Aging Theories
This report outlines the main theories of how the process of aging works.
Since
researchers have not discovered a universally-accepted theory of aging,
the
theories discussed are potential explanations of how we age. The
likelihood of
each hypothesis is considered roughly equal. The different
theories discussed
focus on the workings of different parts of the body, from
the molecular level
of DNA mutations and replication, to the organism level
of becoming "worn
out." Aging is a very complex and gradual process, and its
ongoing operation
is present to some degree in all individuals. It is a
journey to the maturity,
as well as to the degeneration of the body. Because
aging affects every part of
the body, many different steps are involved and
various types of reactions
occur. Changes in DNA take place, which can and
often do affect the way the body
functions; harmful genes are sometimes
activated, and necessary ones
deactivated. A decrease in important body
proteins like hormones and certain
types of body cells is almost inevitable.
These, among many, are characteristic
changes that take place in our bodies
as time moves on and aging continues. At
present, a universal explanation for
how we age or why we age does not exist,
but there are many theories to
explain this puzzle, and they are supported by
continuous research. In this
report, some of the how theories of aging will be
examined. Among them are
theories concerning spontaneous mutations, damage from
free radicals, the
clock gene, cellular aging, a weakened immune system, wear
and tear, and
hormonal and neuroendocrinous changes. Spontaneous Mutations The
spontaneous
mutations theory, also known as the somatic mutation hypothesis,
states that
the crucial events that cause aging are mutations. These are changes
in a
cell=s DNA, which are passed on to daughter cells during mitosis. Since
genes
on DNA code for specific proteins, mutated genes may produce
defective
proteins, which do not work properly. Many proteins can be
affected, such as
enzymes, proteins comprising muscle tissue, and a recently
discovered type of
protein called transcription factors, which bind to DNA
and regulate the
individual activities of genes themselves. Physical mutagens
are substances that
increase the chance of mutation and include such physical
phenomena as x-rays
and radioactivity from radium. The atomic bombs dropped
on Hiroshima and
Nagasaki in Japan are examples of physical mutagens that
caused an increase in
the number of cases of leukemia. Certain chemicals and
radiation cause mutations
to occur in DNA by giving off high energy
particles. These particles collide
with the DNA and knock off atoms of the
DNA randomly, damaging it. DNA consists
of sequences of four possible
nitrogenous bases: adenine, guanine, cytosine, and
thymine, paired so that
adenine always pairs with thymine, and guanine always
pairs with cytosine. As
cells repair the damaged DNA, a different DNA base is
often substituted. This
base-substitution is known as a point mutation and can
cause the production
of a defective or damaged protein. Apart from being caused
by radiation or
chemicals, mutations also occur spontaneously but at lower
rates. Physicist
Leo Szilard and biochemist Denham Harmon proposed that because
most mutations
are harmful, the more spontaneous mutations that arise, the
more
abnormalities that arise as defective proteins are produced. These
could
ultimately kill an individual (Ricklefs and Finch, 1995, 20). Although
it has
been proven that many proteins undergo alterations during aging, the
spontaneous
mutations theory is not the cause (Ricklefs and Finch, 1995, 21).
It has,
however, been proven that DNA is chemically altered during aging.
Modifications
in DNA bases, called I-spots, have been found to increase in
number during
aging. Besides I-spots, another modified base known as
8-hydroxyguanine, the DNA
base guanine with an added OH group, has also been
found to increase during
aging. It is unclear how changes such as these
arise, but similar changes seem
to be caused be exposure to mutation-causing
chemicals, some of which are found
in tobacco smoke (Ricklefs and Finch,
1995, 21). Another factor supporting the
spontaneous mutations theory may lie
in the temporal occurrence of genetic
mutations. Certain cancers and abnormal
growths seem to appear more frequently
as the process of aging continues. Two
tumour suppressor genes called p16 and
p53 are responsible for slowing cell
proliferation, and therefore keep certain
cells from becoming cancerous.
However, if they become mutated, they do not
carry out their function
properly so cells with these mutations begin to grow
and divide quickly,
causing cancer and other growths (Ricklefs and Finch, 1995,
22). Werner’s
syndrome is a disorder that significantly accelerates the aging
process
starting at around 20 years of age. Molecular geneticist
Gerard
Schellenburg has suggested that the function of the enzyme
helicase, which
normally unzips the DNA double helix before replication and
removes randomly
occurring mutations like base substitutions, does not
function properly in
people afflicted with Werner’s. Therefore, the unzipping
of the DNA double
helix is disrupted and mutations are overlooked (Lafferty
et al., 1996, 60).
Moreover, DNA occasionally loses one or more bases
through the process of
spontaneous deletion. This type of mutation seriously
affects the mitochondria
of the cell, a main source of energy within the
cell. Mitochondria have their
own DNA, mtDNA, which allows them to
self-replicate. The mtDNA encodes for
enzymes found within the mitochondria
which help produce ATP, energy-storing
molecules. During aging, the amount of
mtDNA that possess lost segments of DNA
increases. Although still unproven,
it is believed that this abnormal mtDNA may
cause defects in energy
production. Most mtDNA deletions occur in brain, muscle,
and other tissue
with little cell division. By the end of one’s lifespan,
certain parts of the
brain consist of as much as 3% abnormal mtDNA (Ricklefs and
Finch, 1995,
22). Many characteristics of aging have been proven to develop as a
result of
spontaneous mutations. However, many other changes associated with
aging
cannot be adequately explained by this theory. Damage from Free Radicals
A
free radical is a fragment of a molecule or atom that contains at least
one
unpaired electron. Because unpaired electrons are unstable, an uneven
electrical
charge is created and the electrons attract those of other atoms
or molecules to
become stable and rectify the electrical imbalance. As they
gain electrons from
other molecules, they modify the other molecules. In this
way, free radicals can
damage DNA, and it is known that damaged DNA is
involved in the aging process.
Free radicals can be formed when atoms
collide with one another, as in the
impact of x-rays or UV radiation from
sunlight on living cells. They can start a
chain reaction in which atoms or
molecules snatch electrons from one another.
This process of losing
electrons is known as oxidation. Though oxidative damage
can be slowed
through the help of enzymes and the absorption of free radicals
by
antioxidants like vitamins E and C, free radicals continue to cause
damage,
however little, to DNA (Kronhausen et al., 1989, 78). Cross-linking,
or
large-scale fusion of large cell molecules, is involved in a process
responsible
for the wrinkling of skin, the loss of flexibility, and rigor
mortis. It occurs
when little or no antioxidant activity is present to
alleviate the rapid
stiffening of body tissues (Kronhausen et al., 1989, 74).
In older individuals,
oxidized proteins in tissues have been found, and when
proteins become oxidized,
they usually become inactive. Lipids, which
constitute a large part of the cell
membrane, may also become oxidized,
thereby reducing the fluidity of the cell
membrane. Also, it is possible that
vascular diseases are caused by oxidative
damage since oxidized lipids in the
blood cause arteries to thicken abnormally (Ricklefs
and Finch, 1995, 24). In
addition, some scientists believe that difficulty in,
or slowness of movement
(when we age), as well as tremors associated with the
aging disease called
Parkinson=s disease are caused by oxidative damage (Ricklefs
and Finch, 1995,
26). The neurotransmitter dopamine, found in the brain is
damaged by free
radicals produced by enzymes during the removal of dopamine from
the synapses
of the brain. During aging, damaged mtDNA is thought to collect in
parts of
the brain with high dopamine concentrations and is thought to be
caused
indirectly by the presence of these free radicals (Ricklefs and Finch,
1995,
25). Some regions of the brain high in dopamine and damaged mtDNA
happen to be
the basal ganglia, the parts that aids in movement control
(Ricklefs and Finch,
1995, 25). A Free Radical Reaction with Glucose As
the body continues its normal
survival processes, insulin becomes less
effective in encouraging the uptake of
glucose from the blood. In this way,
the body develops insulin resistance. This
condition is similar to the more
serious type of diabetes called maturity-onset
diabetes, or type II diabetes.
If diabetes was left untreated, the excess
glucose in the bloodstream would
not be taken into cells because of insulin
resistance. Instead, the excess
glucose in the blood would react with hemoglobin
in a free radical reaction
through a process called non-enzymatic glycation.
Other proteins such as
collagen and elastin, which make up the connective
tissues between our brain
and skull, and in our joints, can also become glycated.
Once this occurs,
they stop functioning properly. The result of this is that
diverse compounds
called advanced glycosylation end products (AGEs) become
attached to
proteins. The combination of AGEs with proteins forms a sticky
substance that
could dramatically reduce joint movement, clog arteries, and
cloud tissues
like the lens of the eye, leading to cataracts (Lafferty et al.,
1996,
56). Once glycated proteins are formed, they can cause further damage
by
interacting with free radicals from other sources (Ricklefs and Finch,
1995,
26). The Lethal Clock A gene called clock-1, which was believed to
determine an
organism=s lifespan was found in small organisms and a very
similar gene has
also recently been found in humans (Lafferty et al., 1996,
58). Although it is
uncertain whether the clock genes affect how susceptible
cells are to
infections, or if they control the actual aging process, it is
generally agreed
upon that these genes have something to do, either directly
or indirectly, with
aging (Allis et al., 1996, 64). It has been proposed in
the clock theory that
the demise of brain cells, of which we lose thousands
each day, is due to
regular, programmed cellular destruction, and not to
random *accidents= (Keeton,
1992, 50). As cells divide, the number of
divisions that they undergo is
monitored and kept track of. After a certain
number of divisions, the clock
genes are triggered and may produce proteins
responsible for cell destruction
(Keeton, 1992, 50). Cellular Aging In 1961,
a discovery made by Leonard Hayflick
showed that normal, diploid cells from
such continually Areplaced@ parts of the
body as skin, lungs, and bone
marrow, divide a limited number of times. Although
the cells stop dividing at
the point just before DNA synthesis, they do not die.
The longer-lived
the species, the more divisions the cells undergo. As the age
of an
individual increases, the number of potential divisions decreases
(Ricklefs
and Finch, 1995, 29). This discovery was found using fibroblasts,
or cells found
in the connective tissues throughout the body. The cells were
placed in a
laboratory dish under sterile conditions and allowed to grow and
divide until
they filled the dish. Then some of these cells were placed in a
new dish until
it was filled. The number of Areplatings@ necessary until the
cells no longer
grew and filled the dish represented the number of cell
divisions (Ricklefs and
Finch, 1995, 29). It is not known why the cells
stop dividing, but these
AHayflick limits@ may be caused by some genes
responsible for halting the
division of neurons during developmental stages
(Ricklefs and Finch, 1995, 30).
This limited number of cell divisions is
often thought of as cellular aging
(Lafferty et al., 1996, 55), a microcosm
of the process of gradual, yet, actual
deceleration and deterioration of the
body. Though remarkable discoveries
support the fact that cells stop
dividing, this theory does not seem to
recognize why cells stop dividing.
Shortened Telomeres The theory that shortened
telomeres are involved in aging
is an extension of the cellular aging theory.
Telomeres are highly
repetitive sequences of nucleic bases found at the tips of
chromosomes. They
contain only a few genes. Their function is to protect
chromosomes in a
manner similar to Athe way a plastic cuff protects a shoelace@
(Lafferty et
al., 1996, 57). After each DNA replication, telomeres on the
daughter
chromosomes become shorter than those on the parent strand. So after
enough
replications, which happens to be the Hayflick limit, the telomeres
have
become strikingly diminished and cell reproduction ceases. It has been
theorized
that at this point, genes previously protected by telomeres become
revealed and
produce proteins that aid in the deterioration of tissue,
characteristic of the
aging process (Lafferty et al., 1996, 57). To back up
this theory, researchers
have found that cells that do not stop dividing,
such as sperm cells and many
cancer cells, do not lose telomere DNA. These
cells possess an enzyme called
telomerase, which maintain telomeres (Lafferty
et al., 1996, 57). If this is
true, then with an extra boost of telomerase,
DNA may replicate many more times
and in turn, we may be able to live longer.
Yet instead of slowing or stopping
the process of aging, this possibility may
only prolong it, since it has already
been accepted that damaged, not a
shortage of, DNA plays a large role in aging.
The Body’s Weakened Immune
System During aging, the efficiency of the immune
system declines. Normally,
novel antigens, foreign molecules found on the
surface of viruses and
bacteria, activate the production of antibodies secreted
by white blood
cells, or lymphocytes, called B-cells. The antigens act to
neutralize the
virus or bacteria, rendering it harmless. If the novel antigens
are missed by
the antibodies, a Aback-up@ process comes into play. Macrophage
cells
safeguard the body and envelope foreign antigens that they later expose
to
T-cells for destruction. The pieces of virus that the macrophages pick
up
trigger the appropriate T-cell, which in turn replicates, producing more
copies
of itself. These T-cells, called memory T-cells, can recognize and
destroy cells
infected with the virus (Ricklefs and Finch, 1995, 35). These
two methods of
protecting the body from invasion make up the primary immune
response, and this
is the component of the immune system that decreases in
efficiency as we age.
The secondary response is the body=s resistance
against pathogens it has already
met. The reason for the decline in the
immune system=s efficiency is that over
time, we come in contact with more
viral and bacterial infections so that more
of our T-cells have been
stimulated, converted to memory T-cells, and therefore,
used. That is, they
cannot be used to fight off any new viruses or bacteria that
invade the body.
It is possible that the total number of T-cells is set early in
life. If this
is so, then as we grow older, having already fought off a number
of
infections, we have a smaller amount of Aunemployed@ T-cells available
to
fight of infections that come our way (Ricklefs and Finch, 1995, 34).
In
addition to the decrease in unused T-cells, antibodies used against the
body=s
own proteins are occasionally made. This faulty process is common in
autoimmune
diseases like multiple sclerosis (Ricklefs and Finch, 1995, 36).
Whereas this
theory of how we age is a very practical one, it almost assumes
that older
people die as a result of infections, no matter how mild, because
of a weakened
immune systems. This is often, not so. Wear and Tear Just as
machinery and other
equipment gets worn down through use, so too do our
organs and cells. It is
almost inevitable that once our first cells have
developed and our organs begin
functioning, they also begin a very gradual
deterioration through use. In fact,
heavy use of our organs and bodies can
accelerate this deterioration we call
aging (Ricklefs and Finch, 1995, 33).
In typists, for example, carpal tunnel
syndrome and other degenerative
problems come about faster and more commonly
than in those who do not exhibit
such specialized use of their fingers. On the
other hand, problems can also
arise from lack of use. Muscle atrophy, which is
noticed in the elderly is
the result of a lack of muscle use (Ricklefs and
Finch, 1995, 33). So
assuming that moderate use of our bodies is healthy and
will not promote any
degenerative problems seems safe. Still, even regular,
moderate use of one=s
body, however long it can prevent certain problems, does
not hold the body=s
performance at the same level for very long. As aging
continues, a loss of
elasticity from the connective tissues in various parts of
the body is
experienced, and muscle performance, among other things, is reduced
(Ricklefs
and Finch, 1995, 33). In 1900, the life expectancy in the U.S. was 47
years.
It may be thought that this was the length of time the human body
could
withstand *wear and tear= before it Abroke down.@ Today, the life
expectancy in
the U.S. is about 76 years because of modern technology, and
many beneficial
medical breakthroughs (Lafferty et al., 1996, 55). This large
increase in life
expectancies does not necessarily mean that human bodies can
endure heavier use,
or more wear and tear, but that it takes longer for our
bodies to deteriorate
now than it did in previous years. At the molecular
level, lipofuscins, or aging
pigments, appear with increasing frequency in
non-dividing cells. Because they
contain oxidized lipids, it has been
theorized that they are products of
oxidative chemical reactions such as
those involving free radicals (Ricklefs and
Finch, 1995, 34).
Modifications in Hormonal and Neuroendocrine Systems The
pituitary, ovaries,
and testes are part of a system of glands that secrete
hormones into the
blood stream and which are controlled by the brain. This
system is called the
neuroendocrine system. At puberty, a signal is sent by the
pituitary gland to
the ovaries and testes, telling them to produce more sex
hormones such as
estrogens and progesterone in women and androgens in men. In
women,
menopause, a stage in which the reproductive system is shut down, is
reached.
From this point in a woman=s life these hormones are no longer produced
and
many changes are experienced. Because some neurons can become Aaddicted@
to
estrogens, the absence of these hormones induces the brain to respond
in
different ways, such as sending a surge of blood to the skin. This is
sometimes
called a Ahot flash@ (Ricklefs and Finch, 1995, 37). Unlike hot
flashes, a woman
may experience harmful or dangerous changes because of
menopause: osteoporosis,
or the loss of compact bone is accelerated because
bone-mineral metabolism is
dependent on estrogen. Once this condition has
reached a certain stage, it
reduces the ability of bones to support body
weight. It also immensely elevates
the risk of bone fractures. In fact, as a
woman increases in age, her risk of
bone fracture due to osteoporosis
increases exponentially (Ricklefs and Finch,
1995, 43). In men, the
number of abnormal sperm, incidence of lower testosterone
production, and
incidence of impotence have been found to increase with age.
Because the
brain controls the pulses of testosterone, it can be said that some
of these
changes arise because of different signals in the brain (Ricklefs
and
Finch, 1995, 44). The hormonal and neuroendocrine theory collects
evidence
mostly from a female way of life, yet both men and women experience
the aging
process and many of the same characteristics that go with it. The
knowledge that
the process of aging is very complex can be deduced from the
simple fact that
there are many entirely different, yet plausible, theories
of how aging works.
In fact, the possibility that several of these
theories are connected, or play a
combined part in aging is not far fetched.
Yet because the process of aging is
so multifarious, just how humans complete
or even begin the transition from
youth to old age remains a mystery to some
extent. However, with new evidence
and proof supporting some of these
hypotheses, opportunities for a healthier,
longer life may
arise.
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