Everbody's Doing It, But Do You Know Why: Current Theories On How And Why We Age
Number: 00S02. Issue: Spring 2000
Author[s]:
Negar Salehomoum and Lawrence Shiow
Keywords:
Abstract:
It?s the year 2000!
But are you upset that you didn?t make the most out of the biggest New
Year?s? Don?t sweat it because there?s
always 2100! Thanks to cutting edge
technology and a better understanding of how our bodies age, you can be making
a New Year?s resolution for the 22nd century!
Before you
shake your head in disbelief, consider this: the longest anyone has ever lived
was 120 years and 237 days; a record achieved by Shirechiyo Izumi, who passed
away in 1986. It won?t be too much
longer before someone breaks that record as life expectancy increases
dramatically. Average life expectancy in the United States was 47 years in 1900
and has risen to about 75 years in 1990.
So what do
you need to do in order to live until the year 2100? Eat well and exercise regularly?
Or is it based on heredity and thus totally out of your control? From what we understand about aging, many
factors contribute to the deterioration of the human body. Aging can be caused by environmental factors
as well as internal factors. Therefore,
where we live and how we live are just as important as the genes we inherit
from our parents.
Knowing the
factors that affect aging and knowing how aging occurs are two different
things. Understanding both can lead to
improved life expectancy and better living.
Researchers explore many different areas when it comes to aging because
our bodies breakdown in many ways.
Today,
there are two types of theories about how we age: programmed and error. Programmed theories argue that the body
follows a scheme that leads to aging and death. Error theories argue that the body ages through internal or
external factors that damage vital functions.
Programmed Theories
Why would
the body evolve programmed functions to terminate itself? Doesn?t that contradict evolution?s basic
concept of survival of the fittest?
Programmed theories can make evolutionary sense if one considers the
survival of the species benefiting from the aging of individuals. If genetic variation is necessary for a
species to survive, then programmed aging and death of individuals within a
population helps the species overall.
If the population were not reduced, then the new generations would have
to compete with the older ones for the same resources. Therefore, programmed theories are possible
explanations for why we age. It also
seems feasible that the body can continue to follow a program for death, after
following a program for growth and development.
Three
programmed theories that have attracted much attention are the telomere,
endocrine, and immunological theories.
TELOMERE THEORY. The word "program" infers coding
or encryption that contains a set of instructions. Deoxyribonucleic acid (DNA), found within the cells of our
bodies, are miniscule strands of organic molecules that encode the structures
of proteins ? the biological building blocks of life. DNA is an ideal source of encoded instructions that could contain
the "program" for aging.
Indirectly and directly, this genetic material can be a biological clock
that tells the cells different steps to take at different times during an
organism?s life.
Recently,
much attention has been devoted to telomeres as biological clocks within our
genes. Telomeres are the chains of
genetic material that make up the ends of chromosomes, long chains of DNA which
encode cellular processes. Telomeres do not encode cellular processes, but are
made up of repeating base pair segments. They are believed to not only protect
the chromosome but also serve as a clock for cells.
When cells
divide, their chromosomes must also replicate.
The replication process causes the newly-made chromosomes to lack a
small portion of the telomere compared to the original. An enzyme called telomerase can activate to
replicate telomeric DNA, replacing the lost portion. But not all cells contain
telomerase. Studies (Harley, Futcher and Greider 1990) have shown that each
doubling of cells without telomerase causes chromosomes to shorten by an
average of 50 base pairs. The telomere
hypothesis of aging predicts that as cells double, their telomeres shorten
until cellular too much DNA is lost, and replication stops all together.
During DNA
replication, the primary enzyme involved ? DNA polymerase ? copies DNA in only
one direction (5?-to-3?), making it difficult to copy DNA in the opposite
direction. In order to do so a template
of DNA is placed down for the DNA polymerase to start copying. When this template is removed there is an 8-
to 12-base gap at the end of the chromosome.
This missing DNA is part of the telomere and telomerase can correct this
missing gap. However, in cells without
telomerase, chromosomes will shorten over time.
To
understand how cell division is tied to aging, we can look at the symptoms of
Werner?s syndrome, a disease that causes premature aging. Suffers of this disease experience
cataracts, heart disease and osteoporosis when they are only in their 30?s. When comparing the amount of cell division
in individuals, patients with Werner?s syndrome undergo significantly
less. This study (Martin, Sprague, and
Epstein 1970) also showed that the number of cell divisions decreases with age. Werner?s syndrome may be caused by a genetic
error involving a type of enzyme which helps unwind DNA during
replication. When cells do not
replicate, they become old and prone to damage. Replication creates new cellular structures that may function
better than old cells.
Currently
researchers are focusing on the enzyme telomerase, which can maintain or
lengthen telomeres. Interestingly in
cancer cells, which are cells that replicate indiscriminately there is high
telomerase activity. As more is known
about telomeres and telomerase, hopefully a treatment for cancer can be devised
as well as a method to combat aging.
ENDOCRINE THEORY. If
the program our bodies follow for aging is anything like the program our bodies
follow for growing, then the endocrine system plays a major role. Our endocrine systems are made up of glands
that secrete hormones, which trigger certain responses. For a living organism, one of the most
important responses is stress. When
under stress, the human body should release certain steroids or hormones that
cause a number of responses: divert energy from storage, suppress functions not
required during emergencies, and increase blood flow. Over a lifetime, our bodies experience lots of stress. The endocrine theory hypothesizes that
stress causes damage to the neuroendocrine system, contributing to aging.
In 1991,
J.A. van Eekelen studied stress response in aging rats to understand the
mechanisms of the hypothalamic-pituitary-adrenal (HPA) axis, the neuroendocrine
system involved in stress. This system, in both humans and rats, depends on feedback
signals for effectiveness. These studies found that stress-induced secretions
damaged neuron receptors. By damaging the receptors, which are designed to
?turn off? those secretions in a process known as feedback, the body allows an
uncontrolled secretion of steroids and hormones, resulting in misusage of
energy and the shutting down of necessary functions. Other studies by R.M.
Sapolsky in 1990 show that in individuals over the age of 80, there are high
levels of glucocorticoids released in the bloodstream and decreased feedback.
This
mechanism is known to cause problems in rats. However, not enough is known
about the effects in humans. More
studies are needed to understand the mechanism in humans as well as the effects
of high levels of glucocorticoids.
IMMUNOLOGICAL THEORY.
It is well known that when we age, our bodies are more susceptible to
disease. However, a programmed theory
hypothesizes that we age because our body is less capable of fighting off
illness. This immunological theory
focuses on the programmed behavior of the thymus, the origin of T lymphocytes
(T cells).
T cells are
immune cells that spread around the body to combat illness. There are two types of T cells: naïve and
memory. Naïve cells are T cells that
have left the thymus and are not immunologically triggered by a certain
antigen. When a naïve cell encounters
an antigen, it becomes activated to only attack that certain antigen. Some become memory cells, and thus have the
ability to become dormant and quickly respond to future encounter with the
antigen. Memory cells can transmit signals to activiate many naïve cells of its
type.
As we age,
our bodies encounter many viruses and bacterial pathogens. These antigens have developed our immune
system and built up the number of memory cells. However after we reach maturity, our thymus decreases the number
of naïve T cells it produces. Because
of this programmed effect, the amounts of naïve cells in our system decreases
as we age because more of those produced become memory cells. This results in a slower response to new
diseases or illnesses. Thus, the
thymus can be considered an "aging clock."
Although
this model explains how most individuals are affected by disease, it does not
show how our bodies deteriorate, such as with osteoporosis. Like the telomere and endocrine theories,
the immunological theory does not cover all cases of aging. Why is aging so diverse if it is a
programmed phenomenon? Most likely all
forms of programmed theories contribute to aging. However, there are some
aspects of the aging process that porgrammed theories cannot account for.
Error Theories
WEAR AND TEAR THEORY. This theory states that cells and
tissues have vital parts that wear out.
Various stresses and changes in the environment put pressure on the
cells and tissues of an organism, causing them to lose their efficiency. Studies by Verzár, McDougal, and others on
the spontaneous activity and work rate of rats illustrate a decrease in the
ability to cope with work and stress as the rats age. For example, the rats? maximum swinging time and ability to
resist cold decrease as the age of the rats increases.
Further
studies indicate differences in the tissues of younger organisms as opposed to
older organisms. The cells in older
tissues lose their configuration and size in addition to repositioning
themselves. For example, the individual
myocardial bundles in the hearts of older humans vary in size while those in
younger humans lie within a similar size range.
RATE OF LIVING THEORY. An indirect relationship between an
organism?s rate of oxygen basal metabolism and its life span exists. The greater an organism?s oxygen basal
metabolism rate, the shorter its life span.
Experiments proving this theory involved altering the houseflies? rate of
oxygen basal metabolism. The first set
of experiments included placing houseflies in a cage to limit their flying
space. The lower flight activity
induced a lower metabolism that in turn resulted in longer life spans. The second set of experiments reduced the
houseflies? oxygen basal metabolism rate by placing them in a controlled
environment consisting of less than 100% oxygen. The decreased amount of oxygen in the atmosphere forced the
houseflies to have a slower metabolism rate, thus increasing their life
span. Furthermore, in the controlled
environments, the houseflies produced less protein carbonyls, which aid in
decreasing the organism?s life span.
The only problem with these experiments is that they cannot be applied
to birds and primates since they have a higher metabolism rate than other
groups, in addition to having longer life spans.
FREE RADICAL THEORY. Mitochondrial metabolism consumes
oxygen, some of which can turn into radicals and cause cells, and eventually
organs, to stop functioning once the damage accumulates. Evidence supporting the Free Radical Theory
involve comparing the amount of oxygen radicals produced by mitochondria in
pigeons and rats. Pigeons converts
about one tenth the amount of oxygen that rats would convert into radicals. Accordingly, the pigeon?s life span was ten
times longer than that of the rat.
Furthermore, some Drosophila (fruit flies) possess genes coding for
antioxidants, allowing them to get rid of oxygen radicals and live 34% longer
than their control counterparts. Then,
when they were given additional doses of antioxidants, their life spans
increased even further. Thus, there exists an inverse relationship between the
amount of oxygen radicals in an organism and an organism?s life span.
CROSSLINKING THEORY. An accumulation of crosslinked proteins
or DNA damages cells and tissues, slowing down bodily processes. If crosslinking agents attach to one strand
of DNA, the cell?s repair mechanisms remove the affected strand. Then, the cell replaces the missing section
by using the complimentary strand as a template. However, the crosslinking agent becomes harmful when it links
both strands of the DNA together. Although the cell removes both pieces
affected by the crosslinking agent, the cell cannot recreate the missing
genetic material because it does not have a template from which to determine
the missing nucleotide sequences. If the crosslinking agent attaches to both
strands of the DNA as it splits during mitosis, it prevents the strands from
fully splitting during replication, thus preventing the cell from completing
its mitotic division. This incomplete
division prevents the DNA from returning to its normal position.
Although billions of crosslinkages
occur during an organism?s lifetime, most of them are not removed by the cells?
defense mechanisms. Extensive
aggregates become resistant to enzymes that biologically break them down, later
causing bodily processes to slow down.
Experiments by Hart and Seflow (1974) indicate that as the age of an
animal increases, the animal repairs genetic damages at a slower rate, creating
a loop in which the effects of aging lead to further aging.
SOMATIC MUTATION THEORY.
Genetic mutations accumulate with increasing age, causing cells to
deteriorate and malfunction. This
theory originated when Ross and Scott (1939) noticed that irradiation decreased
the life span of rats. Additional
observations by Sacher and Henshaw, who worked on rodents, and Warren, who
worked on humans, conclude that random mutations that destroy genetic material
in postmitotic cells (cells that have stopped dividing) accumulate as an
organism gets older. When the
accumulated mutations reach a critical level, the cell dies.
Mutations
alter the cell?s genetic material, causing the cell to produce different
proteins than the ones originally coded.
The lack of necessary proteins leads to a decrease in the cells? ability
to function well. For example,
experiments by Stevenson and Curtis (1961) found that irradiating mice by X-ray
led to an increase in chromosomal aberrations in the regenerating liver of the
mice and a shortened life span. Curtis
(1963) further concluded that chromosomal aberrations in postmitotic cells
accumulate since the cell no longer divides to get rid of the aberrations. It seems plausible to conclude that
irradiation causes more chromosomal aberrations, causing the organism to age
and die sooner.
ERROR CATASTROPHE THEORY. Damage to mechanisms that
synthesize protein results in faulty proteins that accumulate to a level that
causes catastrophic damage to cells, tissues, and organs. During transcription and translation, errors
occur causing incorrect nucleotides to take the place of the nucleotides for
which the cell was originally coding.
If the mutation changes the amino acid for which the codon codes, a
different protein will be created. The
new amino acids alter the function of the proteins, making them either
partially active or inactive. The mutations may increase exponentially each
time the genetic material is transcribed, leading to an error catastrophe. This prevents the cell from nctioning and
leads to aging. This theory was tested
by placing the leu-5 mutant of the fungus Neurospora in low and high
temperatures since, at higher temperatures, the mutant substitutes leucine for
other amino acids during translation.
The results indicate that the cell produced the mutant at the higher
temperatures. Although the error
frequency remained constant, the cell began to age after seventy hours.
One
objection to the Error Catastophe Theory is evidence that mutagens do not make
mistakes during transcription and translation. Another contradiction to the
theory is that cells exposed to irradiation possess seven times the amount of
leucine than the theory would indicate.
Although
there are many theories of aging, no one theory explains the aging
process. The many theories work
together to describe more correctly how and why we age. The Rate of Living Theory relates the oxygen
released during mitochondrial metabolism to aging. Similarly, the Free Radical Theory discusses how the released
oxygen turns into radicals that decrease the cell's ability to function
well. The Error Catastrophe Theory is
difficult to distinguish from the Somatic Mutation Theory since a single point
mutation (Somatic Mutation) may change the protein the cell synthesizes,
leading to an error catastrophe.
"The ultimate failure of biosystems
derives from arrest of mitosis (selected for because eof the advantages of
specific size and reliable memory storage), followed by a variety of different
kinds of disruptions in structure and function including cell death, loss of
rDNA and similar genes, loss of receptor sites for coordinating endocrine
signals, and consequent decreases in the efficacy of responses to environmental
and internal challenges."
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