposed free radical) activates telomerase just like a drop in testosterone does. Activation by a
drop in an antioxidant hormone level or increase in free radical level suggests that the telomerase gene is
inhibited by antioxidant-induced methylation in these tissues. Many other studies show that telomerase is
active in numerous somatic tissues such as hair follicles (44) , liver (45), epithelial (46) and blood cells,
lymphocytes (47), and endometrium (48). Telomerase has long been believed to be active only in cancer
and germ cell lines and thus is being targeted as a promising therapy for cancer. Recent journal articles
are still promoting this idea. (49). However, it now appears that telomerase activity might be active in
most normally dividing cells. If telomere shortening is occurring with age, at least in sexual tissues, it is
likely occurring due to hormonally-induced inhibition of the telomerase gene rather than as an
independent process.
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(There are even cases of immortalized cancer cell lines that do not endure telomere shortening but
surprisingly do not show any telomerase activity (50). This suggests that there may be other mechanisms
that inhibit telomere shortening which might include some sort of DNA crossover system that adds length
to telomeres, or another version of telomerase which might be activated by a drop in free radical levels
instead of the drop in an antioxidant hormone mentioned above. Possibly another telomere-related aging
mechanism exists but is currently unknown .)
The natural drift towards longevity deactivates AS#1 and AS#2.
If AS#4 co-opted AS#3, did it also co-opt AS#2 and AS#1? The answer is not so simple. If prior to the
evolution of AS #4, most organisms were subject to unrestricted environments, then all the aging systems
eventually should have been selected out of the population. In the case of telomeres, this simply required
the evolution of telomerase that counteracted the shortening of AS#1 but left telomeres intact in the
genome. Mitochondrial aging, however, would likely have been completely lost to have allowed for
increased life spans. Therefore, if the predecessors to aging multi-cellular organisms were virtually
immortal and needed to create a new aging system in the face of predation, the telomeres could be called
on as they already existed, but AS#2 likely no longer existed. However, predation should have quickly
induced a new AS#3 (where any late acting deleterious mutation could be utilized) to emerge as the
temporarily dominant aging system. The newly evolved AS#3 may or may not have co-opted aging related
to telomeres and made other new additions, but the immortalized mitochondria apparently were not co-
opted in human evolution. This can be surmised because mitochondrial-related diseases, that resemble
aging as discussed later, do not show aging symptoms that are common to Progeria. An aging system
linked to sexual tissues to be described (AS#6), however, almost certainly co-opted AS#1 through estrogen
and testosterone control of telomerase. Finally, as will be discussed, some researchers suggest (probably
incorrectly) that Progeria is caused by telomere shortening as shortened telomeres have been noted in the
disease(51a). If this is true, it may suggest that AS#4 also co-opted AS#1 but may act on telomerase
differently than the sex hormones. In AS#4 demethylation, and thus expression of genes is likely to cause
aging. This implies that there should exist a gene that when expressed, inhibits the telomerase gene in
some manner. Thus, when the inhibitor gene was demethylated, telomerase expression would stop.
Another possibility is that telomerase is simply not active in tissues subjected to aging by AS#4. This idea
can be tested by examining FSH (or possibly DHT or cortisol as will be explained) for telomerase
inhibiting activity, or by testing all the antioxidant hormones (GH and testosterone in particular) for
telomerase activating capability in the tissues aged by AS#4. If expression of a gene by demethylation is
resulting in deactivation of the telomerase gene, then telomere shortening would be a result, not a cause,
of Progeria. This, in turn, would suggest that AS#4 also co-opted AS#1.
If telomere shortening actually did cause Progeria or Werner’s syndromes, it would imply that excessively
rapid cell doublings were occurring in these diseases as that is how telomeres presumably shorten in
normal situations. This conflicts with evidence that shows Werner’s cells actually take a longer time than
controls to divide due to an extended S phase (51b). (In fact it may be the extended S phase that leads to
excessive exposure of the genomic 5mC to free radicals as will be discussed later).
Metamorphosis and apoptosis co-evolve and are incorporated into a more easily reversible somatic
atrophy aging system.
One would expect that apoptosis, would appear to be an aging system that could have evolved in single
cell organisms. However, given that it relies heavily, as will be proposed, on the methylation of cytosines
that is common to AS#4, and, as proposed, is a bit more complicated than the simple methylation of a
gene, we can suggest that apoptosis evolved after the simple genetic control mechanism of cytosine
methylation. This, in turn, might imply that apoptosis evolved after the advent of multi-cellular organisms
and thus after AS#4. Before discussing apoptosis let us continue with our reconstruction of evolution.
The aging systems described so far likely evolved in ocean-dwelling single cell or multi-celled organisms.
When periodic, ocean-wide famines were encountered, the evolution of a system of metamorphosis would
be advantageous, allowing an organism to remain in a larval-like state with minimal energy requirements
until food was available. Many scientific studies that show that when an environment contains a single
chemical associated with a pre-metamorphic organism’s food source, that metamorphosis is triggered (i.e.
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52, 53). (Note: most fish go through a larval stage, but it is interesting that elasmobranchs (sharks),
which reportedly almost never get cancer, lack a larval stage. The relevance of this should become more
clear later.)
Eventually, to escape predation, life forms made the evolutionary difficult move from the oceans to land.
Lack of water would be the major risk factor of this new environment. Whereas metamorphosis would be
a beneficial adaptation for ocean-dwelling creatures, it would be absolutely critical in a dry land
environment. Evolution of metamorphosis would allow organisms to remain small and dormant until
water (and to a lesser extent food) was available and development and growth could occur. Keeping in
mind the earlier assumption that evolution, at this time, was likely facing a scarcity of hormones, it
seems logical that the metamorphosis system for a particular cell or tissue type had to rely on a single,
or small group of hormones as signals for the cell division and cell destruction that occurs during
metamorphosis. The goal of metamorphosis was likely ultimately reproductive in nature and probably lead
to the development of a particular soma type that had some advantages in reproduction as compared to the
pre-metamorphic form of the organism. At this point in evolution, reproduction likely occurred through
parthenogenesis and possibly the complete dissociation of the multi-celled organism into a myriad of
single cell, clonal spores; in an unrestricted environment, this would provide a great reproductive
advantage.( Note for future reference the similarity of reproduction by dissociation and the process of
metastasis in cancer.)
In more competitive environments, however, something similar to sexual reproduction would be the
preferred mode of reproduction so that organismic dissociation could be avoided. Non-dissociative
reproduction (budding) in multi-celled plants would allow the organism to retain its positioning in a
densely populated environment (i.e. canopy forest or primordial ooze) to obtain solar energy and thus
avoid a suicidal dissociation while sending out spores that, if fortunate, would find a niche where they
could develop into adults. This was likely the precursor to sexual reproduction, gametes, and sexual
(rather than parthenogenetic) metamorphosis.
Plants likely evolved the ability to survive periods of drought on land by remaining in seed-like states.
Eventually predators would follow the plants onto land and feed on them. Metamorphosis would be a
critical trait in the land-based predators, as well, due to their need to also survive extended drought
periods. In post-metamorphic adults, however, drought-induced death could no longer be avoided by
remaining small and dormant. So a water restriction response similar to caloric restriction likely evolved
which logically should have been more effective than caloric restriction at retarding aging and inhibiting
reproduction. This would make sense if prolonged drought was a more common and potentially longer
lasting selection force than famine. One might expect that during the initial stages of drought, plants and
animals killed by drought would provide plenty of dehydrated food for any surviving predators. (Again,
predators, in this context, includes any animal that acquires its energy from ingesting other organisms
whether plant or animal). If this is true, then it suggests that drought defenses may have evolved to a
higher level than famine defenses in land-based predators.
The evolution of metamorphosis at the cellular and genetic level now requires consideration. What occurs
when a caterpillar undergoes metamorphosis and becomes a butterfly? Somatically the two organisms
appear to have very little in common, but they still developed from the same genome.
In a simplified sense, some of the cells of the caterpillar likely were de-differentiated, and then
reprogrammed into butterfly cells that would then divide. Other caterpillar cells, not needed by the
butterfly could be eliminated through apoptosis. Therefore metamorphosis could be likened to a system
that targets destruction of only certain cells or specific tissues while targeting others for reprogramming
and doubling. What might be a reasonable suggestion for the genetic mechanism behind this metamorphic
cell doubling system? Already there existed cell doubling systems that should be inducible by the newly
evolving free radical hormones in predators; this would have provided half of what was needed to create a
metamorphic cell doubling system. Evolution merely needed to modify the cell doubling mechanism so
that it could also destroy a cell through apoptosis when needed, and the bulk of a metamorphic
mechanism would exist. The solar radiation damage repair enzymes (or any other enzymes that cleave
DNA) could simply be modified to destroy the cell by fragmenting its DNA instead of repairing it.
(Fragmented DNA is a marker used as an indicator to determine if apoptosis is occurring in human and
other types of cells. (i.e. 54)).
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Finally a mechanism was needed to target some cells for mitosis and others for apoptosis. Cytosine
methylation is known to prevent restriction enzymes from cleaving DNA ( 55). (This is also evidenced by
the fact that some viruses that rely on DNA cleavage are inhibited if the cleavage site has methylated
cytosines (56).) So a mechanism could be created where cells undergoing metamorphic mitosis were
subjected to restriction enzymes that would lethally fragment DNA if the DNA was not protected by 5mC.
However, if the DNA was methyl protected , the cells could undergo mitosis. Thus, the mere alteration of
methylation patterns of DNA could preprogram cells for metamorphic mitosis or apoptosis.
Metamorphosis finally needed a mechanism to add a new methylation pattern to the DNA to allow for
creating new cell types. The DNA methyltransferase (MTase) that remethylated the genome of pronuclei
mentioned earlier could easily be adapted for this function. This type of MTase likely originally evolved
with the advent of multi-cellular organisms with different cell types. When it was time for these
organisms to parthenogenetically reproduce by budding or through complete disaggregation of its cells
then the methylation patterns of the released cells would have to be remethylated to de-differentiate them
back to the pronucleus stage. Rather than an error correction (or de-differentiation) process of
demethylation and remethylation of the same sites, a new copy of this DNA MTase could be altered to
perform a reprogramming process.
While preprogrammed methylation patterns could create various metamorphic cell fates, lifetime free
radical surrogate hormone exposure of a cell could also lead to the same end. If free radical hormones
could lead to the demethylation of targeted cytosines, and demethylated DNA can be fragmented, then a
hormonal signal for apoptosis would exist. If the demethylation was abrupt, then apoptosis could be
induced immediately as it should be in metamorphosis; if the demethylation of a group of 5mC’s occurred
gradually, then atrophy of tissues could occur gradually on a cell by cell basis as it does in aging. Also, it
can be expected that the evolution of metamorphosis and apoptosis required the evolution of additional
free radical hormones even though they had the negative side effects of damaging proteins and tissues.
Given a predator / prey arms race of increasing complexity, evolution may have had to settle for the lesser
of two evils: free radical hormones as opposed to extinction.
While the newly evolved free radical hormones may have triggered apoptosis by “washing away” the
methyl protection of the DNA’s restriction sites, due to the increasing complexity of organisms and tissue
types, inducing apoptosis with antioxidant hormones likely also was required. If free radical hormones
lead to gene expression and susceptibility to DNA fragmentation, antioxidant hormones should have the
opposite effect of inhibited gene expression and DNA protection. Antioxidants would induce methyl
protection of nuclear DNA so fragmentation could not occur-was there any way around this? Apparently,
evolution resurrected the mitochondrial aging system for use in apoptosis. This can be surmised because,
as will be explained, diseases relating to mitochondria attack the same tissue types in humans as are
targeted by the diseases of a defective DNA helicase/replisome of AT, XP, & CS. Aging caused by
mitochondrial malfunction or destruction will be referred to as aging system 5A (AS#5A) ; its specific
symptoms and diseases will be discussed in more detail later.
How might an antioxidant-promoted mitochondrial apoptosis system have been created? One could guess
that there would exist a gene in the nuclear DNA that produced a protein(rather than methyl groups) that
protected the mitochondrial DNA from attack by restriction enzymes; when the protein-producing gene
was inhibited by methylation, the protective protein would dissipate, and then an attack of the unprotected
mitochondrial DNA could commence. It is interesting to note that mitochondria are also involved in
apoptosis, and when nuclear DNA is being fragmented, mitochondrial destruction is occurring also ( 57).
What may have happened over time, with the loss of the ability to undergo metamorphosis, is that
mitochondrial apoptosis was co-opted by helicase-induced apoptosis so that there are no longer two
distinct forms of apoptosis. In humans, the entire mechanism may then have been co-opted as an aging
system which will soon be discussed.
Another, more crude, method of achieving apoptosis may have existed before the evolution of the
mitochondrial attack and could have involved timed 5mC to thymine mutations that occur with high
frequency in dividing cells and are more common in methylated rather than unmethylated cytosines (58).
A 5mC to T mutation could lead to a permanent gene knockout due to thymine’s having a permanently
methylated site at the 5 carbon. If the gene knocked out produced an apoptosis suppression protein gene,
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part, without the prior, express, written consent of the author. 16
then another means to achieving antioxidant induced apoptosis would have existed. These ideas will be
explored more thoroughly in a paper in progress related to the evolution of metamorphosis, apoptosis, and
cancer. However, what can be said at this point is that cancer most likely results from a malfunction of
the process of apoptosis which in itself is apparently a modified form of mitosis.
Programming cells for future metamorphic apoptosis could occur by leaving some DNA sites
unmethylated in targeted cells. Given that non-mitochondrial apoptosis likely co-opted the solar radiation
damage excision repair restriction enzymes, it seems likely that the apoptotic restriction sites would be
similar or the same as the solar radiation repair restriction sites. If this is the case, it would provide a
simple system for the targeting of specific internal tissues for apoptosis by altering methylation patterns.
(It is interesting to note many studies show that general apoptosis is also closely linked to genomic
demethylation (i.e. 59). This would make sense if as is proposed, typical (not pre-programmed for
apoptosis) cells’ genomes are methyl-protected and need to be demethylated prior to DNA
fragmentation.)
Because UV damage to DNA would occur almost exclusively in the epidermis, and X-ray and Gamma ray
damage should also likely be concentrated in the outer layers of the soma, internal tissues and cells would
not need protection from solar radiation induced apoptosis as these rays should never penetrate into these
shielded areas. The restriction sites in these tissues could remain unmethylated with little risk of solar
radiation-induced apoptosis (from exposure to repair-related restriction enzymes) occurring. If a signal
for metamorphic mitosis was transmitted to all internal cells during metamorphosis which in turn caused
a restriction enzyme release, some cells and tissues would undergo apoptosis while other methyl-
protected cells would divide. (Given that some of the symptoms of AS#5 seem to be related to atrophy of
the skin (i.e. skin ulcers, scaly skin, and poor healing), it may imply that evolution completely co-opted
what was once a separate solar radiation repair system and targeted it solely to the process of aging or it
could not be used in sun-exposed tissues (possibly topoisomerase which is defective in some forms of AT
evolved in this manner). The other alternative is that attack of the skin (loss of subcutaneous tissue) is
actually a symptom of AS#4 that does not rely on restriction sites but rather on SGE. Please refer to the
chart of aging symptoms presented later for clarification)
Until the genome of a cell that was undergoing metamorphic mitosis was re-differentiated by methylation
, one would expect to see the following: a demethylated genome (as initially occurs in the fertilized
ovum), and various islands of hyper-methylation where the cell doubling mechanism has to repress
genes and protect restriction sites that would interfere with mitosis. Such methylated genes might
include those that code for apoptotic restriction enzymes, the cell’s “housekeeping” methyltransferase
which maintains cell-specific methylation patterns, and any mitosis inhibiting genes. Studies of mice cells
show that when one methyltransferase gene has been knocked out, methyltransferase activity still occurs.
(60) This suggests that there may be at least two, if not more, separate methyltransferases and the
metamorphic cell doubling process possibly has a specific methyltransferase that creates a unique
methylation pattern required for metamorphic cell doubling. Also, in E Coli there are at least two types of
methyltransferases, and a role for one of them is not known (61). This proposed “metamorphic”
methyltransferase, would likely be active during the genomic wide demethylation that should occur prior
to metamorphic redifferentiation and cell doubling. It is frequently noted in the literature that a puzzling
aspect of many cancers is their virtually demethylated genomes that have islands of hyper-methylated
sites (i.e. 62), and that these transformed cells also show very high concentrations of DNA
methyltransferase. (63, 64).
After its evolution, metamorphosis could be harnessed to create a new aging system. Simply, certain vital
organs could be targeted for atrophy through apoptosis which could be programmed to occur gradually as
opposed to the rapid involution of tissues that occur in metamorphosis. Gradualism could possibly be
introduced by altering the methylation levels of the DNA restriction sites. Cells that received the fewest
methylations would be the first to undergo apoptosis when hormone level changes caused additional
demethylation at these sites. This aging system could be induced or reversed by hormonally altering the
rate of cytosine methylation which would then alter the rate of apoptosis vs. mitosis in targeted tissues.
Targeted tissue atrophy in humans and mice is seen in the virtual disappearance of the thymus gland that
occurs gradually over a lifetime, as well as cerebral, muscular, skin, and neural atrophy (i.e. 65,-68).
Additional attacks by this aging system on somatic tissue occur in the eyes (cataracts), the joints
(arthritis), and the bones (osteoporosis). Alzheimer’s and diabetes could also be considered additional
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part, without the prior, express, written consent of the author. 17
attacks of AS#5 against brain and epidermal tissue. Finally, thymic atrophy may lead to the immune
system malfunctions that are the basis of the immunologic theory of aging. Metamorphic/parthenogenetic
apoptosis occurring through nuclear DNA fragmentation will be referred to as (AS#5B).
Examples of the reversibility of targeted organ atrophy are suggested by studies that show that growth
hormone supplementation in elderly men increases their muscle mass (69). Also, the fact that two days of
fasting increased the 24 hour growth hormone production rate by 4 times in aged human subjects (70)
suggests that reversal of the aging process is linked to famine conditions. Melatonin , another antioxidant
hormone, has been shown to be increased in brain and stomach tissues of mice after as little as 48 hours
of CR (71), and is also associated with the inhibition of thymocyte apoptosis.(72). CR also leads to large
decreases of the free radical hormones FSH and LH which are proposed to drive AS#4 and AS#5 ( 73).
As will be explained, lengthy droughts and famines probably selected for organisms that could quickly
reverse the aging process if necessary. AS#5 had an advantage over AS#4, in this area, in that it could
reverse the atrophy in the fewer number of targeted organs more quickly and with possibly a smaller
expenditure of resources as compared to reversing AS#4’ s more widespread cytosine demethylation in all
cells..
Recent research has implicated an impaired DNA helicase, an impaired topoisomerase (both involved in
DNA replication and unwinding and presumably gene access as proposed earlier), as well as a defective
restriction endonuclease (an enzyme involved in DNA fragmentation) in the several diseases that appear
to be accelerated forms of AS#5B (74-76). (It is important to note that topoisomerase cleaves the DNA,
just as restriction enzymes do, to relieve DNA winding tension and thus suggests why it is involved in the
process of apoptosis and aging.)
Access to the aging genes of AS#5B is proposed to be limited by the activity of a DNA helicase that is
different from AS#4’s helicase. A separate helicase would be necessary because if evolution was in need
of hormones, it would want to make use of any metamorphic hormone throughout the organism’s life
for other duties and not just during metamorphosis. So it seems reasonable to assume that a mechanism
would evolve by which the metamorphic gene set could be cloistered from inappropriate metamorphic
signals until the appropriate time. Metamorphosis evolution likely included a new DNA helicase that
evolved from a copy of the original helicase of AS#4 that restricted access to the metamorphosis gene
set until the appropriate time. Prior to activation of this metamorphic DNA helicase, metamorphic genes
would remain hidden from hormones by residing in double-stranded DNA that was tightly wound and
untranscribable.
Several premature aging syndromes that are characterized by various forms of somatic tissue atrophy,
and sensitivity to either UV, X, or Gamma rays include Ataxia Telangiectasia (AT), Xeroderma
Pigmentosum(XP), and Cockayne Syndrome (CS). These diseases exhibit various nuclear DNA
aberrations such as crossovers, deletions, etc. Also, they are typically associated with a wide variety of
cancers. These syndromes will be examined in more detail later, and will be suggested to be caused by an
impaired DNA helicase, topoisomerase, or endonuclease malfunctions that lead to incomplete and/or
accelerated aging related apoptosis. It is interesting to note that diseases associated with mitochondrial
malfunction, which will be shown to attack the same types of tissues targeted by AS#5B, typically show
similar aberrations in the mitochondrial DNA such as deletions. So possibly, the entire theme of AS#5 (A
& B) is an attack of the DNA of targeted cells whether it is nuclear or mitochondrial.
(An interesting speculation emerges as follows: Water restriction or fasting as an effective therapy for
cancer might be anticipated. This will be due to the expectation that cancer is associated with apoptosis
that evolved with metamorphosis, and metamorphosis was modified in land animals primarily as an
adaptation to survive drought. Drought (or water restriction/fasting), then, might lead to the inhibition of
the mechanisms that drive metamorphosis, and in turn, cancer.) Now a closer look at mitochondrial
aging:
The facts used in the following discussion of mitochondrial diseases were entirely adapted from
“Mitochondrial DNA in Aging and Disease” by Douglas C. Wallace; Scientific American, August, 1997
unless otherwise noted.
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part, without the prior, express, written consent of the author. 18
There is significant evidence that mitochondrial decline is programmed to occur with age in that the
mitochondrial DNA found in normal human cells show very few mutations through the age of 40. But
after age 40, the mitochondrial DNA mutations increase exponentially. If these mutations were just a
random process, one would expect to see their accumulation occur at a constant rate, and not beginning at
40 years. Also, the onset of Huntington’s disease has long been suspected of being triggered when the
mutated Huntington’s gene located in the genomic DNA becomes demethylated and transcribed(77),
typically when the afflicted reach their 40’s (this has yet to be proven however). Huntington’s disease is
associated with higher levels of mitochondrial DNA deletions in brain cells as compared to brain cells
from non-afflicted individuals. This might suggest that there is a gene in the genomic DNA that is
sequestered through methylation until the age of 40 where changes in surrogate free radical hormone
levels lead to its demethylation and thus activation. This gene might produce a product that then slowly
attacks mDNA (or inhibits a protein that protects the mDNA) in order to cause the decline of the
organism. In Huntington’s patients, the mutated gene might cause this process to become hyperactive in
some way whereas in normal individuals it might be considered another aging symptom of AS#5A and
occur gradually.
It is interesting to note that although calorically restricted animals produce the same amount of
intracellular energy as controls(78), they accumulate less mitochondrial DNA damage. This surely adds
weight to the idea that mitochondrial aging or damage is a non-random process and seems to be under
control of the nucleus. The idea that mitochondrial aging is controlled by genes that reside in the genome
and not in the mitochondria should be testable by transplantation of nuclei from older cells into
enucleated younger cells. If the mitochondria in the younger cells then show accelerated damage, then
AS#5A would appear to be under control by the nucleus.
Finally, the demethylations triggered by AS#5 should be promoted by the hormone LH similar to FSH’s
role in AS#4. LH was found to be associated, after a Medline search, with a wide range of cancers. Also,
although AS#5 was superior to AS#4 in terms of reversibility, it still suffered the drawback of being
subject to rapid de-evolution during periods of unrestricted environments as there was no mechanism to
lock it into place for long periods.
Sex chromosomes and sex types- The ultimate aging system:
Aging System #6
Eventually an aging system emerged that had two important advantages over AS#4 or AS#5. The first
advantage allowed for the evolution of faster aging rates in response to very brief episodes of predation.
The second advantage was that the faster aging rate was locked in place after removal of the episodic
pressure from the population. This allowed a species to retain the advantage of aging for longer periods.
The new aging system that had these major advantages was sex chromosomes where the male receives a
smaller dose of X-linked genes than the female.
Why did sex types evolve? They seem to be very common, much like the phenomenon of aging itself.
However they also seem to have significant disadvantages such as the need to find a mate in order to
reproduce, and the elimination of half the population as potential mating partners. Let us try to decipher
the advantages of sex types and sex chromosomes.
Over evolutionary time frames, genes can migrate, through non-homologous crossovers, to reside on
whatever chromosome provides the most advantage to the species. Since the X and the Y chromosomes
are the most unique, they must be scrutinized with this in mind. Possibly whatever traits needed to rapidly
evolve back and forth between phenotypes depending on changes in the environment, or traits that were
important for inter-species competition and needed to evolve rapidly would best be maintained on the X
chromosome. Because males receive a pure dose of one gene on the X, it allows for more rapid and
accurate selection of single genes than if the male had two genes that might mask each other as they do in
the female. This suggests that selection for most sex-linked genes occurs mainly in the male, and that the
male is the experimental testing ground for environmental conditions. (Additional weight is given to this
idea in that females, in many species, spend a significant portion of their lives protected from the
environment while they are rearing their young.) This situation is logical given that a single male could
repopulate a large portion of a species with his unlimited ability to produce sperm after his pure X
-linked phenotype has been selected. If all but one male were wiped out by environmental selection, and
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only one male was left with the appropriate X-linked genes for survival, these genes could quickly
saturate the population.
The main advantage to sex chromosomes described so far is that gene pool changes are accelerated by
several generations. However, considering the disadvantages of sex types, it is likely that evolution would
never have created sex chromosomes and sex types unless there was some other truly compelling
advantage to them. Sex chromosomes likely evolved to impose a more rapid and long-lasting change in
the rate of aging in the population when the population was exposed to brief episodes of periodic
selection pressure.
Sex chromosomes and sex types evolve as an aging system.
A mechanism allowing for predator-induced acceleration of the aging rate should be a valuable trait in a
prey species. What would be optimal would be a selection mechanism that selected for a faster aging rate
in a ratchet like manner. Easy to select for, but much harder to select against. So, when faced with just a
brief period of predation the rate of aging (or rate of genetic drift) of the prey species will be quickly
accelerated and will remain in this accelerated state for long periods of time. When this occurs, with a
faster turnover rate in the population, it will only require a few intermittent encounters with a predator
that is to come in full force later to cause the population to drift to homozygosity for an important
defensive adaptation.
Sex chromosomes act as a ratchet where selection for more rapid aging occurs in the male, which can
happen quickly through exposure to the environment, and then is undone in the female, which will
happen slowly on the X chromosome-in a two-gene/masked autosomal fashion. How do these types of
selection happen?
Consider if:
-Maximum life span is tied to the maximum reproductive life span (menopause), and to the age of
reaching puberty through the Werner’s DNA helicase, and
-The number of females is what limits the population of a species,
then in order for the species to acquire genes for longevity , they likely must be selected for in the
female. This would happen through the natural drift towards longevity, where the older the age at which
the female can reproduce, the more offspring she can have that carry her longer-life span genes.
Randomly-generated life span-increasing mutations (or just reversal of deleterious mutations) that are
expressed in the female genome will gradually accumulate in the population upon removal of the
predator. This will occur slowly, however, as waiting for the selection and spread in a pseudo-autosomal
manner through a population of either a single dominant mutation or two double-recessive mutations in
both X chromosomes in the female’s X-mosaic phenotype should take a reasonably long time. The rate
at which this would occur would most likely be the same rate that autosomal mutations occur and are
selected for by evolution. This slow-changing female trait would be much different than the male’s single
X chromosome. This is because:
-In the male, phenotype changes can be caused by just a single mutation of any kind (recessive or
dominant) because all genes on the male’s single X chromosome are the only copies of a gene that he has,
and are expressed as if they were dominant.
-Also in the male, selection for a positive mutation (one that enhances his reproductive potential in a
predatory environment) will occur rapidly in the environment as the predator would quickly cull the less
fit males who lacked the required positive mutation for survival to mating age.
In addition to the ability to outrun predators mentioned earlier, a positive mutation that could enhance a
male’s reproductive potential in a predatory environment where he is likely to die young, is the ability to
reproduce at an earlier age than other males. Also, among males, selection can be extreme without
consequence to the reproductive potential of the population as a single male could repopulate the whole
species with his more fit, single, X-linked gene. This contrasts sharply with the females’ limited
reproductive capacity.
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An earlier age of reaching fertility would increase reproductive fitness in males in the face of early death
imposed by predation . This accelerated fertility program is proposed to be linked to an accelerated
development program and probably occurs through the simple acceleration of the lifetime hormone
patterns. Altering the accelerated development program so that it affected only age of fertility and not
other variables like maximum life span is likely not possible in the short run if these traits are tied
together by a single DNA helicase. This, in turn, means not only will the more fit male and his offspring
become fertile sooner, it will also cause them to age faster as well. Also, this implies that subsequently-
born females should reach menopause and maximum life span more quickly as the gene spreads
through the population, and if the altered gene simply affects hormone levels and patterns, litter sizes
could be increased as well. Is there any evidence that this occurs in nature? A recent study showed that
when guppies, that previously had not encountered predation in the wild , were then subjected to
predation for five years, reached fertility at an earlier age and also showed a shortened life span. (79)
Body size becomes linked to maximum life span.
One other aspect of the accelerated development program might be a change in the size of the species
subject to predation. If cells can divide during development at only a certain maximum rate that is fixed in
the evolutionary short-run, and development is completed by an earlier age, it seems reasonable that
cessation of growth of the individual would be linked to sexual maturation. This would lead to smaller
individuals. It is interesting to note that body size (if birds, bats, humans, some reptiles, and a few other
animals are excluded) is roughly correlated with maximum life span in most animals. One only needs to
consider the maximum life spans of typical mice (3 years), dogs (15 years), and horses (40-50 years) to
see the relationship. Reduced body size could also be an effective defense against predation just as
accelerated aging is. Instead of one large target that provides more food per kill, smaller individuals
provide many smaller targets that provide less food per kill. As this line of reasoning would predict, in
the guppy study previously mentioned, the size of the guppies decreased as their rate of aging increased .
Methylation status of the genome and rate of aging:
Hormones are known to drive pubertal and sexual changes in humans, but are not generally thought of as
a cause of aging. Hormones are seen at work causing rapid aging in many types of animals and often
affect the sexes unequally. The most dramatic examples include the Pacific salmon that grows old and
dies several days after reproduction, but where the male lives up to three additional years if castrated (80).
Similar observations have been noted for some species of octopus (81) as well as some mice (82). In the
case of male salmon and mice, rapid death appears to be triggered by a testicular controlled rise in
corticosteroid levels which leads to lowered immunoglobin levels and increased susceptibility to
infection. (Studies referenced later show that glucocorticoids can trigger apoptosis in thymus cells. The
thymus is known as the seat of immunity in many organisms.) Annual flowering plants also age and die
rapidly after reproduction is complete.
The methylation of cytosine in the genome varies greatly among species from apparent nonexistence to
substantial proportions (83). Various estimates suggest that 1% (84) of the human genome, and up to
25% of the genome in higher (flowering) plants is methylated (85). It might be posited that the same
number of genes that are methylated are also involved in aging and development. A relationship might
exist where the higher the level of methylation in a species’ genome, the faster the members of the
species need to develop, age and die in order to retain the evolutionary advantage conferred to them by
an accelerated aging program.
The Werner’s DNA helicase links the timing of expression of genes that control puberty, menopause,
and maximum life span in humans.
What is the link between puberty and aging under this system? Later, a disease known as Werner’s
Syndrome that leads to accelerated aging symptoms that appear at around age 20, but is expected by the
author to actually begin around the time that an individual begins puberty will be examined. It will be
proposed that, like Progeria and its defective DNA helicase (proposed herein to time childhood
development), Werner’s syndrome is the result of a defective DNA helicase proposed to time pubertal
development. This DNA helicase’s main function, in its normal state, is proposed herein to be to allow
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part, without the prior, express, written consent of the author. 21
access by certain hormones to various genetic sites that control the initiation and completion of pubertal
development as well as menopause, aging and maximum life span. It appears that while the DNA
helicase likely continually exposes the developmental and aging genes through strand separation, the
pattern and level of hormone changes are the ultimate determiners of the pace of development and aging.
The Werner’s DNA helicase probably evolved from a copy of the parthenogenetic/metamorphic DNA
helicase of AS#5. Originally, the Werner’s helicase probably controlled metamorphosis into a sexually, as
opposed to a parthenogenetically reproducing organism. While still retaining its functions in sexual
metamorphosis, this helicase also expanded its role to control the aging process as well. Eventually it
became the dominant aging system by allowing access to the aging genes of AS #4, AS#5 as well as
adding some new aging symptoms of its own. Such tinkering should be more adaptive than the time-
consuming process of de novo creation of new aging systems given survival likely depended on rapid
evolution. Finally, as FSH is expected to promote AS#4, and LH AS#5, estrogen should be found to
induce the aging specific to AS#6. (Declines in antioxidant hormones such as testosterone, DHEA, and
GH could also be considered as driving the aging process, but the huge increases of FSH, LH and to a
lesser extent estrogen appear to represent the more aggressive assault towards genomic demethylation and
the author suggests that by convention they should be the primary hormones associated with the aging
systems that they demethylate).
Changes in genomic methylation status due to long-term changes in sex hormone levels lead to
hormone dependent apoptosis and cancer
At first glance, one sees that almost all of the aging symptoms that are seen in Werner’s disease such as
atherosclerosis , somatic atrophy and somatic cancers in reality belong to AS#4 and AS#5. Thus, it can
be surmised that the Werner’s DNA helicase is merely allowing access to these genes. In fact, it appears
that AS#6 may not have any unique aging symptoms and that its sole function is to act as a ratchet.
Maybe this was how evolution originally created AS#6, but we can now see in addition to the non-lethal
atrophy of the sexual tissues such as breast, uterus, vagina, ovaries, and prostate a few deleterious
mutations are beginning to accumulate in this aging system which consist of various atrophy/apoptosis
malfunctions that lead to cancers of these various tissues as well as hypertrophy of the prostate.
In AS#6, apoptotic atrophy of the female’s reproductive tissues is the expected primary goal. Breast
atrophy is common in post-menopausal women and is referred to by some as the “empty breast” because
the mammary tissue becomes replaced with fat after menopause (86). Also urogenital atrophy in females
is reported to be common (87). However, testicular atrophy with age in human males may not be normal.
Although studies are few, one study of deceased men over age 40 found that testicular weight showed no
clear association with age (88). It is common knowledge that there is a high incidence of breast, ovarian,
and uterine cancer in females near and after the time of menopause. Cancer, and hypertrophy of the
prostate is also seen in the male around these ages. Given that inhibiting reproduction in the female is all
that would be necessary to mimic the evolutionary effects of a bygone predator on population control, it
would be expected that evolution would mount a more determined assault against the female’s
reproductive equipment as compared to the male’s. In fact, statistics indicate that 30% of female cancer
deaths, while only 11% of male cancer deaths, occur from cancer of the reproductive tissues (89). Also in
Werner’s Syndrome, where cancers of the female reproductive tissues are somewhat common ,
presumably there has only been one reported case of prostate cancer in male Werner’s patients (90). Quite
possibly, however, Werner’s Syndrome actually shows the effects of aging as it originally evolved,
prostate atrophy without cancer. While Werner’s prostate cancers are quite rare, prostatic hypertrophy is
a bit more common while quite a few cases of prostate atrophy have been noted (91).
How might AS#6 initiate apoptosis in the female tissues? If hormone levels are examined in the human
female as she approaches and goes through menopause, the circulating level of estradiol is seen to climb
from about 100 pg./mL at around 30 years of age to 130 pg./mL by age 50. It is around this time that the
large increase in the incidence of cancers and atrophy of the female reproductive tissues begins. The
estradiol level then crashes at the completion of menopause to about 75 pg./mL on average by age 50 and
continues declining until stabilizing at a low level at around the age of 60 (92). Some researchers have
found that menopausal women eventually show a 90% reduction in the estradiol blood concentration when
compared to women in their reproductive years (93). Some estimates of normal , post-menopausal
estradiol levels are as low as 15 pg/mL (94). Possibly the pre-menopausal surge in estradiol is designed to
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part, without the prior, express, written consent of the author. 22
induce apoptosis by washing away methyl protection while simultaneously stimulating the cell doubling
mechanisms required for apoptosis. The subsequent crash in estrogen levels would then prevent the
stimulation of mitosis that might rejuvenate these organs.
(Unlike most other hormones that are thought to signal the outer receptors of the cell, the two sex
hormones, estrogen and testosterone, are taken directly into the cell’s nucleus where the DNA resides.
Several studies have shown that there is a great deal of free radical damage that occurs in the tissues
where prostate cancer occurs. According to one researcher, it appears that estrogen causes the free radical
damage in cancerous prostate cells. (95). This gives additional support to the idea that estrogen is a free
radical hormone. )
Reversibility of aging in the reproductive tissues:
Earlier it was suggested that the effects of famine on AS#5 lead to rejuvenation of the thymus and muscles
through hormonal alterations. Likewise AS#6 should provide for famine-induced rejuvenation of female
reproductive ability. Cases of reproductive rejuvenation have been noted in rats. A compound which is
produced by the pineal gland (which is the same gland that produces melatonin) called epithalamin was
reported to restore fertility and allow reproduction by elderly female rats aged 16-18 months (or about 60-
70 in human years) (96) . Also deprenyl, an antioxidant, has been shown to reinitiate estrus in old acyclic
rats (97). It is expected that either of these compounds works by altering the level of other hormones
involved in controlling female fertility rather than acting directly. This should be true as reproductive
rejuvenation is likely to be too complex a process for a single hormone to directly control.
Why declining female fertility and litter size with age? Why menopause instead of death?
One thing that does not make sense so far in this theory is why do females of almost all species experience
decreased fertility and reduced litter sizes with age? If death from aging is advantageous for species
survival one would expect instantaneous death once a certain age was reached. However, the advantage of
a declining litter size is that it also acts like a ratchet, preventing existing aging systems from being lost
too quickly. Older females that are able to reproduce past the normal age of menopause are prevented
from making a large contribution to the gene pool, as even though their reproductive lives are longer than
most other females’, the declining litter size slows down the rate that their genes will crowd out the faster-
aging genes of other females. Thus the advantage of aging will be retained in the population for longer
periods. Menopause in humans is really just the ultimate decline in litter size, from 1 to 0.
One should then ask how maximum human life span can so greatly exceed the age of menopause? This
suggests that in our evolutionary past, as some sort of organism, we at one point evolved maximum
reproductive life spans (or experienced the ultimate drift to longevity) where menopause and maximum
life span coincided. After this occurrence in time, predation was subsequently encountered that ratcheted
the age of female menopause down to about the 40% of maximum life span seen today. In the absence of
predation, eventually the age of menopause and maximum life span should reach unity as it has in the
Fulmar, an isolated bird that shows no signs of aging or decline in reproductive function prior to its death.
The Fulmar is discussed later.
Interaction and Co-opting Between the Aging Systems:
As we shall see, AS#6 triggers all the symptoms of aging of AS#4 and AS#5 and also has some unique
aging symptoms of its own which include female sex organ atrophy and cancer, prostate atrophy, cancer
and BPH and possibly depression. It likely co-opts the other aging systems simply by being driven by a
DNA helicase that allows access to all of the aging genes of these systems. The hormones FSH, LH, and
estrogen probably act only on each of their unique set of aging genes or else high levels of estrogen would
be detrimental, rather than beneficial to post-menopausal women; more on this later. AS#6 also
apparently co-opts AS#1 as discussed before. Suggestive of this is that Werner’s syndrome has been
associated with defective telomere maintenance (98). (This might also, however, be due to excessive
crossovers in the telomere regions allowed by the loosely wound DNA found in Werner’s. This would lead
to satellites of telomeric DNA and shortened chromosomal telomeres. The expected loss of 5mC
methylation caused by this disease might also make crossovers more likely through loss of restriction
site protection.)
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part, without the prior, express, written consent of the author. 23
AS#5 co-opted (or revived) parts of AS#2 (mitochondrial aging) as AS#5A. Likewise, AS#4 likely, co-
opted almost all of AS#3’s mutation accumulation genes by methylating them and postponing their
transcription. Possibly AS#4 also co-opts AS#1 through a telomerase inhibition gene, but currently there
is no evidence supporting this speculation. It may even be possible that in some tissues, AS#1 is co-opted
by AS#5 as well.
The most recently evolved aging system (AS#6), is likely to be dominant and be the first system to impose
what in some respects is the evolutionary equivalent of death on the organism before the other systems
do. Death and menopause are somewhat equivalent in an evolutionary sense as far as reproduction are
concerned, but the female still lives and slows the genetic drift in finite populations by consuming food
that could be consumed by juveniles. So sex may have evolved merely as an aging related mechanism as
opposed to an aging system. However, once deadly mutations started accumulating within the domain of
this aging mechanism, it became an actual aging system as well. Evolution of new aging systems,
however, was not likely an overnight process. Co-opting of the previously existing aging systems may
have occurred by a newly evolved mechanism and may not have included new, unique, aging symptoms
initially . Deleterious mutations could accumulate in the new aging mechanism over time. This line of
reasoning may, in turn, explain the seemingly increasing lethality of the aging systems. AS#6 (menopause
with a small incidence of cancer) seems to be much less lethal and more survivable than the somatic
atrophy of AS#5 which includes somatic cancer, diabetes, and Alzheimer’s disease, while AS#4 which
includes heart attack and stroke appears to be the most lethal. And of course, it is likely that no one has
ever escaped AS#1 which, as suggested, may be what limits the maximum human life span to 120 years.
If all six aging systems are active in an individual, it would be expected that AS#6, the dominant system,
would be the most exact and thorough, and thus we see menopause occurring in all women in a
reasonably tight age bracket. From evolution’s perspective, in an unrestrictive environment, there should
be no difference if AS#6 culls through the death of the female, or through menopause. There is, however,
a slight disadvantage if the female dies in that it would reduce the pool of potential rejuvenated survivors
of a famine or a drought. Also, a female who has survived to the age of menopause, likely has developed
exceptional survival skills or knowledge that might increase her survival prospects as compared to
younger individuals in a period of severe environmental stress. The evolutionary selection pressure to
keep the post-menopausal female alive was probably weak and sporadic. Because of this, some human
females may die from the effects of AS#6, while others survive. If a female survives AS#6 then AS#5
likely becomes the next hurdle. Somatic tissue cancers, and immune dysfunction from thymic atrophy
would seem to be the biggest threats of this aging system. Additionally, atrophy of the muscles, brain,
nerves, and skin would begin. Surviving AS#5 leads to AS#4 where the risk of heart attacks and stroke
are the major killers. In actuality, all three of the aging systems would be at work and it is simply a race to
see which system causes death first. If these aging systems are survived, then another hurdle is
encountered.
Because AS#2 is likely to be almost fully co-opted by AS#5 and AS#3 by AS#4 respectively, they
probably no longer play much of a role by themselves. However, with AS#3, mutation accumulation, there
may be some very late acting deleterious genes (LAD genes) that had accumulated but were never co-
opted by AS#4’s helicase and they would become active so late in life that they never affected
reproductive fitness and therefore were not co-opted into AS#4. If a species had not been allowed to drift
towards longevity long enough, a few “loose cannons” may be waiting in the genomes of individuals that
make it past aging systems #4 through #6. Individuals that reach this point should have successfully
avoided succumbing to the mortality curve law which implies that every day of living leads to a greater
chance of dying. If AS#4-AS#6 are survived, the stray, very late-acting, unco-opted, LAD genes should
be encountered. At this point, if the ages of activation of these LAD genes is skewed to the left (with age
of onset being the x-axis), the longer one lived, the longer one would be expected to live. There would be
many hurdles closely bunched in the first part of this aging process, but later the hurdles would be fewer
and further between. Why the variance in the prevalence of these LAD genes?
Genetic drift would be less likely to have lead to homozygosity in this gene set in the population because
these genes were likely never or rarely expressed and therefore the genetic drift could not be pushed in a
particular direction. So there is likely a broader distribution of these LAD with some members of the
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part, without the prior, express, written consent of the author. 24
population having none of the LAD genes at all. (In human terms, these would be the people who live to
the age of approximately 120 years.)
Is there any experimental evidence to support this reasoning? Studies have shown that after fruit flies
reach a certain old age, the Gompertz equation (mortality curve law) no longer holds and that their
chance of dying each day does not increase as the fly gets older; rather, their chance of living longer
actually increases (99). The most elderly flies would be likely succumbing to the expression of either LAD
genes (AS#3) or possibly telomere shortening (AS#1). Which aging system sets the maximum life span
in humans? This question might be answered by measuring the methylation content and the length of the
telomeres of different cell types taken from the very old. Now that an idea as to how the different aging
systems might act together in an individual has been established , how longevity evolves over time needs
to be considered.
If a population was not subject to predators, or other periodic risks for long periods, then evolution
should initially select against AS#6 until the age of menopause increased to synchronize with AS#5’s
expected age of dying. AS#5 and AS#6’s synchronized ages of death would continue increasing until they
encountered AS#4’s age of death. AS#4-AS#6 times of death would then lengthen to synchronize with
AS#3’s and so on until only AS#1 was left, or AS#1-AS#6 were all timed to kill simultaneously.
An interesting example of a species that has probably lost all its aging systems other than telomere
shortening has been observed: There is a bird called the Fulmar that inhabits, for brief times, an isolated
island off of the coast of Scotland that exhibits none of the classical signs of aging, and eventually it
simply expires at the age of about 50 years (100). When it is not on the island it lives on the open sea. Its
defenses to predation include both flight and extreme isolation which has likely resulted in a very long
period of the natural drift to longevity. As would be expected in this case, this bird does not have a
cessation of fertility until death.
Examination of mitochondria-related diseases, Progeria, a group of three progeroid syndromes, and
Werner’s Syndrome reveal specific symptoms of aging systems #4, # 5, and #6.
The six aging systems can all interact to create some very interesting and confusing aging syndromes:
such as Progeria and Werner’s syndromes which have been reported to not be true forms of premature
aging only because they purportedly don’t show all the components of all the systems of aging (101).
This assumption, however, appears to be incorrect. Progeria should be shown to be an acceleration of
AS#4 and Werner’s Syndrome an acceleration of AS#6 which shows all of the symptoms of aging.
The symptoms of Progeria are commonly known to include among other things, atherosclerosis, alopecia,
and gray hair (102). Although Progeria patients typically die at age 12, what is not commonly known is
that some older-living Progeria patients (age 20+) also develop hypertension (103). This is interesting in
that all these aging symptoms are commonly seen in men at earlier ages and higher rates than seen in
women ( (i.e. 104),. Also, a number of studies have shown that some of these symptoms of aging such as
gray hair, alopecia, and heart disease are also linked in the normal process of aging. (105)
AS#5 can be seen in the three progeroid syndromes of Ataxia Telangiectasia, Cockayne Syndrome, and
Xeroderma Pigmentosum which are proposed to be accelerated versions of various portions of AS#5B.
The mitochondrial diseases of CPEO, Dystonia, Leigh’s Syndrome, LHON, MELAS, MERRF,
mitochondrial myopathy, and NARP are proposed herein to be accelerated versions of AS#5A. In the
majority of the accelerated aging diseases of AS#5A+5B, the targeted tissues include the muscles, brain,
and nerves. Although the damage to the individual is caused by apoptosis in the case of AS#5B, and
mitochondrial malfunction in AS #5A, it is interesting that the same types of tissue are targeted, and that
hypothetically the damage in both cases could logically be caused by an attack ( or cessation of protection
from attack) of DNA by restriction enzymes. We will also make the case that the aging symptoms of
AS#5 include all the diseases that can be considered to constitute an attack on somatic tissues such as
osteoporosis, cataracts, arthritis, Alzheimer’s, and diabetes. This is possible because in addition to their
regularly known symptoms of muscle wasting, thymic atrophy, and somatic cancers in AT, poor healing,
skin ulcers, scaly skin, and somatic cancers in XP, and basal ganglion calcification in CS, as well as a
neuronal degeneration and brain atrophy in all three syndromes, these syndromes also lead to higher
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part, without the prior, express, written consent of the author. 25
incidences of other diseases. CS patients often display cataracts (106), osteoporosis (107), and lipofuscin
accumulation (108). XP patients often also display lipofuscin accumulation(109). AT patients often also
display a high incidence of diabetes (110), and arthritis (111). Finally, there have been cases reported of
Alzheimer’s developing in XP patients (112). Also, cells from patients with Alzheimer’s disease show
very striking similarity in their response to UV and IR exposure, and share complementation groups with
XP, and AT as well as with Down’s Syndrome which is also associated with premature aging (113, 114).
The reason Alzheimer’s disease might not be seen more often in these syndromes will be addressed later.
Finally, it is very interesting to note that most of the diseases of AS#5 are seen at a higher rate in women
than in men. This is likely due to women’s LH levels (as a group) increasing to a much higher level than
men’s from their respective, age 40, baseline levels on a percentage basis.
Why Alzheimer’s Disease and hypertension are so rare in the rapid aging syndromes.
One question that arises is why hypertension is so rarely seen in Progeria, and Alzheimer’s so rarely
seen in the accelerated aging diseases of AS#5. This also leads to the question of why these diseases are
also rarely seen in Werner’s Syndrome which is supposed to show all the aging symptoms of AS#4 and
AS#5. It is the dearth of the incidence of these two diseases in rapid aging syndromes that has led many
gerontologists to assume that Alzheimer’s disease and hypertension are never seen in Progeria or
Werner’s Syndrome (115). This, in turn, is used as a major rationale as for why Progeria and Werner’s
Syndrome are considered to not be true forms of accelerated aging.
Before we attempt to explain the question above, the record needs to be set straight. Amyloid plaques
which may be indicative of Alzheimer’s have been seen in Werner’s patients (116), as well as
hypertension (117). And as mentioned before, hypertension has been seen in exceptionally old Progeria
patients.
It seems that the two diseases are appearing in these syndromes, but at much later ages than would be
expected based on the acceleration of the other symptoms of aging. What does this suggest? That the DNA
helicases that allow access to the aging and development genes are also participating in DNA replication
for cell division. This implies that Alzheimer’s and hypertension are being caused by genes located in
purportedly non-dividing cells such as the neurons of the brain. Dividing tissues will show the effects of
the defective helicase much more so than non-dividing cells. Genomes of dividing cells are being
demethylated both during mitosis and during developmental and aging gene access while the non-
dividing brain cells are exposed to the defective helicase much less frequently only during aging gene
access. This, in turn, can explain why the symptoms of aging may appear to be abnormal in Werner’s and
Progeria. The differences in the rate of cell division between tissue types will create unsynchronized rates
of aging amongst the tissues. So, the skin of a 50 year old Werner’s patient may in effect be similar to
that of someone who had reached the age of 200, while the brain will have aged like a 70 year old’s.
The other possibility that could explain the above phenomenon is that development and aging are
dependent on cell division; one cannot occur without the other. If this is true, then it suggests that brain
cells are dividing in vivo, but simply at an imperceptibly slow rate. This question might be settled by
measuring and comparing the lengths of telomeres and/or methylation status of brain neurons from the
very young and very old. I t certainly would lead to an elegant result and would simplify and merge many
aspects of this theory, however, if aging required cell division for its occurrence.
A table of aging systems and symptoms:
Aging that is linked to AS#6 which seems to have co-opted all the prior aging systems should include all
of the symptoms seen in AS#1-#5 and should also include the newly evolved aging symptoms of sex-
related cancers, sexual tissue atrophy, menopause, and possibly depression. Whatever symptoms that are
seen in Progeria belong to Aging System #4. AS#4’s symptoms are not seen in the three progeroid
syndromes CS, XP and AT and mitochondrial diseases associated with AS#5. A table makes this easier to
visualize.
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part, without the prior, express, written consent of the author. 26
Aging System #4 Senescent
Gene Expression: FSH/DHT
driven, seen in men at higher
rate. (co-opts #3) (and #1?)
Aging System #5A Somatic
atrophy: Mitochondrial
Apoptosis, LH/hCG driven, seen
in women at a higher rate
(co-opts #2)
Aging System #5B Somatic
atrophy: nDNA Fragmentation
Apoptosis, LH/hCG driven, seen
in women at a higher rate
Aging System # 6 Sex tissue
atrophy:
estrogen/DHT driven, seen in
women at higher rate (co-opts
#4, #5, (and #1))
Progeria only. Defective DNA
helicase type #1.
Mitochondrial Myopathy (MM),
NARP (N), CPEO (CP),
MELAS (ME), MERRF (MR) ,
KSS (K), Dystonia (D), Leigh’s
Syndrome (LS)
Ataxia Telangiectasia (AT),
Xeroderma Pigmentosum (XP),
Cockayne Syndrome (CS).
Defective DNA helicase type
#2.
Werner’s Syndrome. (WS),
Bloom’s Syndrome (BS),
Defective DNA helicase type #3.
Original to #4 alone (likely
defects of development)
Coxa Valga & necrosis of head
of femur
Dysplastic osteoporosis
Symptoms of #4 co-opted by #6 Symptoms of #6 co-opted from
#4
Atherosclerosis Atherosclerosis-WS
Hypertension Hypertension-WS
Gray Hair Gray Hair-WS
Alopecia Alopecia-WS
Calcification of Heart Valves Calc. of Heart Valves-WS
Laryngeal Atrophy Laryngeal Atrophy-WS
Loss of subcutaneous tissue Loss of subcut. tissue-WS
Hypermelanosis of Skin Hypermelanosis of Skin-WS
Hypogonadism (defect of
development?)
Hypogonadism -AT, XP Hypogonadism -WS, BS
Symptoms of #5A also seen in
#5B and co-opted by #6
Symptoms of #5B also seen in
#5A and co-opted by #6
Symptoms of #6 co-opted from
#5A and #5B
Muscle Wasting-MM, N Muscle Wasting-AT Muscle Wasting-WS
Neuronal Degeneration/Brain
Atrophy-CP, ME, MR, K
Neuronal Degeneration/Brain
Atrophy -AT, XT
Neuronal Degeneration, Brain
Atrophy -WS
Basal Ganglion Calcification -
D, LS
Basal Ganglion Calcification -
CS
Basal Ganglion Calcification
-WS
Cataracts-K Cataracts-CS Cataracts-WS
Diabetes-K Diabetes-AT Diabetes-BS, WS
Alzheimer’s Disease-
mitochondrial induced
Alzheimer’s Disease-XP Alzheimer’s Disease-WS
Symptoms of #5B co-opted by
#6
Symptoms of #6 co-opted from
#5B
Poor Healing -XP Poor Healing -WS
Skin Ulcers -XP Skin Ulcers -WS
Thymic Atrophy-AT Thymic Atrophy-BS, WS
Scaly Skin-XP Scaly Skin-WS
Somatic Cancers-XP,AT Somatic Cancers- BS, WS
Lipofuscin Accumulation-
CS,XP
Lipofuscin Accumulation-WS
Arthritis-AT Arthritis-WS
Peripheral Osteoporosis-CS Peripheral Osteoporosis-WS
Symptoms unique to #6
Menopause-WS
Breast, Uterine, and Ovarian
atrophy and cancer-WS
Prostate atrophy-WS,
hyperplasia-WS, and cancer-WS
Depression-WS?
Let us now take a closer look at the aging syndromes from the table and try to decipher what mechanisms
may be at work. Progeria and Werner’s Syndrome are a good starting point. Both of these syndromes have
similar , unusual, cell types. The cells in these syndromes show chromosome instability, non-
homologous crossovers, and a high presence of oxidized proteins (118). (Bloom’s syndrome is caused by a
defect in a helicase almost identical to Werner’s and seems to be a milder version of Werner’s syndrome
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part, without the prior, express, written consent of the author. 27
causing similar but a fewer number of aging symptoms than Werner’s so it will not be addressed
separately.) The gene responsible for Progeria has been discovered to be a mutated version of a DNA
helicase, and a third RecQ type of DNA helicase is defective in XP, and CS (119). One version of AT,
however, has been linked to a defective topoisomerase (120) that is also involved in unwinding as well as
cleaving the DNA; this topoisomerase likely associates with the normal XP / CS RecQ helicase’s
replisome during its unwinding function (121). (Other forms of AT involve UV damage repair defects
such as defective endonucleases.) DNA helicase’s primary function is thought to be to unwind the DNA
for synthesizing new strands of DNA or transcriptional purposes. However, in this theory of aging, it
appears that one of its major roles may be to unwind DNA simply to allow, or cause, cytosines to be
methylated or demethylated. If this is true, demethylation could be either inhibited or reversed by
antioxidant hormones, and accelerated by free radical hormones that are influencing the cell. The
methylation status of a gene thus would determine whether it is transcribed for purposes of
development and/or aging as proposed for AS#4. Additionally, the methylation status of various
stretches of DNA would determine the cell’s vulnerability to attack from restriction enzymes or
endonucleases as proposed for AS#5 and AS#6. Thus, if the DNA helicase is defective and is leading in
some manner to the rapid demethylation of the genomic 5mC, the accelerated expression of aging genes
and/or loss of protection of apoptotic restriction sites could be leading to the rapid aging seen in these
syndromes.
Cytosine methylation protects DNA restriction sites. In addition to promoting apoptosis and SGE , a loss
of methylation should lead to easier and more frequent cleavage of the DNA. Reduced methylation could
then explain the excess of extra crossovers, deletions, seen in the cells of Werner’s, Progeria, CS, XP,
and AT patients if these changes depend on DNA cleavage. If this is true then the same type of
chromosomal aberrations should also be seen in normal, but senescent cells (due to their expected lower
level of cytosine methylation). One study did indeed find higher levels of chromosomal rearrangements
in older cells (122).
Oxidized proteins in Werner’s Syndrome and Progeria implicate DNA helicase as intracellular
source of free radicals.
Is there any evidence that the DNA helicases are generating free radicals? Oxidized proteins have been
detected in the cytoplasm of cells from patients with both Progeria and Werner’s Syndrome (123). If we
know that a DNA helicase is the culprit in Progeria and Werner’s, then it is not a great leap to guess that
the DNA helicase, as it operates, generates free radicals that migrate from the nucleus into the cytoplasm
and cause free radical damage to proteins.
Evidence exists that suggests that this idea is correct when viewed in an evolutionary context:
A DNA helicase protein that is produced by simian virus 40 has been reported to unwind DNA at the
expense of ATP. This helicase can also act to separate RNA strands (acting as an RNA helicase), but this
occurs outside of the nucleus, in the cytoplasm. The report states that “surprisingly”, while acting as an
RNA helicase, the only cofactors it will work with are UTP, CTP, or GTP. ATP is not utilized during the
RNA helicase function. (124). How does this support the hypothesis? Remember that earlier, the cAMP
signaling pathway was implicated as being associated with the free radical surrogate hormones. One
would guess that it is the cAMP pathway that generates free radicals. From this point, it can be suggested
that adenosine in its various forms, is associated with free radical production. It could be expected that
when ATP is converted into cAMP, ADP, or AMP that free radical activity is generated. It is not likely
that evolution would allow free radicals to circulate in the cytoplasm haphazardly, so it would not likely
allow adenosine, in the form of ATP, to be a cofactor for the RNA helicase, as the RNA helicase function
occurs outside of the nucleus in the cytoplasm where free radicals would cause unnecessary damage.
However, given that the DNA helicase requires free radicals to perform its signaling/demethylating
function in the nucleus, then the use of ATP for powering the DNA helicase can be understood.
More on DNA helicase:
Researchers have noted that single-stranded DNA’s cytosines are deaminated to uracils about 140 times
faster than those of double-stranded DNA (125). Given this, it seems likely that cytosines would also be
demethylated (or remethylated) at a much faster rate when the DNA is unwound by DNA helicase as
compared to when DNA is tightly wound in a double-stranded configuration. In a cell with normal DNA
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part, without the prior, express, written consent of the author. 28
helicase and replisome function, it would seem likely that when it was time for the development program
to be activated, the helicase/replisome would unwind certain areas of DNA so that genes located in these
areas could be influenced by hormonal signals.
The logic of this theory suggests that Progeria is a disease where there would be a rapid demethylation of
the genome, and therefore, rapid aging. The same should be true for Werner’s syndrome as well, which is
also caused by a defective DNA helicase. Progeria victims usually die around 12 years of age, just when
puberty is beginning, but some live much longer. If Progeria victims’ cells were examined at this point, it
would be likely that most genes related to AS#4 should be completely demethylated.
Werner’s Syndrome likely begins at the age when puberty begins which is basically the point where the
defective Progeria DNA helicase would have finished its developmental demethylating activities in
normal individuals. Given that AS #6 co-opts AS #4 and AS#5, it would be expected that when Werner’s
patients reach the end of their lives, which is usually around 50 years of age, that virtually their entire
genome should be demethylated. Whatever methylated cytosines remain, could probably be considered to
not be involved in the aging or development processes or could be considered un-coopted LAD genes.
Also, by comparing the methylation pattern between Progeria, the three progeroid syndromes AT, XP, and
CS, and Werner’s cells in the oldest living individuals with these syndromes, the different gene sites
involved in aging could be identified and assigned to their proper aging systems. This theory predicts that
only partial demethylation of the genome would occur in Progeria patient’s cells while almost full
demethylation would have occurred in the cells of Werner’s patients. This would be true if Progeria cells
should retain the doubling capacity associated with the methylated gene sites of AS#5 and AS#6 that
were untouched by the DNA helicase of AS#4. While on the other hand, Werner’s cells would show very
little doubling capacity as all the sites related to Aging Systems #4 through #6 would have been
demethylated. By using the cell doubling capacity as a proxy for methylation status we can test this
hypothesis: The experimental evidence upholds the predictions of this theory in that in vitro cell doubling
capacity of Werner’s syndrome fibroblasts is about 10 to 20 divisions, while fibroblasts from Progeria
patients can divide from 20 to 60 times and cells from controls about 60 to 90 times (126).
Caloric restriction: the aging program override?
Although aging serves a very important purpose in the long term battle between predators and prey, in the
short run, there are times where it would be extremely disadvantageous to a species for the process to
occur. Times when the aging program should be overridden would be during famine or drought. It would
be during these times that predation becomes secondary to whether the species survives or not. The
primary concern would be for some members of the population to survive the famine or drought and to be
reproductively fertile when prosperity returns. So the logical response would be to curtail reproduction
and delay or reverse reproductive senescence during these periods. Curtailed reproduction leads to fewer
mouths chasing a dwindling food or water supply which increases the chances of survival for the few.
Delayed aging leads to members of the species being physiologically young enough to reproduce when
the famine or drought abates.
What happens during food deprivation? Caloric restriction (CR) has been studied extensively, and one of
the obvious results of reduced food intake is a decrease in body size. The decrease occurs primarily in
various nonessential soft tissues, but other tissues (i.e. eyes, bone, brain, etc.) remain the same size. How
is the shrinkage occurring? There are two possibilities. The first is that the organism retains the same
number of cells and the cells are becoming smaller, or secondly, a large number of cells are being
destroyed through the process of apoptosis. After a review of the literature, many studies indicate that
much of the somatic shrinkage is occurring through apoptosis (i.e. 127) and that CR’d animals are
smaller because they have fewer cells. The author believes that a similar process should occur with water
restriction (WR) as well.
The implications of this large scale apoptosis are that fragmented DNA will be released into the soma of
the organism while it is losing cells. In fact, it is likely that the release of DNA is a major factor leading to
the life-extending effects of CR. A study suggesting this possibility was reported in 1973 where 750 day
old rats with only an additional 100 days of expected life span were subjected to weekly injections of
DNA. Most of the rats lived to about 1700 days, and one reportedly lived 2,250 days or about three times
the normal life span(128). This is the longest experimental extension of life span ever reported in the rat.
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part, without the prior, express, written consent of the author. 29
Unfortunately a repeat of the experiment was never attempted. What could be the mechanism behind this
result? It was earlier suggested that cGMP was the antioxidant cell signaling pathway. Free DNA could
simply be supplying a source of guanosine which could then be converted into cGMP which would then
tip the balance of the cellular environment of the organism to remethylation from demethylation. (Given
that typical cellular cAMP levels are generally believed to exceed cGMP levels by 8 to 1 then equal
additions to both pools would increase the overall cGMP/cAMP ratio dramatically). Is there any
indication that this might be occurring? One study showed that dietary cGMP conferred normal longevity
to Neurospora deficient in 5 of the 12 known antioxidant deficiencies and that cGMP was not only a
determinant of cellular longevity but also of normal growth and development (129). The expected CR-
induced increase in cGMP activity can also explain some other studies implicating uric acid levels with
aging. Uric acid is an antioxidant, but may be secondary in importance to cGMP. If one compares the
chemical structure of guanine to uric acid, one will see that the only difference between the two
molecules can be accounted for by an ammonia and two water molecules. Given that an ammonia
molecule would have to be removed from guanine to end up with uric acid, the presence of uric acid and
ammonia in the urine is understandable. Thus, uric acid levels may be a indicator of the level of cGMP
antioxidant activity that is occurring. However, uric acid itself is a potent antioxidant and also may play a
role in retarding the aging process. (Note: while cAMP can also break down into uric acid, it is higher up
in the reaction pathway than cGMP and thus might not make as large a contribution to uric acid level
changes as cGMP breakdown products would.)
Uric acid is found in the longest living animals (relative to body size) such as birds, primates, and reptiles
(130). During weight loss in humans (a proxy for CR) uric acid levels are known to increase (131).
During dehydration this has also been shown to be true where in one study dehydration led to uric acid
increasing to levels as much as seven times higher than normal in humans (132). Also, in primates, uric
acid levels are highly correlated with maximum life span (133).
Many other animals including rats and mice which conform to the metabolic rate / body size life span
prediction do not normally have uric acid circulating in their systems due to the existence of an enzyme
called uricase which breaks down uric acid. Their DNA break down products consist of I-compounds,
which like uric acid in humans, have been show to increase during CR(134). Finally, another study
showed that the higher the level of I-compounds in different strains of rats, the longer their life spans
(135).
DNA, or its breakdown products cGMP, I-compounds, or uric acid seem to be candidates for being the
active ingredient of life extension during CR, but this effect can only last for so long. Once the animal
reached its smallest sustainable size, the excess apoptosis would no longer occur (without killing the
animal) and there would no longer be a source of sacrificial DNA to produce the excess cGMP. This is
likely to be true as the author, in correspondences with humans who are voluntarily practicing CR has
been informed that after longer term CR and a stabilization in body size that their serum uric acid levels
actually drop to a very low level. This suggests that there must be a longer-term component of CR.
Melatonin: the famine and drought hormone.
During famine conditions or CR one would expect that in addition to the increase in cGMP activity, that
an increase in cGMP stimulating hormones would be seen. Also, one would expect a decline in cAMP
stimulating hormones. In a study of human males undergoing 5 days of fasting (136) the following
hormone level changes were seen, (for hormones not measured in this study other references are noted):
cAMP stimulating hormones:
TSH declined by 67%-as expected
LH decreased by 33%-as expected
FSH decreased by 33%-as expected
cortisol increased by 110%-unexpected
estrogen -increased by 10%-unexpected
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cGMP stimulating hormones
Melatonin increased +/-100% in rats (137)-as expected
GH increased 200%-400% in men (138) -as expected
DHEA-S increased 100%-expected
Testosterone-decreased 50%- unexpected
T3 and T4 were relatively unaffected, and prolactin declined 25% but is not listed because it is an
“ambidextrous” hormone stimulating both cAMP and cGMP depending on which receptors it influences.
The above results reasonably conform to expectations based on the prior hypothesis regarding cAMP and
cGMP stimulating hormones. However, by examining the exceptions additional important insights can
be gained. First, the cortisol increase of 110% is definitely not expected as it is a cAMP hormone and the
hormone is widely known to be implicated in accelerating the diseases of aging in persons where it is
chronically elevated. What is also known about cortisol is that it has been implicated in triggering
apoptosis is various cell types including thymocytes of the thymus gland (139). If the early stages of CR
require a large scale induction of apoptosis in various cells, it is likely that the increased cortisol is
involved. The other contradiction about the large cortisol increase is that when it occurs during CR one
must assume that it does not lead to the deleterious accelerated age changes that are normally associated
with high cortisol levels as CR’d animals live much longer than controls. One study explains the
contradiction: during CR, although the baseline levels of cortisol are elevated, increases in peak cortisol
levels from stress are shown to be lower in CR’d animals than in ad lib fed animals (140). The idea that
evolution has designed stress so that at times it kills and at other times it does not suggests that stress is
also an aging system. This idea will be explored shortly.
The other exceptions include a 10% increase in estrogen and a 50% decrease in testosterone. If one
remembers that inhibition of reproduction would be a primary goal of the CR response, then a drop in the
male reproductive hormone is not illogical even though it is a cGMP hormone. The corresponding
increase in DHEA of 100% which in absolute terms is of equal magnitude to the testosterone decline
might be seen as CR’s version of testosterone that does not induce sexuality in the male. Finally, if the
only male aging symptoms associated with AS#6 include prostatic atrophy (assuming no malfunctions in
apoptosis) then the estrogen increase of 10% can also be seen as an anti-reproductive hormone change.
An estrogen increase however, would not be expected to occur in the female during CR, and studies show
that this is likely true (141).
CR leads to quite a complicated array of hormone changes, but can it all be simplified? A simple Medline
search of melatonin against each of the individual hormones mentioned above provides the answer.
Melatonin administration has been shown to suppress LH (142), FSH (143), and testosterone(144) while
increasing DHEA(145), GH(146), and in some cases cortisol(147) levels in either rats, mice or humans.
In females, 300 mg. of melatonin was shown to suppress estrogen (E2) levels (148). More definitive
studies do need to be made in this area, however, as most studies are short term in nature while melatonin
induced hormone changes seem to take much longer to occur in humans. Melatonin’s effect on prolactin,
however, was not clear and is generally suggestive of increasing levels in humans but this might only be a
short term effect due to the short term nature of human melatonin studies. Melatonin, did however,
reduce prolactin levels in the rat pituitary (149). TSH was also shown to be suppressed in the rat by
melatonin (150) In most cases of hormone changes induced by CR, melatonin administration induced the
same effect. What is also interesting, a reduction in body temperature in animals is seen during CR and
posited by some to be the potential candidate as the active life-extending mechanism in CR. As one would
expect, melatonin administration leads to reduced body temperature as well (151a). It is interesting to note
that water deprivation, as would be expected, has also been shown to increase melatonin levels in rodents
(151b).
Stress as an aging system
The fact that evolution designed the stress response of increased cortisol to lead to accelerated aging and
death while deactivating this effect of stress in animals undergoing CR suggests that there is an
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evolutionary reason that stress kills. What can the reason be? Additionally, are there any other important
effects of stress?
In addition to accelerating the onset of aging-related diseases, the stress hormone cortisol can also be
suspected of impairing immunity by causing apoptosis of cells in the thymus (152). Another interesting
effect of cortisol is that, like melatonin, it also leads to lowered testosterone levels in the male (153), and
lowered reproduction-related hormones in ovarian tissues (154). While studies exist that suggest that
cortisol inhibits reproduction, it could also promote aging if it had the ability to demethylate all the same
aging genes that are affected by FSH, LH, and estrogen. Given the possible truth of the old wives’ tales
that stress can lead to gray hair, alopecia, hypertension, or heart attacks, it seems possible that cortisol
might preferentially demethylate the genes controlled by FSH in AS#4 as compared to AS#5 or AS#6.
What does all this suggest? That when an animal is experiencing stress, evolution considers the animal
not well- adapted to its environment, and wants to remove its genes from the gene pool. It can do this by
accelerating the aging process, as well as by inhibiting reproduction. In the case of an isolated population
free of predation, stress simply would act to cull the genes of the less fit members from the population.
The stress could be induced simply through competition with other members of the species for a limited
food supply, or loss of competition in winning mates.
In the case where a prey species has been separated from predators and renewed predation ensues, then
the purpose of stress-induced aging is understandable. To our isolated group of fast and slow rabbits, let
us add another speed category of medium. The slows rabbit will all be eaten, while those in the medium
category will be stressed by close encounters with predators. The fast rabbits will experience little stress
as they can easily escape. In this situation, even though the medium speed rabbits survive the predators, if
the stress is sufficient enough it will inhibit their reproduction if not kill them. The end result of this is a
higher incidence of fast genes in the gene pool which is the result that would most likely lead to the
survival of the species.
Melatonin: the ultimate birth control.
If melatonin is the famine hormone, in large enough doses, it should lead to a complete inhibition of
female fertility, as well as a slowing of the aging process. If this was true, then melatonin should prove to
be the best from of birth control available as it should avoid any health risks associated with estrogen-
based birth control. The hormones estrogen , FSH, and LH all cycle on a monthly basis in the fertile
female and train her reproductive system. The hormones interact in later years and appear to be closely
associated with the changes of menopause. It has been proposed herein that these three hormones also
drive the three aging systems that include almost all the deleterious changes associated with aging. If
melatonin is the active, long-term, effector of CR that inhibits the aging process, it should then suppress
these three hormones in the female. Evidence has already been noted to suggest that this is true in males.
The inhibition of these three hormones, however, should also lead to the inhibition of female fertility and
should lead to a postponement of menopause rather than its acceleration which possibly could occur with
estrogen contraceptives. What is interesting about this analysis is that it suggests that aging and
reproduction in humans are driven by the same mechanism (hormones) just as they are in our
hypothetical single-celled, organism with telomeres (cell division).
Currently studies are underway in Europe that are studying melatonin as birth control (155). Women are
given 75 mg per night for 20 days per month. The 10 melatonin-free days allow the woman to menstruate.
The ten day lay off may be a mistake if one was interested in retarding aging. Abandoning the melatonin-
free days should mimic the effects of continual CR and might lead to the cessation of menstruation
without any harmful side effects. This should be very similar to the loss of menstruation seen in females
with very low body fat levels. One would predict that within several years, melatonin will be the only
oral contraceptive prescribed for females barring any unforseen side effects. Also, if one would expect that
during extreme enough CR that any pregnancies would be aborted or absorbed by the mother, then large
doses of melatonin over a certain period might also induce reabsorption or expulsion of the fetus without
any need for medical intervention. If this was not effective, combining melatonin with food or water
fasting might complete the process if that is what was desired.
The estrogen paradox explained
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It is well-known that estrogen suppresses LH and FSH. One study shows that estrogen supplementation in
post-menopausal women decreased both the mean LH and FSH release rates triggered by GnRH. In
essence, this could be considered an attenuation of the peaks of LH and FSH (156). When estrogen is
elevated , FSH and LH peaks are inhibited. If high levels of estrogen are maintained at all times, then
FSH and LH surges should be continually suppressed. This in turn should inhibit the hormonal changes
caused by FSH and LH that allow a woman to become pregnant. Thus, estrogen can be and is used as
birth control.
Having broken down the aging systems and identified the hormones that drive them, we can now
understand why many studies show that estrogen supplementation in post-menopausal women (that have
dramatic reductions in estrogen levels) increases their risk of breast and uterine cancer but decreases their
risks of heart disease (from AS#4) , and osteoporosis (from AS#5), and increases the expected life span
overall (i.e. 157). This can occur by simply by suppressing LH and FSH which drive AS#4 and AS#5
while simultaneously promoting AS#6 with an estrogen increase. While breast, uterine, and vaginal
atrophy is the expected outcome of the programmed decline in estrogen levels, increased estrogen inhibits
the atrophy but may do so by increasing the rate of mitosis (and possibly also apoptosis) in sexual tissues
which can lead to cancer if a malfunction occurs.
We can of course predict that estrogen supplementation will also lead to reduced risk of all the symptoms
of AS#5 which include somatic cancers, Alzheimer’s, diabetes, cataracts, muscle, brain and nerve
atrophy, and others. As mentioned, many studies show that osteoporosis, Alzheimer’s, cataracts, and
arthritis of AS#5 occur at a higher rate in women than they do in men (i.e.158-160) . This is not
surprising, however, if one considers that LH increases by a much higher percentage from base levels in
women than it does in men after age 40. Men have the opposite problem with larger percentage increases
in FSH from base levels than women and therefore are at higher risk, as a group, of diseases such as the
atherosclerosis of AS#4. Estrogen should also lead to inhibition of the other effects of AS#4 such as gray
hair, alopecia, and hypertension. The benefits of estrogen supplementation are real and numerous and
should have the same protective effects in men as in women, but melatonin supplementation should
induce the same protective effects as estrogen without the breast, uterine, or prostate cancer risk. (Studies
on melatonin’s long term effect on human estrogen levels are surprisingly few, and if estrogen is
ultimately shown to not be reduced by melatonin then it would be expected that estrogen receptor
expression in sexual tissues would be diminished or altered by melatonin to create the same effect.)
Simplistically, one would expect high does of melatonin, if it suppresses estrogen, to promote female
sexual tissue atrophy. However, evolution logically should have endowed melatonin with the ability to
maintain the functionality, if not rejuvenate, female sexual tissues in the face of diminished estrogen
levels. Additionally, in pre-menopausal women, high melatonin levels may be able to delay menopause
entirely.
Body fat, fat distribution, and disease
Consider that higher body fat in post-menopausal women protects against osteoporosis, but increases the
risk of breast cancer (161,162). This finding looks very similar to estrogen’s effect in women . It is no
surprise then that increased body fat in post-menopausal women is associated with higher estrogen levels
(163). Given that cholesterol, which is usually associated with dietary fat, and estrogen show very similar
chemical structures, it seems that body fat is converted into estrogen. If body fat is converted into one
aging hormone why not others?
Other studies show that persons that carry a large percentage of their body fat around the abdomen suffer
from heart disease and diabetes at a higher than expected rate (164). This might suggest that different
areas of fat storage preferentially produce different hormones and that FSH and LH are produced in high
quantity from abdominal fat. Estrogen may likely be preferentially produced from fat around the buttocks
which is more prevalent in women; thus, large fat deposits around the buttocks might predispose persons
to a higher risk of cancer of the sexual tissues.
Other life-extending regimens
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During the study of aging and CR, a researcher will come across numerous references in the literature that
the only proven way to extend maximum life span in animals is through CR. This is, however, not true. A
methionine restricted diet (165) as well as a protein deficient diet (166) can also extend maximum life
span. There is also a study that shows that tryptophan restriction can also dramatically increase life span
of rodents but initially kills many of them (167). And as in CR, in all the other life span increasing
regimens mentioned above, growth is inhibited in juveniles. Like CR, the methionine and protein
restricted diets imposed on juveniles lead to smaller individuals even while, in some cases, the subjects
were reported to be eating the same amount of calories as controls in the early stages of the experiment
(168a).
One unusual study showed that intermittent fasting also lead to significant increases in life span without a
corresponding decline in body size (actually the fasted males were bigger than controls) (168b). Given
that increases in life span can occur with a larger than normal than body size, the assumption that it is the
reduction in calorie intake that is causing the increase in life span is certainly called into question. This
also counters the common argument that all these other approaches are doing is inducing CR by
inhibiting appetite.
Possibly both CR and protein restriction lead to a methionine deficiency that triggers the other CR
responses such as hormone changes and possibly changes in DNA methyltransferase activity discussed
shortly . Given that WR is shown to lead to a reduced appetite (169), methionine could be restricted in
this proposed life-extending regimen as well. An interesting experiment would be to see if CR’d rats
supplemented with large amounts of methionine and hormones that are decreased by CR still showed an
increased life span. How might methionine fit into the picture?
Methyltransferase, the last piece of the puzzle:
If this theory is on the mark , then it should be expected that symptoms of rapid aging might possibly be
seen in cases where DNA methyltransferase activity might be defective. In the event that remethylation of
various genes was required to inhibit the aging process, possibly in this hypothetical situation the
remethylation could be impaired. The accelerated aging diseases all show a great deal of recombination
and crossovers in the DNA., and while the author found no specific progeroid diseases related to DNA
MTases, it is interesting to note that lambda bacteriophages that were deficient in DNA methyltransferase
activity experienced increased genetic recombination (170). This would make sense if methyl groups
protect restriction sites, and recombination depends on cleavage of DNA by restriction enzymes. (Possibly
impaired DNA MTase activity is so lethal that rapidly aging phenotypes associated with them are
typically not seen in higher organisms.)
DNA methyltransferases need a source of methyl groups with which to methylate the DNA. Many studies
show that S-adenosyl methionine (SAMe) acts as a methyl donor during the methylation of cytosine in
DNA (i.e.171). After it has donated the methyl group it becomes S-adenosyl homocysteine (SAH) which
presumably may act as a methyl acceptor in conjunction with a DNA MTase. (If this is true, then
administration of SAH to experimental animals should lead to rapid aging.)
Similarly, the amino acid methionine, when demethylated, becomes homocysteine. A study in humans
showed that when given large doses of methionine, homocysteine and SAMe levels increase dramatically,
however, SAH levels were not altered (172). This may suggest that excess methionine is converted to
homocysteine until an equilibrium is reached, and another reversible pathway equilibrates the levels of
methionine with SAMe. The unchanged levels of SAH might suggest that no active, or at least rapid,
pathways exist between it, and methionine, SAMe, or homocysteine, and that possibly the increased
SAMe was synthesized from methionine and another unidentified substrate. (Another, more interesting
possibility is that the SAH levels are maintained at a constant level and that methionine is first converted
to homocysteine, then the homocysteine to SAH which then removes a methyl group from a 5mC to
become SAMe and thus the SAH levels would be maintained at a constant level while SAMe levels are
allowed to fluctuate unless influenced by hormones). However, most importantly, the unchanged levels of
SAH may suggest that increased levels of SAMe do not necessarily lead to increased methylation of DNA.
Another study shows that a diet with excess methionine fed to rats over a two year period lead to vascular
changes that resembled aging-related atherosclerosis (173). At this point, we can make the case that
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excess methionine and its effects appear to be deleterious, and that deficiencies of methionine and its
effects, as noted earlier, seem to be beneficial to increasing life span. This creates a paradox, however,
in that excess methionine leads to increased S-adenosyl methionine levels which are supposed to
methylate the DNA. Methylated DNA in our theory is supposed to inhibit the aging process. How can
this be resolved?
A study published in 1971 may shed some light on this paradox (174). The study examined the two major
homocysteine methyltransferases found in mammals. The first was betaine homocysteine
methyltransferase (BH-MTase), and the second was N5-methyltetrahydrofolate-homocysteine
methyltransferase (N5-MTase). It was found that under unrestricted dietary conditions, or in diets
supplemented with methionine or high in protein, that BH-MTase was more active while N5-MTase was
less active. However, during dietary restriction, and protein or methionine deprivation, they found that
N5-MTase activity increased while BH-MTase activity declined. The effects of various hormones were
then tested on the activity of these MTases and it was found that most hormones changed the activity of
these enzymes. How does this answer our question?
We already know that caloric restriction alters hormone levels, so we might presume that at the basic level
it is really only hormones that alter the activity of DNA MTases and no other factor (except short-term
cGMP increases) leads to CR’s effects. Thus to support this idea ,evidence that methionine
supplementation or high protein diets leads to either altered hormone levels that alter DNA MTase
activity, or simply to direct changes in DNA MTase activity similar to those induced by hormones needs
to be found. Studies were scarce on this question but one study in lambs found that supplementing their
diets with protein and methionine lead to alterations in their hormone levels such as increases in insulin,
glucagon, cortisol, and T4 and decreases in GH, prolactin, and somatostatin (175). Also the fact that
methionine deficiency leads to changes in homocysteine MTase activity has already been noted. If
methionine-induced hormone changes and/or methionine by itself, are found to alter DNA MTase activity
as well, then the paradox will have been resolved.
Also, if decreased protein ingestion leads to decreased methionine levels, then the reason protein
restriction leads to extended life span may also have been revealed . Before moving on to DNA MTase’s,
one last fascinating aspect of this study is that it was found that the activity of N5-MTase declined in some
tissues dramatically with age (i.e. from 10.7 units/mg in young subjects to 3.7 units/mg in older subjects).
We now must take a look at the possibility of hormonal and/or methionine control of DNA MTase
activity as a potential major factor in regulating the process of aging.
If hormones can control homocysteine MTases, then we should expect that hormones may also control
DNA MTases. Review of the literature reveals many examples of this being the case with one study
showing that FSH, as would be expected, decreased the activity of DNA MTase (176). This all might
suggest that the level of methyl donors is not so important for DNA methylation , as is the hormonal
milieu’s effect on the activity of the DNA MTase. It seems likely that the DNA MTase might be involved
in demethylating the DNA in addition to its obvious role as a methylator of DNA depending on which
hormones are acting upon it, and whether it is bound to SAMe or SAH.
As far as methionine itself altering the activity of DNA MTase independent of any influence it may have
on hormone levels, a Medline search revealed little to no evidence that either supports or contradicts this
idea. However, the author believes that there is a strong possibility that like its dramatic effects on altering
homocysteine methylatransferase activity, methionine will also be found to strongly alter DNA
methyltransferase activity towards the demethylation of 5mC while deficiencies in methionine will lead to
cytosine methylation. If this turns out to be the case, then it may shed some light on why diets high in soy
protein (soy is low in methionine) are thought to confer numerous health benefits and diets high in meat
and dairy proteins which are have high methionine content are generally believed to be unhealthy.
If high cholesterol levels lead to a high level of estrogen which, in turn, protects against heart disease,
might we assume that high cholesterol has nothing to do with heart disease per se? Instead, high
cholesterol might be indicative of an animal protein based diet which in turn implies a high methionine
intake. If methionine alters the DNA MTase activity to favor demethylation of 5mC, then the expression
of the aging genes of AS#4 and AS#5 would occur more rapidly. Of course we need to ask why would
evolution want to accelerate the aging process of an animal that consumes other animals even if that
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animal is a top predator such as man? The answer may be as simple as to increase the rate of genetic drift
to allow the faster evolution of offensive adaptations to offset the prey’s evolution of defensive
adaptations. If the predator cannot keep pace with the prey, then extinction will be his fate as well.
(Note: A very interesting study encountered during research of this topic (177) showed that DNA that was
newly-synthesized in the presence of sodium butyrate (apparently acting as an antioxidant) acquired and
retained a hypermethylated status upon subsequent divisions, while pre-existing DNA subjected to the
same treatment acquired a hypermethylated state, but lost it upon subsequent cell divisions.)
Adult mammal cloning suggests that cellular aging is reversible
Some authorities suggest that 5mC to T mutations may play the primary role in reducing the level of
5mC found in the genome with advancing age (178). However, the fact that an adult mammal nucleus can
be rejuvenated into a perfectly functioning embryonic pronucleus (179), suggests that increased free
radical exposure of DNA from helicases and hormones that occur in aging organisms are the primary
cause of the loss of 5mC from DNA. For if loss of 5mC was primarily caused by C to T mutations, then it
should be impossible to remethylate an adult nucleus so that it could undergo embryogenesis.
In vitro doubling potential should be limited by the amount of methylation remaining in the genome at
the time the cell is plated (assuming mitosis inhibiting genes are the last to be demethylated). The 5mC
level should depend on the amount of free radical or antioxidant exposure that the DNA had encountered
in the cell’s lifetime prior to its plating. Free radical exposure would depend on the free radical surrogate
hormone levels and the activity of the DNA MTases and helicases. Helicase activity should be seen in
mitosis, during DNA repair, and during developmental and aging gene access. The hormonal milieu
surrounding the DNA helicase may lead to either increased or decreased methylation by affecting the
DNA MTase.
If cellular genomes are remethylated while undergoing mitosis their doubling capacity should be
unlimited assuming the avoidance of a C to T mutation that triggers apoptosis or inhibits cell division , or
a telomere limitation caused by deactivation or nonexpression of the telomerase gene. Also, given that
an adult nucleus can be remethylated and become a viable pronuclei, this result should be achievable in
senescent cells as well. Given that demethylation should lead to the expression of additional genes, the
loss of proliferative potential in older cells should be caused primarily by SGE. It has been shown that
expression of p21 has been associated with inducing the Hayflick limit in some cells, and that when p21 is
knocked out, the cell can continue dividing up to ten additional times with continued telomere shortening
(180). One would expect that inducing telomerase expression concurrently with a p21 knock out (or
simple remethylation) could lead to cellular immortality. If the DNA could retain a youthful methylation
pattern through proper manipulation with antioxidants, a non-aging, immortalized, differentiated cell type
should be possible to create.
When scientists cloned an adult mammal cell, the nucleus donor cell was deprived of nutrients for an
extended time. This likely induced the caloric restriction response at the cellular level and lead to genomic
remethylation presumably by the production of antioxidants or alteration of DNA MTase activity. A
highly antioxidant cellular environment in conjunction with activation of the (proposed) error correcting
remethylation program ( a special DNA MTase) active in embryonic cells mentioned earlier, eventually
should lead to the complete remethylation of the genome (and possibly rebuilding of any shortened
telomeres?). This analysis suggests why it has been more difficult to clone cells as the age of the donor
cell increases. Older cells require more time to allow for a larger remethylation/repair process. One
would expect that the very low success rate seen in cloning of adult cells could be improved by the
addition of cGMP and methyl donors such as SAMe to the medium containing the clonal pronucleus.
If the above reasoning is correct, then the Hayflick limit of most cells is primarily entered through
demethylation of the genome. Interestingly, one group of researchers was able to overcome the Hayflick
limit in senescent fibroblasts by exposing them to an extract made from fetal liver cells (181).
Possible therapies for premature aging syndromes of AS#4, AS#5, and AS#6:
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The diseases of Progeria, Werner’s, or Bloom’s syndromes, and most of the premature aging syndromes of
AS#5 are proposed herein to be caused by a DNA unwinding defect that is creating excessive amounts
free radicals. The excessive free radical-induced demethylations might be preventable by maximizing the
antioxidant status of the intracellular environment.
For Progeria, treatment could include an FSH and cortisol antagonist, agonist, high doses of cGMP, uric
acid, DNA injections, and high doses of melatonin, which should suppress the production of FSH( as
well as LH, and estrogen in females). Inhibin, which suppresses FSH, might also be helpful.
Additionally, since it is can be expected that the Progeria DNA helicase evolved before most of the free
radical surrogate hormones, that its gene sites should respond primarily to antioxidant hormones. With
this in mind administration of GH, Prolactin, DHEA, Insulin, and testosterone could be helpful. Also,
Proscar might help in suppressing the conversion of testosterone into DHT which stimulates the cAMP
pathway and is also associated with hair loss which is a symptom of AS#4. However, most of these
effects might also be achieved with simple caloric, protein, or methionine restriction while water
restriction may be even more effective.
The three diseases of CS, XP, and AT might be treated in a similar manner as Progeria with the exception
of focusing on suppressing LH as opposed to FSH.
Given that the Werner’s helicase should allow access to all the aging genes of AS#4 and AS#5, treatment
for Werner’s should include all of the above treatments to suppress FSH and LH while also attempting to
suppress estrogen as well. Given that estrogen suppresses LH and FSH, it might also be helpful in treating
the diseases of AS#4 and AS#5, but melatonin would seem to be the best candidate for AS#6.
Additionally, suppression of all the free radical surrogate (cAMP) hormones through antagonists or
otherwise, might be considered as potentially helpful. If the cellular environment can be pushed to a high
enough, net, antioxidant level, or altered to promote methylation, then the excessive free radicals
generated by the defective helicases might be overcome.
Other diseases linked to demethylation of cytosines that might be prevented in a similar manner, are
AIDS (182), and neurofibromatosis (183) (and possibly Huntington’s (184), which apparently become
active after cytosine demethylations occur.
Odds and Ends
Sun and accelerated skin aging:
If solar radiation causes DNA damage to occur in epidermal cells, DNA repair systems will be activated.
During DNA repair, the DNA helicase likely has to unwind the DNA at various sites. As suggested
earlier, the DNA helicase itself likely generates free radicals when it is in the act of unwinding DNA.
This, in turn, demethylates the genome and may cause accelerated aging in the skin in a similar manner
as to what is occurring in Progeria and Werner’s Syndrome.
With respect to the increased incidence of cancer, DNA damage would likely lead to the apoptosis of
extensively damaged cells as well as cell proliferation to replace the lost cells. The more apoptosis and
cell proliferation that occur, the more likely there is to be a malfunction in this process and the subsequent
transformation of a cell. This would be especially true if damage to the DNA was repaired incorrectly
leading to mutations in apoptosis related genes. And of course the additional proliferation would also lead
to more demethylating DNA helicase activity. Sun-induced skin aging may be a model of pure helicase-
induced aging without the compounding effects of hormones. (A thought related to this topic is that it
would be interesting to discover if UV exposure of internal tissues leads to their rapid aging, or simply
apoptosis (due to a preprogrammed methylation pattern) and if the rate of either potential result would
be modulated by various hormones.)
Unsolved mysteries:
The many paradoxes of cigarette smoking
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The model of human aging that has been developed so far apparently is a bit simplistic as it does not
adequately explain the many paradoxes of cigarette smoking. Exceptions have been found to be exciting
markers of areas that require further research to gain an even further understanding of the aging process.
Nicotine and cigarette smoking have been shown to cause major endocrine changes in humans. The
majority of the literature suggests that smoking reduces (or does not affect) estrogen but increases
testosterone in women, while not affecting testosterone and increasing estrogen in men. In both sexes,
increased cortisol , and vasopressin levels are observed as well as a decrease in LH. (185a, 185b, 186 ).
The well known increase in lung cancer may be explained by vasopressin as high levels of vasopressin
have been implicated in being potentially involved in inducing lung cancer (187). If the contact of smoke
with the lugs was the primary cause of lung cancer, then one might expect to see high incidences of lung
cancer in marijuana smokers which is apparently not the case. Also, the gender differences in smoking’s
effects on sex hormones seems to be consistent with the cortisol-related inhibition of fertility mentioned
earlier.
Cigarette smoking is well known to be associated with increasing the risks of myocardial infarction
(188), and may be involved in accelerating hair loss, hair graying, and facial wrinkling, all symptoms of
AS#4 (189) This occurs without any apparent smoking-induced increase in FSH , but can be explained if
cortisol, as earlier proposed, can act cooperatively with FSH to demethylate the aging genes of AS#4.
The interesting paradoxes are found in that smoking seems to confer a protective effect against
Alzheimer’s (AD) , Parkinson’s disease (PD) and Tourette’s Syndrome which all likely belong to AS#5
(190), and seems to protect against uterine and endometrial cancer in women (191), while not increasing
the incidence of breast cancer (192). Much of this makes sense in that reduced LH should lead to
inhibiting the brain atrophy of AS#5, and a reduction in estrogen should lead to an inhibition of the
cancers of sex tissues of AS#6.
Additional weight is given to the LH / Alzheimer’s connection by the recently publicized suggestion that
ibuprofen administration reduces the risk of Alzheimer’s after two studies were found through a Medline
search that show that ibuprofen suppresses LH ( 198, 199a).
(Note: The reduced LH levels seen in PD patients and Tourette’s patients (195) might be seen as
invalidating the LH link to these diseases, however this argument can be countered by the fact that PD
attacks the substantia nigra of the brain, and Tourette’s the globus pallidus which are both implicated in
stimulating LH secretion (196 , 197). Thus, LH increases could still have hypothetically triggered the
onset of PD or Tourette’s through activating a particular gene through demethylation or triggering
apoptosis while LH later fell to low levels after the disease took hold. Furthermore, these diseases may be
caused more by a hypersensitivity to prolonged LH exposure by certain brain cells rather than a greatly
increased level of LH.)
With respect to the smoking-induced reduction of uterine and endometrial cancers in women, estrogen
reduction could certainly be the causative factor, but possibly LH attenuation could be playing a role
as endometrial carcinomas express a high level of LH/hCG receptor gene (193).
Mysteriously, even though LH is suppressed by smoking, smoking has also been shown to be linked to
bone loss, and cataracts (194). It was postulated before in this theory that these diseases were driven by
LH alone and should be suppressed by smoking. This paradox suggests some interesting possibilities.
A plausible explanation is that the smoking -induced cortisol increase and LH decrease affect tissues
differently. Possibly LH can easily penetrate the blood brain barrier while cortisol is not as effective at
this. Thus reduced LH levels would protect the brain from AS#5. Outside of the brain, however, we might
find that the cortisol rise more than offsets the LH decrease and accelerates some symptoms of AS#5. It is
interesting to note a study that shows that corticosteroid administration can lead to osteoporosis and
cataracts (199b).
Other possibilities to explain smoking-associated bone loss and cataracts in the face of a decrease in LH
and estrogen with an increase in cortisol include:
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part, without the prior, express, written consent of the author. 38
Possibly estrogen counteracts LH ( and also FSH) at the level of the DNA MTase in replicating cells but
not in non-dividing cells. Thus a drop in LH could inhibit the activation of brain diseases, but in dividing
cells, the drop in estrogen more than offsets the drop in LH and the changes become what is tantamount
to an increase in LH.
Possibly cortisol only demethylates the 5mC in dividing cells as opposed to non-dividing cells irrespective
of the levels of estrogen or LH encountered.
The paradoxes of smoking’s effects on hormones and their effects on the different aging systems are
complex, potentially numerous, exciting to contemplate, and require further study.
More questions:
One question is that although estrogen levels in males continue to climb to high levels with age, the
increased levels of estrogen do not seem to suppress the FSH and LH rise seen in men about this time.
One explanation is that the data mentioned herein are average values, and the important age-related
hormonal events deal with the peaks and valleys rather than the mean. Another is that possibly long term
exposure to higher testosterone levels in men somehow, over time, desensitizes the endocrine tissues to
the LH and FSH suppressing effects of estrogen. Or that testosterone also suppresses FSH and LH and its
decline in males has more effect on FSH and LH than the estrogen increase. Finally, a most interesting
observation is that the pre-menopausal estrogen rise seems to coincide with the increasing levels of FSH
and LH seen in women at menopause. However, after the estrogen crash of menopause the mean FSH and
LH levels no longer increase nor do they decline but rather just level off. In men, the three hormones
estrogen, FSH, and LH climb together. In both men and women it appears that in the long run as if only
estrogen increases drive FSH and LH up to higher levels but estrogen decreases only lead to lower FSH or
LH levels in the short run, but not long run. If this is true, then if the long term estrogen rise in men
(and premenopausal rise in estrogen in women) could be suppressed, the long term rise in FSH and LH
might not occur.
Another question is why women can tolerate lifetime levels of FSH and LH that are anywhere from 4 to
10 times the levels that occur in males without accelerated aging occurring. Females likewise have much
higher levels of estrogen than males and maybe at high levels estrogen inhibits the deleterious effects of
high levels of FSH and LH. At the lower levels of all three hormones that occur in the male, possibly the
protective effect of estrogen does not occur.
Another interesting mystery is why DHT, a breakdown product of testosterone, is implicated in hair loss.
(Proscar, a 6-alpha-reductase inhibitor, which inhibits the conversion of testosterone to DHT also
inhibits hair loss). Hair loss belongs to FSH and AS#4, while one would presume that DHT is specific to
AS#6 and would promote only prostate cancer, atrophy, or BPH (which it apparently does). Has DHT
been co-opted into helping FSH demethylate the aging genes of AS#4 along with cortisol? Many studies
make reference to the fact that FSH works in conjunction with testosterone to induce development (i.e.
200), another shows that DHT accumulates at a higher rate with age (201), and one that shows that DHT
stimulates cAMP production (202) . In addition to cortisol and FSH, it seems quite likely that DHT
demethylates the genes of AS#4. If this was true, the well known effect of castration leading to longer life
spans and full heads of hair in males would be understandable. The use of minoxidil as both a treatment
for hypertension and baldness also seems to begin to make sense. Overall, the evidence seems to indicate
that Proscar should be found to be an effective preventative for heart disease and hypertension as well as
being effective for treating BPH.
Finally, the literature is full of references to short term melatonin administration leading to significant
hormone level changes in rats and mice similar to those that occur during short term CR. However, many
of the human studies involving large dose melatonin administration claim no effect on most hormones
such as FSH, LH, estrogen, GH, testosterone, cortisol, TSH, and only report an increase in prolactin
levels (i.e. 203). If melatonin had no effect on these hormones, how could it be used for birth control?
This suggests short-term melatonin administration in humans is not sufficient to induce relevant
hormone level changes and these studies should be viewed in this light. The same effect is seen in many
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part, without the prior, express, written consent of the author. 39
short term fasting studies of humans where no changes in hormones are noted. However, the longer-term
5 day fast in human males mentioned earlier in this paper showed quite dramatic hormone changes
similar to those seen in rodents undergoing short-term CR or melatonin administration. Apparently
hormonal response time is accelerated in rodents and mice (just as aging is) as compared to humans.
INTER-SPECIES AGING RELATIONSHIPS: EXPLANATIONS AND EXCEPTIONS:
Relationships between maximum life span and metabolic rate/body size (204) or brain size/body size
ratios (205), are well known to gerontologists. Earlier it was explained how body size, age of reaching
fertility and maximum life span could all be reduced in a species through the imposition of an earlier age
of death in a species. A rough relationship is seen in most mammals where the smaller the animal, the
shorter its life span. However, what is much more interesting and informative are the most dramatic
exceptions to this relationship. Most notably in mammals the exceptions include man who can live to 120
years while being much smaller than, for example, a horse that can only live up to 40-50 years. Also,
some bats have been reported to live up to 23 years (206) even though rats of similar size only live about 3
years. Birds are typically left out of this comparison by gerontologists because they invalidate the
relationship altogether. The oldest proven living captive bird was thought to be a 68 year old eagle owl
(207) according to Alex Comfort in his “Biology of Senescence”, 1974 while there are unproved reports
of many types of birds living to much older ages. Some birds living to 90 years in captivity have been
reported (208). Also, reptiles are not included in this comparison because many of them live well beyond
their predicted age based on body size. It is common to encounter authenticated reports of various species
of tortoises living for 100 to 150 years (i.e. 209).
What is the source of deviations from this relationship between body size and maximum life span? Some
gerontologists suggest that bats hibernate so that is why they don’t fit the body size/life span relationship .
However, bears hibernate and they are not an exception; also a comparison between hibernating and non-
hibernating bats revealed no difference in longevity (210). Birds, humans, and tortoises don’t hibernate
either. We can understand the exceptions only by examining what the exceptions have in common. Bats
fly, birds fly, humans think, tortoises have shells, and reptiles are typically isolated in a desert
environment (at least during ice ages). The common thread running through all these traits is that they
provide an effective defense to predation where predation does not prevent these animals from aging in
the wild on a continual basis. Because of this, these species have dropped out of the predator prey arms
race and begun the natural drift to longevity. (Note that juveniles of otherwise predator-defended species
may still be subject to heavy rates of predation. Juveniles killed by predators, however, are evolutionarily
irrelevant and can just be considered a cost of producing a reproductively able adult, much as an
unfertilized ovum or wasted sperm cell could also be considered a cost of reproduction. Evolution can
adjust for predation of juveniles by simply adjusting litter size. A prime example of this is the high
mortality of juvenile alligators and crocodiles (long-living top predators) where of 50 live juveniles per
clutch of eggs, typically only one survives to adulthood.)
Another item some of these long living animals, such as man, reptiles, and birds have in common is uric
acid. If uric acid is a requirement for a species achieving exceptional longevity relative to body size, then
this idea could be tested quite simply. Rodent bats, with flight, have evolved exceptional longevity for
their body size. Being a rodent, however, they should produce large amounts of uricase which breaks
down uric acid. Their ultimate DNA breakdown products should be I-compounds, not uric acid. If it is
found that these rodent bats maintain high levels of uric acid. then it argues for the idea that uric acid
may be a prerequisite for a species achieving exceptional longevity. The same should apply to clams
which can live up to 220 years.
Let us now examine the brain weight to body size ratio to longevity relationship. Humans are the
mammal with the longest life span and have the highest brain/body weight ratio of any animal, and
humans are the one species that has no predators. Also, the brain size/body weight ratio might be expected
to correlate positively with intelligence in animals. With these ideas in mind, the conclusion might be
made that intelligence is the most effective defense against predation for land mammals. This suggests
that the larger the brain as a percent of body weight, the more intelligent the animal. Although
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part, without the prior, express, written consent of the author. 40
intelligence tests for animals basically do not exist, support for this idea can be found in other areas. For
example, various human studies show a larger head size has been shown to give an advantage of 25 to
35 IQ points to an individual (i.e. 211) . If head size is related to brain size, then this fact supports the
hypothesis. (It is also interesting to note that intelligence is thought to be X-linked given its importance as
an evolutionary survival advantage (212). If humans are shown to be the only or the first species where
the intelligence (or head size) gene is or became X-linked, it might suggest how intelligence or brain size
could have evolved so rapidly in humans as compared to other animals. Males with larger heads and
brains presumably should have been more intelligent and thus more likely to survive in a dangerous
environment. Pure expression of the intelligence gene in the male would allow for rapid amplification of
this trait ).
Possibly the land-based predator/prey arms race of offense and defense began first through the
development of somatic weapons and shields like claws, poison, and shells, but eventually turned into an
arms race of intelligence. Humans, recently in evolutionary terms, won that race. However, signs of
intelligence are seen in many other animals. For example, an ape (KoKo) has been taught to speak in sign
language (213), monkeys to count and use number symbols (214), sea otters to use tools (215), rats to run
mazes, dogs to recognize voice commands, etc. The list is long and suggests that intelligence is evolving
in many different species.
The reason for linkage of fertility and aging variables.
The linkage of the age of fertility to the age of menopause, the maximum life span and to body size seems
to not make any sense at first glance as this relationship would preclude the selection by evolution for the
perfect predator species. The ultimate predator species should become fertile very quickly, reproduce
rapidly with large litter sizes, and grow as quickly as possible into a large predator with perfect offense as
well as defense to predation of all types (large size is anticipated to help deter would-be predators and
suggests the reason for the body size/life span relationship). However, the evolution of a super-predator is
not compatible with the continuation of life. For if a super-predator evolved, and its reproduction was
unchecked, it would quickly grow in numbers and devour all the other species (which may also include
plants) and then it too would become extinct. By linking maximum life span, body size, age of reaching
fertility and menopause, and litter size, evolution has created a safeguard against the evolution of a super-
predator. It might work in the following manner:
As the adult predator evolved better offense and a defense to all other predators, it would drift towards
longevity, as a longer reproductive life span in females would be selected for. The push towards a longer
reproductive life span inadvertently would lead towards a longer maximum life span and an older age of
reaching fertility if all three of these factors were linked by the Werner’s DNA helicase. However,
increasing the age of reaching fertility by one year, would require a greater than one year increase in the
total number of years of reproductive life span or no reproductive advantage would be conferred by
mutations in this direction. So it is likely that a one year increase in the age of reaching fertility will
translate into say a two year increase in the reproductive years, and an overall increase in lifetime
reproductive potential, and an increase in maximum life span. This suggests that in most land animals,
there should exist a mathematical relationship between age of reaching fertility, menopause, and
maximum life span , and body size that should be relatively constant. It is probably timed by the pattern
and level of hormones produced by the species and one might expect to see higher cAMP hormone levels
per kg of body weight for shorter lived species than longer lived ones. This relationship is likely what
leads to the metabolic rate/ body size/ life span continuum. If this relationship did not exist, then one
would expect large body size to evolve rapidly in all animals as a defense against predators, but this
adaptation would also lead to a need for more food consumption, a dangerous combination. To offset this
somewhat, metabolism could be slowed, but if the large animal species was a prolific reproducer, the
animal’s success could one day lead to its extinction due to rapid exhaustion of its food source.
Additional considerations include that mortality rates for juveniles of all species is usually very high.
This represents another factor that should come into play in preventing the evolution of a super-predator.
For even if litter sizes were relatively large, a high mortality rate among juveniles combined with a longer
period of juveniles remaining in the developing, non-reproductive state, would serve to limit the number
of potential super-predators reaching reproductive maturity. If the total number of individuals of a
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part, without the prior, express, written consent of the author. 41
potential super-predator species was kept low, then the species could not be considered a true super-
predator as their numbers would be too limited to cause extinction of most other life forms.
This line of logic suggests that the relationship between body size, maximum life span, age of reaching
fertility, litter size, and juvenile mortality rates are interrelated to prevent the evolution of a super-
predator. Other than juvenile mortality, all these factors, at least in humans, seem to be under hormonal
control as hormones are implicated in triggering precocious puberty in children as well as multiple births
in “infertile” females. Steroids increase the size of body builders while GH controls the growth of
children, midgets, and giants. Are hormones involved in aging as well? It seems that the case has already
been made.
Super-predators would cause mass extinctions of most life forms. This in turn would lead to the super-
predator’s own extinction. By reducing the rate at which the potential super-predator species can
reproduce, evolution has basically leveled the playing field so that the super-predator will not wipe out its
food supply. Is it possible that the dinosaurs were super-predators? If body size increased as a defense to
predation in the herbivore dinosaurs which triggered a corresponding increase in carnivore dinosaur body
size, large increases in food consumption would follow. If this body size race continued along with
increasing populations, the planet would become grazed to the limit and the system would become
unstable. So, if a large meteor happened to hit the planet and possibly led to reduced amounts of
vegetation, large reductions in herbivore populations sizes could occur. If the carnivore dinosaurs were
then able to hunt the remaining herbivores to extinction, and then consume each other, they themselves
would then become extinct. This may suggest that whatever mass extinctions occurred throughout
evolution may have occurred from the periodic evolution of a super-predator. This may also include man.
This line of reasoning suggests that species with safeguards against evolving into super-predators were
more likely to avoid extinction than those without. Body size increases may have been a great defense to
predation in the dinosaurs but ultimately may have lead to their extinction. Will increased intelligence in
man lead to a similar fate? Time will tell.
Conclusion:
This paper presents several novel ideas some of which are highlighted as follows:
•Aging in a species evolved as a defense to predation, and aging serves a useful purpose.
•Extreme longevity is the natural state of a species, over time, in an unrestricted environment.
•At least six different aging systems evolved and exist in humans.
•Aging and development are timed by the same mechanisms and are linked by various DNA
helicases.
•A major manner in which genetic signaling occurs is through alteration of the methylation status
of 5mC in genes. 5mC demethylation is catalyzed by free radicals and methylation by
antioxidants.
•Hormones are in reality antioxidants, free radicals, surrogate antioxidants or surrogate free
radicals.
•Hormones likely affect the aging process by altering the activity of DNA methyltransferases, and
methionine may also be involved in this process.
•Sex types evolved primarily as a way to modify aging rates in the short run, and lock-in aging
systems in the long run.
•Estrogen, LH, and FSH are the primary hormones that induce age changes while cortisol and
DHT act cooperatively with the primary hormones to initiate aging.
•The Hayflick limit should be reversible through remethylation of the appropriate genomic
cytosine sites.
•The rate of loss or gain of methylation in most cells is modulated by the net free radical or
antioxidant level affecting its DNA methyltransferases rather than cell division per se.
•Flight, intelligence, shells, and isolation as defenses to predation explain the exceptions to the
body size life span relationships seen in various animals.
The main assumptions that this theory relies upon are that free radicals catalyze the demethylation of
5mC while antioxidants catalyze the methylation of 5mC by influencing DNA methyltransferase activity.
This theory was constructed prior to the author’s knowledge that there existed any evidence that
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part, without the prior, express, written consent of the author. 42
supported the above assumptions. After studies were located that confirmed the major assumptions of this
theory, the likelihood of it being correct increased significantly. This theory generates a large number of
explanations and relies only upon a few simple ideas which suggests that it is a step in the right direction
to understanding the process of aging. In opposition to current gerontological thought, this theory might
be summed up with the following sentence. Although accidental events drive the process of evolution,
the results of evolution are anything but accidental.
Sources:
1. Medawar P. An unsolved problem of biology. London: H. K. Lewis 1952
2. Burnham Curtis M. Bronte C. Otoliths reveal a diverse age structure for humpers lake trout in Lake
Superior. Transactions of the American Fisheries Society 125(6). 1996. 844-851; and Iwasa M.
Atkinson S. Analysis of corpora lutea to estimate reproductive cycles of wild Hawaiian monk seals .
Marine Mammal Science 12(2). 1996. 182-198.; and Sapolsky R. Altmann J. Incidence of
hypercortisolism and dexamethasone resistance increases with age among wild baboons. Biological
Psychiatry. 30 (10). 1991 1008-1016.
3. Brown W. Kieras F. Houck G. Dutkowski R. Jenkins E. A comparison of Adult and Childhood
Progerias: Werner Syndrome and Hutchinson-Gilford Progeria Syndrome. Advances in Experimental
Medicine and Biology Vol. 190 pp. 229-243. 1985.
4. Perls T. Alpert L. Fretts R. Middle-aged mothers live longer. Nature pg. 133 Vol 389 1997 Sep. 11
5. Holiday R. The evolution of human longevity. Perspectives in Biology and Medicine. 40 (1). Fall.
1996
6. Grassia G. Mclean K. Glenat P. Bauld J. Sheehy A. A systematic survey for thermophilic
fermentative bacteria and Archaea in high temperature petroleum reservoirs. FEMS
Microbiology Ecology 21(1). 1996. 47-58.
7. Weinert T. Hartwell L. Characterization of RADS9 of Saccharomyces-Cerevisiae and evidence that
its function acts post-translationally in cell cycle arrest after DNA damage. Molecular & Cellular
Biology 10 (12). 1990.6554-6564.
8. Walford R. Maximum Life span. Avon Books, 1983. He cites various species of organisms that
achieve life span increases through CR including, mice, rats, and Tokophyra (a carnivorous
microorganism), and Walford R. Caloric Restriction (CR) and Age Retardation. Internet Posting
1998 at Geron-Sci anthology.
9. May P. et. al. Failure of dietary restriction to retard age-related neurochemical changes in mice.
Neurobiology of Aging 13 (6), 1992. 787-791.
10. Siegfried Z. Cedar H. DNA methylation: a molecular lock. Current Biology. 7(5):R305-7, 1997 May
1.
11. Weitzman S. Patrick T. Milkowski D. Kozlowski K. Free radical adducts induce alterations in DNA
cytosine methylation. Proc. Natl. Acad. Sci. Vol. 91, pp. 1261-1264, 1994, Feb.
12. Romanenko E. Alessenko A. Vanyushin B. Effect of sphingomyelin and antioxidants on the in vitro
and in vivo DNA methylation. . Biochemistry and Molecular Biology Int. pp. 87-94 35 (1). 1995 Jan.
13. Yeivin A. Levine A. Razin A. DNA methylation patterns in tumors derived from F9 cells resemble
methylation at the blastula stage. FEBS Letters. 395(1):11-6, 1996 Oct. 14
14. Panning B. Jaenisch R. DNA hypomethylation can activate Xist expression and silence X-linked
genes. Genes & Development. 10(16):1991-2002, 1996 Aug. 15.
15. Mazin AL. Genome loses all 5 methylcytosine during life span. how is this related to accumulation of
mutations with aging? Molekulyarnaya Biologiya (Moscow) 27 (1). 1993a. 160-173.
16. Butt, WR The Gonadotrophins, page 164 (refers to LH and cAMP) page 75 refers to ACTH and
cAMP), Hormone Chemistry 2nd (Revised Edition). John Wiley & Sons Volume 1, 1975
17. Minegishi T. et. al. Functional expression of the recombinant human FSH receptor. Journal of
Endocrinology. 141(2):369-75, 1994 May. (an example of the many studies)
18. Moran, Scrimegeour, Horton, Ochs, Rawn. b. Biochemistry 2nd edition. pp12-36 1994.
19. Liehr, J. G. Dual role of estrogens as hormones and procarcinogens: Tumor initiation by metabolic
activation of estrogens. European Journal of Cancer Prevention.-in press.
20. Butt, WR Insulin and Glucogen, page 236, GH on page 98 Hormone Chemistry 2nd (Revised
Edition). John Wiley & Sons Volume 1, 1975
21. Jakubowicz D. Beer N. Rengifo R. Effect of DHEA on c-GMP in men of advancing age. Annals of
the New York Academy of Sciences. 774:312-5, 1995 Dec. 29.
22. Faillace M. Keller-Sarmniento M. Rosenstein R. Melatonin effect on the cGMP system in the golden
hamster retina. Brain Research. 711(1-2):112-7, 1996 Mar 4
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 43
23. ibid. 18
24. Barsony J. Marx S. Receptor-mediated rapid action of 1 alpha, 25-dihydroxycholecalciferol: increase
of intracellular cGMP in human skin fibroblasts. Proc of Nat Acad of Sci of USA. 85(4):12223-6,
1988 Feb.
25. Aggeler J. Murnane J. Enhanced expression of procollagenase in AT and XP fibroblasts. In Vitro
Cell Dev Biol 26: 915-22(1990).
26. Millis A. Hoyle M. McCue H. Martini H. Differential expression of metalloproteinase and tissue
inhibitor of metalloproteinase genes in aged human fibroblasts. Exp Cell Res 201:2 373-9. 1992 Aug.
27. Wilson, VL. Smith RA. Ma S. Cutler RG. Genomic 5-methyldeoxycytidine decreases with age.
Journal of Biological Chemistry. 262(21):9948-51, 1987 Jul. 25.
28. Mazin AL. Genome loses all 5 methylcytosine during life span. how is this related to accumulation of
mutations with aging? Molekulyarnaya Biologiya (Moscow) 27 (1). 1993a. 160-173.
29. Mazin A L, The loss of all genomic 5-methylcytosine coincides with Hayflick limit of aging in cell
lines Molekulyarnaya Biologiya (Moscow) 27 (4). 1993b. 895-907
30. Moroz E. Verkrhatsky N. Hypophyseal-gonadal system during male aging. Arch Gerontol Geriatr, 4 .
13-19. 1985 in Biological Aging Measurement, Clinical Applications; Ward Dean MD. Center For
Bio-Gerontology, Pensacola, Florida 1988.
31. Baker H. Burger H. deKretser D. Hudson B. Endocrinology of aging: Pituitary testicular axis. in
Korenman S. Endocrine aspects of aging, New York, Elsevier Biomedical, 1982 in Biological Aging
Measurement, Clinical Applications; Ward Dean MD. Center For Bio-Gerontology, Pensacola,
Florida 1988.
32. Wills M. Harvard B. Laboratory investigation of endocrine disorders, Boston Butterworths, 1983 in
Biological Aging Measurement, Clinical Applications; Ward Dean MD. Center For Bio-Gerontology,
Pensacola, Florida 1988.
33. Kenny R. Fotherby K. The sex steroids and trophic hormones in: Clinical Biochemistry of the elderly,
by Malcom Hodkinson (ed). Churchill Livingstone, London, 1984 in Biological Aging Measurement,
Clinical Applications; Ward Dean MD. Center For Bio-Gerontology, Pensacola, Florida 1988.
34. Dilman V., Dean W. The neuroendocrine theory of aging and disease. p.35 Figure 4-6 (adapted from
Dilman, 1991) The Center for Bio-Gerontology. 1992
35. Vermeulen A. Rulens R. Verdonck L. Testosterone secretion and metabolism in male senescence, J
Clin Endocrinol Metab, 34: 730-735. 1972 adapted in Biological Aging Measurement, Clinical
Applications; Ward Dean MD. Center For Bio-Gerontology, Pensacola, Florida 1988.
36. Orentreich N. Brind J. Rizer R. Vogelman J. Age changes and sex differences in serum DHEA sulfate
concentrations throughout adulthood. Journal of Clinical Endocrinol Metab, 1984, 59:551-555 in
Biological Aging Measurement, Clinical Applications; Ward Dean MD. Center For Bio-Gerontology,
Pensacola, Florida 1988.
37. Zumoff B. Strain G. Miller L. Rosner W. 24 hours mean plasma testosterone concentration declines
in normal premenopausal women. Journal of Clinical Endocrinology & Metabolism. 80 (4):1429-30,
1995 Apr.
38. ibid. 36
39. Nair N. Hariharasubramanian N. Pilapil C. Thavundayil J. Plasma Melatonin-an index of brain aging
in humans? Biol Psychiatry, 1986, 21: 141-150 in Biological Aging Measurement, Clinical
Applications; Ward Dean MD. Center For Bio-Gerontology, Pensacola, Florida 1988.
40. Finkelstein J. Roffwarg H. Boyar R., et. al. Age-related changes in the 24 hours spontaneous secretion
of growth hormone. J Clin Endocrinol Metab 35: 665-670. 1972, in Biological Aging Measurement,
Clinical Applications; Ward Dean MD. Center For Bio-Gerontology, Pensacola, Florida 1988.
41. Meeker A. Sommerfeld H. Coffey D. Telomerase is activated in prostate and seminal vesicles of
castrated rat. Endocrinology. 137(12):5743-6, 1996 Dec.
42. Saito T., et. al. Proliferation-associated regulation of telomerase activity in human endometrium and
its potential implication in early cancer diagnosis. Biochemical & Biophysical Research
Communications. 231(3):610-4, 1997
43. Kyo S. Takakura M. Kohama T. Inoue M. Telomerase activity in human endometrium. Cancer
Research. 57(4):610-4, 1997.
44. Telomerase activity concentrates in the mitotically active segments of human hair follicles. Journal of
Investigative Dermatology. 108(1):113-7, 1997 Jan.
45. Burger A. Bibby M. Double J. Telomerase activity in normal and malignant mammalian tissues:
feasibility of telomerase as a target for cancer chemotherapy. British Journal of Cancer. 75(4):516-22,
1997.
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 44
46. Yasumoto S. et. al. Telomerase activity in normal human epithelial cells. Oncogene. 13(2):433-9,
1996 Jul. 18
47. Norrback K. Dahlenborg K. Carlsson R. Roos G. Telomerase activation in normal B lymphocytes and
non-Hodgkin’s lymphomas. Blood. 88(1):222-9, 1996 Jul.
48. Kyo S. Takakura M. Kohama T. Inoue M, Telomerase activity in human endometrium. Cancer
Research. 57(4):610-4, 1997 Feb. 15.
49. Morin G. Telomere control of replicative life span. Experimental Gerontology 32(4/5) pp. 375-382,
1997.
50. Biessmann H. Mason J. Telomere maintenance without telomerase. Chromosoma. 106(2):63-9, 1997.
51. a. Allsopp R., et. al. Telomere length predicts replicative capacity of human fibroblasts. PNAS
-USA(89(21):10114-8, 1992.
b. Hanaoka F. Yamada M. Takeuchi F. Goto M. Miyamoto T. Hori T. Autoradiographic studies of DNA
replication in Werner’s Syndrome cells. Brown, editor, Advances in Experimental Medicine and
Biology, 1984.
52. Gosselin P. Jangoux M. Induction of metamorphosis in Paracentrotus lividus larvae (Echinodermata,
Echinoidea). Oceanologica Acta 19 (3-4). 1996. 293-296.
53. Naidenko T K. induction of metamorphosis of two species of sea urchin from Sea of Japan. marine
Biology (Berlin) 126 (4). 1996. 685-692
54. Hiraishi K. Suzuki K. Hakomori S. Adachi M. Le-Y antigen expression is correlated with apoptosis
programmed cell death. Glycobiology 3(4). 1993. 381-390.
55. Moran, Scrimegeour, Horton, Ochs, Rawn. c. Biochemistry 2nd edition. pp12-36,37 1994c.
56. Xia Y. Burbank D. Uher L. Rabussay D. Van Eten J. Il-3A virus infection of a Chlorella-like green
alga induces a DNA restriction endonuclease with novel sequence specificity. Nucleic Acids
Research. 15(15):6075-90, 1987 Aug. 11.
57. Zamzami N. Hirsch T. Dallaporta B. Petit P. Kroemer G. Mitochondrial implication in accidental and
programmed cell death: apoptosis and necrosis. Journal of Bioenergetics & Biomembranes.
29(2):185-93, 1997.
58. Beletskii A. Bhagwat AS. Transcription-induced mutations: increase in C to T mutations in the non-
transcribed strand during transcription in Escherichia Coli. Proceedings of the Nat. Acad. of Sci. of
USA 93(24):13919-24, 1996 Nov. 26.
59. Yamada T. Ohwada S. Saitoh F. Adachi M. Morishita Y. Hozumi M. Induction of Le-y antigen by 5-
aza-2’-deoxycytidine in association with differentiation and apoptosis in human pancreatic cancer
cells. Anticancer Research 16(2). 1996. 735-740
60. Beard C. Li E., et. al. Loss of methylation activates Xist in somatic but not in embryonic cells.” 9 (19)
Genes Dev 9 (19) 1995.2325-2334.
61. Palmer B. Marinus M. The dam and dcm strains of E Coli- a review. Gene. 143(10:1-12, 1994 May
27.
62. Yeivin A. Levine A. Razin A. DNA methylation patterns in tumors derived from F9 cells resemble
methylation at the blastula stage. FEBS Letters. 395(1):11-6, 1996 Oct. 14.
63. Jones PA. et. al. De Novo methylation of the MyoD1 CpG island during the establishment of
immortal cell lines., Proceedings of the National Academy of Sciences of the USA. 87(16):6117-21,
1990 Aug.
64. Issa J P J., et. al. Increased cytosine DNA methyltransferase activity during colon cancer progression.
Journal of the National Cancer Institute. 85(15). 1993. 1235-40.
65. Carmeli E. Reznick A. The physiology and biochemistry of skeletal muscle atrophy as a function of
age. Proceedings of the Society for Experimental Biology & Medicine 206(2). 1994. 103-113
66. West, M. The cellular and molecular biology of skin aging. Archives of Dermatology 130 (1). 1994.
87-95.
67. Fukatsu R., et. al. Aging brains and dementias. Hokkaido Journal of Medical Science 71 (3). 1996.
297-301
68. Aspinall R. Age-associated thymic atrophy in the mouse is dye to a deficiency affecting
rearrangement of the TCR during intrathymic T cell development. Journal of Immunology.
158(7):3037-45, 1997 Apr. 1.
69. von Werder K. Growth hormone therapy in adulthood. Fortschritte der Medizin. 110(3):41-2, 45,
1992 Jan 30.
70. Hartman M. Pezzoli S. Hellmann P. Suratt P. Thorner M. Pulsatile GH secretion in older persons is
enhanced by fasting without relationship to sleep stages. Journal of Clinical Endocrinology &
Metabolism. 81(7):2694-701, 1996 Jul.
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 45
71. Bubenik GA, Ball RO, Pang SF. The effect of food deprivation on brain and gastrointestinal tissue
levels of tryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin. J Pineal Res 1992 Jan
12:1 7-16
72. Provinciali M. Di Stefano G. Bulian D. Tibaldi A. Fabris N. Effect of melatonin and pineal grafting
on thymocyte apoptosis in aging mice. Mechanisms of Ageing & Development 90(1). 1996. 1-19.
73. Schweiger U. et. al. Diet-induced menstrual irregularities: effects of age and weight loss. Fertility &
Sterility. 48(5):746-51, 1987.
74. Hwang, et. al. A 3’ -->5’XPB helicase defect in repair/transcription factor TFIIH of xeroderma
pigmentosum group B affects both DNA repair and transcription. Journal of Biological Chemistry.
271(27):15898-904, 1996 Jul 5.
75. Sijbers A, et. al. Xeroderma pigmentosum group F caused by a defect in a structure-specific DNA
repair endonuclease. Cell 86:811-22 (1996).
76. Fritz E. Elsea S. Patel P. Meyn M. Overexpression of a truncated human topoisomerase III partially
corrects multiple aspects of the ataxia telangiectasia phenotype. Proceedings of the National Academy
of Sciences of the USA. 94(9):4538-42, 1997 Apr. 29.
77. Reik W. Maher ER. Morrison PJ. Harding AE. Simpson SA. Age at onset in Huntington’s disease
and methylation at D4S95. Journal of Medical Genentics 30 (3). 1993. 185-188.
78. Masoro E. Dietary restriction and aging. Journal of the American Geriatrics Society. 41(9):994-9,
1993.
79. Reznick D. Life history evolution in guppies (Poecilia Reticulata): guppies as a model for studying the
evolutionary biology of aging. Experimental Gerontology 32(3). 1997 245-258
80. Robertson O. Wexler B. Histological changes in the organs and tissues of senile castrated Kokanee
salmon (Oncorrhynchus nerka kennerlyi). Gen. Comp. Endocrinol. 1962 2:458-472.
81. Wodinsky, J. Hormonal inhibition of feeding and death in Octopus: Control by optic gland secretion.
Science. 1977. 198:948-951.
82. Calaby, J. Taylor J. Reproduction in two marsupial mice, Antechinus bellus and Antechnicus bilarni
(Dasyuridae), of tropical Australia. J. Mammal. 1981 62:329-341
83. Rae PM. Steele RE. Absence of cytosine methylation at C-C-G-G- and G-C-G-C sites in the rDNA
coding regions and intervening sequences of Drosophila and the rDNA of other insects. Nucleic
Acids Research 6(9):2987-95, 1979 Jul 11.
84. Shen JC. Rideout WM 3rd. Jones PA. The rate of hydrolytic deamination of 5-methylcytosine in
double stranded. Nucleic Acids Research. 22(6):972-6, 1994 Mar 25.
85. McClelland M. The frequency and distribution of methylatable DNA sequences in leguminous plant
protein coding genes. Journal of Molecular Evolution. 19 (5):346-54, 1983.
86. Schwarz E. Eiter H. Taxer F. Cancer of the so called “empty breast” and its relation to Wolfe’s
classification of parenchymal patterns. ROFO: Fortshritte auf dem Gebeite der Rontgenstrahlen und
der Nuklearmedizin. 139(1):81-4, 1983.
87. Brown K. Hammond C. Urogential atrophy. Obstetrics & Gynecology of North America. 14(1):13-32,
1987 Mar.
88. Harbitz T. Testis weight and the histology of the prostate in elderly men. An analysis in an autopsy
series. Acta Pathologica et Microbiologica Scandinavica-Section A, Pathology. 81(2): 148-58, 1973
Mar.
89. Gao, G. Influence of diet on tumors of hormonal tissues. Progress in Clinical & Biological Research.
394:41-56, 1996.
90. Epstein C. et.al. Werner’s syndrome: a review of its symptomatology, natural history, pathologic
features, genetic and relationship to the natural aging process. Medicine 45: 177-221, 1966 in
Werner’s syndrome and human aging, Salk D. Fujiwara Y. Martin G. editors. (page 89 and
111)Advances in Experimental Medicine and Biology Vol. 190, Plenum Press, 1985
91. Ishii T. , et. al. Pathology of the Werner Syndrome. (table 1) Advances in Experimental Medicine and
Biology Pages 187-219 Edited by Salk D., Fujiwara Y., and Martin G. Volume 190, 1985 Plenum
Press
92. Dilman V., Dean W. The neuroendocrine theory of aging and disease. p.39 Figure 4-10 (adapted
from Dilman, 1991 and Moroz and Verkhratsky, 1985) The Center for Bio-Gerontology. 1992b.
93. Longcope C. Metabolic clearance and blood production rates of estrogens in postmenopausal women.
Am. J. Obstet. Gynecol. 11:778, 1971.
94. Sherman B. West J. Korenman S. The menopausal transition: analysis of LH, FSH, estradiol and
progesterone concentrations during menopausal cycles of older women. J. Clin. Endocrinol. 42:629-
636
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 46
95. ibid. 19.
96. Anisimov V. Khavinson K. Morozov V. Twenty years of study on the effects of pineal peptide
preparation: epithalamin in experimental gerontology and oncology,” Annals of the N. Y. Academy
of Science 719:483-93, 1994.
97. Thyagarajan S; Meites J; Quadri SK, Deprenyl reinitiates estrous cycles, reduces serum prolactin, and
decreases the incidence of mammary and pituitary tumors in old acyclic rats. Endocrinology, 1995
Mar, 136:3, 1103-10.
98. Schulz, et. al. Accelerated loss of telomeric repeats may not explain accelerated decline of Werner
syndrome cells. Human Genetics. 97(6):750-4, 1996 Jun.
99. Tower, J. Aging mechanisms in fruit flies. Bioessays 18 (10): 799-807, 1996.
100.Mitchell, Terri, The Ageless Bird-A Genetic Mystery, Life Extension Magazine. pp12-15. Life
Extension Magazine, October 1996
101.Hayflick L. Origins of Longevity. in Modern Biological Theories of Aging, edited by H. R. Warner
et . al. Raven Press, New York 1987.
102. ibid. 3.
103.Manschot W. A case of Progeronanism (Progeria of Gilford). pg 158-164. Acta Paediatrica (39) 1950
104.Schnohr P. Lange P. Nyboe J. Appleyard M. Jensen G. Gray hair, baldness, and wrinkles in relation
to myocardial infarction: the Copenhagen City Heart Study. American Heart Journal 130(5):1003-10,
1995 Nov. and
Wingard D. Cohn B. Kaplan G. Cirillo P. Cohen R. Sex differentials in morbidity and mortality risks
examined by age and cause in the same cohort. American Journal of Epidemiology. 130(3):601-10,
1989.
105.Eisenstein I. Edelstein J. Gray hair in black males a possible risk factor in coronary artery disease.
Angiology. 33(10):652-4, 1982 Oct.
106. McElvanney A. Wooldridge W. Khan A. Ansons A. Ophthalmic management of Cockayne’s
syndrome. Eye. 10(Pt 1):61-4, 1996.
107.Besman A. Favre C. Kaufmann H. The spectrum of X-ray manifestations in Cockayne Syndrome.
Skeletal Radiology. 1981; 7:173-177.
108.Levin P. Green W. Victor D. MacLean A. Histopathology of the eye in Cockayne Syndrome. Archives
of Ophthalmology. 101(7):1093-7, 1983 Jul. lipofusicin in eye.
109.Roytta M. Anttinen A. Xeroderma pigmentosum with neurological abnormalities. A clinical and
neuropathological study. Acta Neurologica Scandinavica. 73(2):191-9, 1986 Feb.
110.Swift M. Genetics and epidemiology of ataxia telangiectasia. Kroc Foundation Series. 19:133-46,
1985.
111.Fleck R. Myers, L. Wasserman R. Tigelaar R. Freeman R. Ataxia-Telangiectasia associated with
sarcoidosis. Pediatric Dermatology. 3 (4):339-43, 1986 Sep.
112.Dorndorf D. Wesseel K. Vieregge P. Verleger R. Kompf D. Presenile dementia in xeroderma
pigmentosum. Nervenartz. 62(10):641-4, 1991 Oct.
113.Chen P. Kidson C. Lavin M. Evidence of different complementation groups amongst human genetic
disorders characterized by radiosensitivity. Mutation Research. 285(1):69-77, 1993 Jan
114.Parhsad R. et. al. Fluorescent light-induced chromatid breaks distinguish Alzheimer disease cells
from normal cells in tissue culture. PNAS 93(10:5146-50, 1996 May 14.
115.Russell R. Programmed Aging-The Evidence, in Modern Biological Theories of Aging, pages 35-61.
edited by H. R. Warner et . al. Raven Press, New York 1987.
116. (In a presentation given by Gerald Schellenberg of the VA Medical Center in Seattle Northwestern
University entitled “Genetic approaches to aging and Alzheimer’s disease” he described finding
amyloid plaques in both of the two brains of Werner’s patients that he autopsied.
117.Ishii T., et. al. Pathology of the Werner Syndrome. (Case #4) Advances in Experimental Medicine
and Biology Pages 187-219 Edited by Salk D., Fujiwara Y., and Martin G. Volume 190, 1985 Plenum
Press
118.Ahn B. Jung Y. Chay K. Protein oxidation in relation to aging and drug toxicity. Chonnam Journal of
Medical Sciences 7(2). 1994. 134-140
119.Epstein C. Motulsky A. Werner syndrome: entering the helicase era. Bioessays. 18(12):1025-7, 1996,
Dec.
120.Fritz E. Elsea S. Patel P. Meyn M. Overexpression of a truncated human topoisomerase III partially
corrects multiple aspects of the ataxia telangiectasia phenotype. Proceedings of the National Academy
of Sciences of the USA. 94(9):4538-42, 1997 Apr. 29.
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 47
121.Duguet M. When helicase and topoisomerase meet. Journal of Cell Science 110(12). 1997. 1345-
1350.
122. Weirich-Schwaiger H. Weirich H. Gruber B. Schweiger M. Hirsch-Kauffmann M. Correlation
between senescence and DNA repair in cells from young and old individuals and in premature aging
syndromes. Mutation Research. 316(1):37-48, 1994 Feb.
123.Ahn B. Jung Y. Chay K. Protein oxidation in relation to aging and drug toxicity. Chonnam Journal of
Medical Sciences 7(2). 1994. 134-140
124.Scheffner M. Knippers R. Stahl H. RNA unwinding activity of sV40 large antigen. Cell 75, 955-963,
June 16, 1989.
125.Beletskii A. Bhagwat AS. Transcription-induced mutations: increase in C to T mutations in the non-
transcribed strand during transcription in Escherichia Coli. Proceedings of the Nat. Acad. of Sci. of
USA 93(24):13919-24, 1996 Nov. 26.
126.Brown W. Zebrower M. Kieras F. Progeria, a model disease for the study of accelerated aging. In:
Molecular Biology of Aging, edited by A. D. Woodhead, A.D. Blackett, and A. Hollaender, pp. 375-
396. Plenum Press, New York. 1984.
127.Hikata H. Vaughan J. Pitot H. The effect of two periods of short-term fasting during the promotion
stage of hepatocarciogenesis in rats: The role of apoptosis and cell proliferation. Carcinogenesis
(Oxford) 18(1). 1997. 159-166.
128.Odens, M. Prolongation of Life Span in Rats. Journal of the American Geriatrics Society, pp. 450-
1.1973, October.
129.Munkres K. Pharmacogenetics of cyclic guanylate, antioxidants , and antioxidant enzymes in
Neurospora. Free Radical Biology & Medicine. 9(1):29-38, 1990.
130.Russell R. Programmed Aging-The Evidence, Modern Biological Theories of Aging, pages 35-61.
1987.
131. Vaisman N. Sklan D. Dayan Y. Effect of moderate semi-starvation on plasma lipids. International
Journal of Obesity. 14(12):989-96. 1990.
132.Adler R. Robinson R. Pazdral P. Grushkin C. Hyperuricemia in diarrheal dehydration. American
Journal of Diseases of Children. 136(3):211-3, 1982 Mar.
133.Cutler, RG. Antioxidants and Longevity. Free Radicals in Molecular Biology, Aging, and Disease,
pp.235-267. 1984.
134.Randerath K. Zhou GD. Hart RW. Turturro A. Randerath E. Biomarkers of aging: correlation of
DNA I-compound levels with median life span of calorically restricted and ad libitum fed rats and
mice. Mutation Research. 295(4-6):247-63, 1993 Dec.
135.Randerath E. Hart RW. Turturro A. Danna TF. Reddy R. Randerath K. Effects of aging and caloric
restriction on I-compounds in liver, kidney, and white blood cell DNA of male Brown-Norway rats.
Mech. Aging Dev 1991 May:58 (2-3) 279-96
136.Veldhuis JD Iranmanesh A Evans WS Lizarralde G. Thorne MO. Vance ML. Amplitude suppression
of the pulsatile mode of immunoradiometric LH release in fasting-induced hypoandrogenemia in
normal men. Journal of Clinical Endocrinology & Metabolism 76 (3). 1993. 587-593.
137.Golombek D. Burin L. Cardinali D. Time- dependency for the effect of different stressors on rat
pineal melatonin content. Acta Physiologica, Pharmacologica et Therapeutica Latinoamericana.
42(1):35-42, 1992.
138.Hartman M. Pezzoli S. Hellmann P. Suratt P. Thorner M. Pulsatile GH secretion in older persons is
enhanced by fasting without relationship to sleep stages. Journal of Clinical Endocrinology &
Metabolism. 81(7):2694-701, 1996 Jul.
139.Kato, et. al. Role of TNF-A and glucocorticoid on lipopolysaccharide (LPS)-induced apoptosis of
thymocytes. FEMS Immunology & Medical Microbiology. 12(3-4):195-204, 1995 Dec.
140.Wronska, D. Niezgoda J. Sechman A. Bobek S. Food deprivation suppress stress-induced rise in
catabolic hormones with a concomitant tendency to potentiate the increment of blood glucose.
Physiology and Behaviour 48(4). 1990. 531-538.
141.Schweiger U, et. al. Diet-induced menstrual irregularities: effects of age and weight loss. Fertility
and Sterility. 48(5):746-51, 1987 Nov.
142. Bhagat L. Duraiswami S. Muralidhar K. Modde of action of inhibin-like pineal antigonadotropin is
different from melatonin during compensatory ovarian hypertrophy. Journal of Pineal Research.
16(4):193-7, 1994.
143. ibid. 142.
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 48
144.Champney T. Prado J. Youngblood T. Appel K. McMurray D. Immune responsiveness of splenocytes
after chronic daily melatonin administration in male Syrian hamsters. Immunology Letters. 58(2):95-
100, 1997 Jul.
145.Haus E. et al. Stimulation of the secretion of DHEA by melatonin in mouse adrenals in vitro. Life
Sciences. 58(14):PL263-7, 1996.
146.Valcavi R. Zini M. Maestroie G. Conti A. Portioli I. Melatonin stimulates GH secretion through
pathways other than the gh-rh. Clinical Endocrinology. 39(2):193-9, 1993 Aug.
147.Cagnacci A. Soldani R. Yen S. Melatonin enhances cortisol levels in aged women: reversible by
estrogens. Journal of Pineal Research. 22(2):81-5, 1997 Mar.
148. Voordouw, et al. J Clin Endocrinol Metab 74 (1): 108-117 1992. and
Okatani Y. Sagara Y. Enhanced nocturnal melatonin secretion in women with functional secondary
amenorrhea: relationship to opioid system and endogenous estrogen levels. Hormone Research 43:5
194-9 1995.
149. Vriend J. Effects of melatonin and thyroxine replacement on thyrotropin, LH, and prolactin in male
hypothyroid hamsters. Endocrinology. 117(6):2402-7, 1985
150.Mitsuma T. Nogimori T. Effects of various drugs on thyrotropin secretion in rats. Hormone &
Metabolic Research. 17(7):337-41, 1985.
151.a.Van Den Heuvel C. Reid K. Dawson D. Effect of atenolol on nocturnal sleep and temperature in
young men: Reversal by pharmacological doses of melatonin. Physiology & Behavior 61(6). 1997.
795-802.
b. Golombek D. Burin L. Cardinali D. Time-dependency for the effect of different stressors on rat
pineal melatonin content. Acta Physiologica, Pharmacologica et therapeutica Latinoamericana.
42(1):35-42, 1992.
152. Baldwin D. Wilcox Z. Baylosis R. Impact of different housing on humoral immunity following
exposure to acute stressor in rats. Physiology & Behavior 57(4). 1995. 649-653.
153. Morrison D., et. al. Testosterone levels during systemic and inhaled corticosteroid therapy.
Respiratory Medicine 88(9). 1994. 659-663.
154.Calogero A., et. al. Effects of corticotropin-releasing hormone on ovarian estrogen production in
vitro. Endocrinology, 1996 Oct, 137:10, 4161-6
155.Silman R. Melatonin: a contraceptive for the nineties. European Journal of Obstetrics , Gynecology,
& reproductive Biology. 49(1-2):3-9, 1993 Apr.
156.Rossmanith W. Handke-Vesely A. Wirth U. Scherbaum W. Does the gonadotropin pulsatility of post-
menopausal women represent the unrestrained hypothalamic-pituitary activity? European Journal of
Endocrinology. 130(5):485-93, 1994 May.
157.Grodstein, et. al. Post-menopausal hormone therapy and mortality. New England Journal of
Medicine. 336(25):1769-75, 1997 Jun. 19
158.Carlsson B. Sjostrand J. Increase of cataract extractions in women above 70 years of age. A
population based study. Acta Opthalmologica Scandinavica 74(1):64-8, 1996 Feb.
159.Verbrugge L. Women, men and osteoarthritis. Arthritis Care & Research. 8(4):212-20, 1995 Dec.
160.Baron Y. Bricat M. Galea R. Baron A. The epidemiology of osteoporotic fractures in a Mediterranean
county. Calcified Tissue International. 54(5):365-9, 1994 May
161.Albala, et. al. Obesity as a protective factor for post-menopausal osteoporosis. International Journal of
Obesity and Related Metabolic Disorders. 20(11):1027-32, 1996 Nov.
162.Zhang, et. al. Bone mass and the risk of breast cancer among post-menopausal women. New England
Journal of Medicine. 336(9):611-7, 1997 Feb. 27
163.Heber D. McCarthy W. Ashley J. Byerley L. Weight reduction for breast cancer prevention by
restriction of dietary fat and calories: rationale, mechanisms and interventions. Nutrition. 5 (3): 149-
54, 1989 May-Jun.
164. Kissebah A. Intra-abdominal fat: Is it a major factor in developing diabetes and coronary heart
disease? Diabetes Research & Clinical Practice 30(Suppl.). 1996. S25-S30.
165.Orentreich N. Matias J. Defelice A. Zimmerman J. Low methionine ingestion by rats extends life
span. Journal of Nutrition 123 (2). 1993. 269-274.
166.McCay C. Dilley W. Crowell M. Growth rates of brook trout reared upon purified rations, upon dry
skim milk diets, and upon feed combination of cereal grains. Journal of Nutrition 1(3) Jan. 1929.
167.Segall P. Interrelations of dietary and hormonal effects in aging. Mechanisms of Ageing &
Development. 9(5-6):515-25, 1979.
168. a.ibid. 166
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 49
b. Carlson A. Hoelzel F. Apparent prolongation of the life span of rats by intermittent fasting. Journal of
Nutrition 31:363 1946.
169.Huang. Wan. Siu-Lan Lee. Sighvatur S. Arnason.Mats Sj. Dehydration natriuresis in male rats is
mediated by oxytocin-Amer journal of Physiology 270 pt 2 R427-33 1996 Feb.
170.Korba B. Hays J. Partially deficient methylation of cytosine in DNA at CCATGG sites stimulates
genetic recombination of bacteriophage lambda.
171.O'Gara M; Klimasauskas S; Roberts RJ; Cheng X Enzymatic C5-cytosine methylation of DNA:
mechanistic implications of new crystal structures for HhaL methyltransferase-DNA-AdoHcy
complexes. J Mol Biol, 1996 Sep 6, 261:5, 634-45
172.Loehrer FM; Haefeli WE; Angst CP; Browne G; Frick G; Fowler B Effect of methionine loading on
5-methyltetrahydrofolate, S-adenosylmethionine and S-adenosylhomocysteine in plasma of healthy
humans.Clin Sci (Colch), 1996 Jul, 91:1, 79-86
173. Fau D. Peret J. Hadjiisky P. Effects of ingestion of high protein or excess methionine diets by rats fro
two years. Journal of Nutrition. 118(1):128-33, 1988.
174.Finkelstein J. Kyle W. Harris B. Methionine metabolism in mammals. Regulation of homocysteine
methyltransferases in rat tissue. Archives of Biochemistry and Biophysics 146, 84-92 (1971).
175.Barry T. Manley T. Redekopp C. Davis S. Fairclough R. Lapwood K. Protein metabolism in growing
lambs given fresh ryegrass , cover pasture ad lib. 2. Endocrine changes, glucose production, and their
relationship to protein deposition and the partition of absorbed nutrients. British Journal of Nutrition.
47(2):319-29, 1982 Mar.
176.Reddy PM. Reddy PR. Regulation of DNA methyltransferase in the testis of the rat. Biochemistry
International. 16(3):543-7, 1988 Mar.
177.Parker M. de Haan J. Gevers W. DNA hypermethylation in sodium butyrate-treated WI-38
fibroblasts. Journal of Biological Chemistry. 261(6):2786-90, 1986.
178. ibid. 28
179.Wilmut I. Schnieke E. McWhir J. Kind A. Campbell K. Viable offspring derived from fetal and adult
mammalian cells. Nature 385, pg. 810-813. 1997. Feb.
180.Brown J. Wei W. Sedivy J. Bypass of senescence after disruption of p21 CIP1/WAF1 gene in normal
human fibroblasts. Science 277 (5327):831 1997. Aug.
181.Antmann E. Edde E. Sauer G. Westphal O. Restoration of the responsiveness to growth factors in
senescent cells by an embryonic cell extract, Experimental Cell Research 1990; 189:202-7.
182.Schulze Forster K. Goetz F. Wagner H. Kroeger H. Simon D. Transcription of HIV-1 is inhibited by
DNA methylation. Biochemical & Biophysical Research Communications 168 (1). 1990. 141-147.
183.Andrews J. Mancini D. Singh S. Rodenhiser D. Site and sequence specific DNA methylation in the
neurofibromatosis (NF1) gene includes C5839T: the site of the recurrent substitution mutation in
exon 31. Human Molecular Genetics. 5(4):503-7, 1996 Apr.
184.ibid. 77
185. a. Van Voorhis B. Syrop C. Hammitt D. Dunn M. Snyder G. Effects of smoking on ovulation
induction for assisted reproductive techniques. Fertility & Sterility. 58(5):981-5, 1992.
b. Ochedalski T. Lachowicz-Ochedalska A. Dec W. Czechowski B. Examining the effects of tobacco
smoke on levels of certain hormones in serum of young men. Ginekologia Polska. 65(2):87-93, 1994
Feb.
186.Fuxe K. Andersson K. Eneroth P. Harfstrand A. Agnati L. Neuroendocrine actions of nicotine and
exposure to cigarette smoke medical implications. Psychoneuroendocrinology. 14(1-2):19-41, 1989.
187.Hong M. Moody T. Vasopressin elevates cytosolic calcium in small cell lung cancer cells. Peptides
(Elmsford) 12 (6). 1991. 1315-1320.
188. Trappolini M. Matteoli S. Chillotti F. Curione M. Del Vecchio L. Puletti M. Cigarette smoking and
acute myocardial infarct. Minerva Cardioangiologica. 44(12):608-16, 1996, Dec.
189.Mosley J. Gibbs A. Premature gray hair and hair loss among smokers: A new opportunity for health
education? British Medical Journal 313(7072). 1996. 1616
190. Riggs J. The “protective” influence of cigarette smoking on Alzheimer’s and Parkinson’s diseases.
Quagmire or opportunity for neuroepidemiology? Neurologic Clinics. 14(2):353-8, 1996 May.
191. Baron J. Beneficial effects of nicotine and cigarette smoking: The real the possible and the spurious.
British Medical Bulletin 52(1). 1996. 58-73.
192. Brinton L. Schairer C. Stanford J. Hoover R. Cigarette smoking and breast cancer. American Journal
of Epidemiology. 123(4):614022, 1986 Apr.
Copyright pending, this paper may not be copied, transmitted, or reproduced in any way, in whole or in
part, without the prior, express, written consent of the author. 50
193. Lin J. Lei Z. Lojun S. Rao C. Satyaswaroop P. Day T. Increased expression of LH/hCG receptor gene
in endometrial carcinomas. Journal of Clinical Endocrinology & Metabolism. 79(5):1483-91, 1994 .
194. Wald N. Hackshaw A. Cigarette smoking: an epidemiological overview. British Medical Bulletin.
52(1):3-11, 1996. Jan.
195. Bonuccelli U. et. al. Reduced LH secretion in women with Parkinson’s disease. Journal of Neural
Transmission-Parkinson’s Disease & Dementia Section. 2(3):225-31, 1990.
196.a.Oomura Y. Nakamura T. Manchanda S. Excitatory and inhibitory effects of globus pallidus and
substantia nigra on the lateral hypothalamic activity in the rat. Pharmacology, Biochemistry &
Behavior. 3 (1 Suppl):23-36, 1975.
197.Haber S. Kowall N. Vonsattel J. Bird E, Richardson E. Gilles de la Tourette’s syndrome. A
postmortem neuropathological and immunohistochemical study. Journal of the Neurological Sciences.
75(2):225-41, 1986, Sep.
198.Gibson M. Aulette F. Effect of prostaglandin synthesis inhibition on human corpus luteum function.
Prostaglandins, 31(6):1023-8, 1986 Jun.
199.a.Bieniarz A. Berger T. Nishimura K. diZerega G. Ibuprofen modulation of hCG-induced ornithine
decarboxylase activity and ovulation in the rabbit ovary. American Journal of Obstetrics &
Gynecology. 147(3):327-32, 1983 Oct. 1
b.Caldwell J. Furst D. The efficacy and safety of low-dose corticosteroids for rheumatoid arthritis
[Review] Seminars in Arthritis & Rheumatism. 21(1):1-11, 1991, Aug.
200.Steinberger E. Root A. Ficher M. Smith D. The role of androgens in the initiation of spermatogenesis
in man. J. Clin. Endocrinol. Metab. 37:746-751
201.Effect of aging on kinietic parameters of 3 alpha(beta)-hydroxysteroid oxidoreductases in epithelium
and stroma of normal and hyperplastic prostate. Journal of Clinical Endocrinology and Metabolism.
71(3):732-9. 1990 Sep.
202.Nakhla, et. al. 5 alpha-Androstan-3 alpha, 17 beta diol is a hormone: stimulation of cAMP
accumulation in human and dog prostate. Journal of Clin. Endocr. & Metab. 80(7):2259-62, 1995 Jul.
203.Waldhauser F. et. al. A pharmacological dose of melatonin increases PRL levels in males without
altering those of GH, LH, FSH, TSH, testosterone or cortisol. Neuroendocrinology. 46(2):125-30,
1987.
204.Pearl R. The rate of living. New York:Knopf 1927
205.Sacher G. Relation of life span to brain weight and body weight in mammals. In the Life span of
Animals G. Wolstenholme & M O’Conner editors. pp. 115-133. Ciba Foundation Colloquia on
Ageing, vol. 5. London: Churchill; Boston: Little, Brown and CO. 1959.
206.Herreid C. Bat longevity and metabolic rate. Experimental Gerontology 1:193-200. 1964
207. Flower, S. Contributions to our knowledge of the duration of life in vertebrate animals. (4) Birds.
1365.
208.Mitchell, Terri, The Ageless Bird-A Genetic Mystery, Life Extension Magazine. pp12-15.Life
Extension Magazine, October 1996
209.Flower, S. Contributions to our knowledge of the duration of life in vertebrate animals. (3) Reptiles
911. 1938
210.Flower, S. Contributions to our knowledge of the duration of life in vertebrate animals. (3) Reptiles
911. 1925 and Herreid C. Bat longevity and metabolic rate. Experimental Gerontology 1:193-200.
1964
211.Jensen A. Johnson F. Race and sex differences in head size and IQ. Intelligence 18(3). 1994. 309-333
212.Leherke R. A theory of X-linkage of major intellectual traits. Am F Ment Defic. 1927; 76:611-19
213.Patterson F. Holts C. Saphire L. Cyclic changes in hormonal physical behavioral and linguistic
measures in a female lowland gorilla. American Journal of Primatology 24 (3-4). 1991 181-194
214.Discovery Channel programming: Wild Discovery. During 1997 Season showed a Chimpanzee able
to use number symbols by selecting numbers on a computer screen when asked to count the number of
objets presented. Research being performed by Dr. Sarah Boysen at University of Ohio.
215.Discovery Channel programming: Wild Discovery/Animal Intelligence. During 1997 Season showed
sea otter pups learning from their mothers and from humans how to use rocks while floating on their
backs to break open shellfish. Orphaned pups did not instinctively have this ability.
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part, without the prior, express, written consent of the author. 51