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.


Allis, S. et al.., 1996. Older, Longer. Time Magazine. Fall 1996:60-64

Keeton, K. 1992. Longevity: the Science of Staying Young. Penguin Books USA

Inc., New York, NY. Kronhausen, E. et al. 1989. Formula for Life. William Morrow
and Company, Inc., New York, NY. Lafferty, E. et al., 1996. Can We Stay Young?.

Time Magazine. 25/11/96:53-62 Ricklefs, R.E. and Finch, C.E. 1995. Aging; A

Natural History. W.H. Freeman and Company, New York, NY. Bibliography Aging, The

Concise Encyclopedia of Science and Technology, 1978 ed. Allis, S. et al..,

1996. Older, Longer. Time Magazine. Fall 1996:60-64 Keeton, K. Longevity: the

Science of Staying Young. New York, NY: Penguin Books USA Inc., 1992. Kronhausen,

E. et al., Formula for Life. New York, NY: William Morrow and Company Inc.,

1989. Lafferty, E. et al., 1996. Can We Stay Young?. Time Magazine.

25/11/96:53-62 Ricklefs, R.E. and Finch, C.E. Aging; a Natural History. New

York, NY: W.H. Freeman and Company, 1995. Segall, P. and Kahn, C. Living Longer,

Growing Younger. Toronto, ON: Random House of Canada Limited, 1989. New York,

NY: Random House Inc., 1989.