Genetic Mechanisms
Running head: GENETIC MECHANISMS OF AGING
Genetic Mechanisms Involved in the Aging Process
Erica F. Reinig
Creighton University
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Genetic Mechanisms
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Genetic Mechanisms Involved in the Aging Process
Throughout time, society has been obsessed with the concept of immortality. The
Spanish explorer Ponce de León is famous for his exploration of the New World in
search of the fountain of youth. Even today, people are intrigued by the idea of
immortality. J.K. Rowling’s increasingly-popular book Harry Potter and the Sorcerer’s
Stone tells the story of how a young wizard must keep an evil Lord Voldemort from
gaining possession of the Sorcerer’s Stone, an unusual object that can produce an elixir
that allows the drinker to live forever. Although explorers never found the fountain of
youth and the Sorcerer’s Stone exists only in imagination, humanity has held onto its
feverish pursuit of immortality. People long to become a modern-day Methuselah, rebel
against death, and avoid separation from loved ones. Despite their high hopes, many
people have declared immortality to be a physical impossibility. However, recent
advances in the field of biology and genetics have yielded interesting insights into the
causes of aging. This new information on the role of telomeres, telomerase, oxidative
stress, and many other influences in the processes of aging causes scientists to question
whether or not immortality might one day be possible.
The secrets of cellular aging begin in the cycle of cellular mitosis. During mitosis,
the DNA of the cell duplicates and the cell divides. Continual replication results in
damage to the DNA strands of cells. Molecular structures called telomeres work to
protect DNA strands from damage. Complete telomere loss leads to an instability within
genetic information, causing the cell to die (Von Zglinicki, 1998). Telomeres consist of
several repeat sequences that reduce the rate of DNA erosion. This sequence, 5’‘(TTAGG)n-3’ in humans, repeats itself an average of 2,300 times in germ line cells
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(Von Zglinicki). Telomeres also have a very high degree of length polymorphism.
However, cellular division erodes telemetric DNA, causing telomeres to become shorter,
with 5-30 telometric repeats lost per division (Von Zglinicki). If telomeres become too
short, cells are no longer able to divide. This point in the cellular cycle in which cells are
unable to undergo mitosis is known as the Hayflick limit (Von Zglinicki). If telomere
shortening does not occur, through telomere lengthening or maintenance, then cellular
aging does not occur. An area of great diversity, the length of telomeres is extremely
important in determining the rate of the aging process.
Humans also display a great deal of variance in length of telomeres. Statistics
suggest that sex, age, and smoking may be influential in telomere length and rate of
deterioration (Nawrot, Saessen, Gardner, & Abraham, 2004). Perhaps the most notable
difference exists between men and women. The women’s telomeres shorten at a rate of
0·019 kb per year while men’s telomeres shorten at a rate of 0·024 kb per year (Nawrot et
al.). While the exact cause of these differences is not certain, researchers believe that they
may know the time that these differences begin to arise. Because telomere length in white
blood cells is very similar in newborn girls and boys, this sexual dimorphism may not
begin to appear until after individuals are born (Nawrot et al.). One possible cause of
telomere differences between sexes relates to reactive oxygen. Females produce lower
levels of reactive oxygen, a substance that increases telomere erosion, and metabolize
these levels more quickly than men (Nawrot et al.). Reactive oxygen may also account
for shorter telomere length in smokers. The levels of reactive oxygen are often much
higher in smokers than in non-smokers (Nawrot et al.). Other substances and situations
may also lead to an increased rate of telomere erosion. A recent study suggests that
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telomere erosion may increase in the presence of UVA irradiation, a type of ultraviolet
radiation which penetrates deep into the dermal layers of the skin (Oikawa, Tada-Oikawa,
& Kawanishi, 2001).
Some scientists now believe that telomere length may be an X-linked trait
(Nawrot et al., 2004). Researchers recently studied white blood cell DNA in families in
order to compare telomerase length in hopes of finding a genetic correlation for the aging
process (Nawrot et al.). After experimenting and gathering and comparing data,
researchers came across an extraordinary correlation. There were high levels of similarity
of telomere length between fathers and daughters, mothers and sons, and mothers and
daughters, leading researchers to believe that telomere length may likely be an X-linked
trait (Nawrot et al.). Researchers then began to look for specific genetic loci on the X
chromosome that would support their conclusion.
Several specific connections between telomere length, longevity, and the X
chromosome support this X chromosome hypothesis. The DKC1 gene, which encodes for
dyskerin, can be found on the X chromosome and plays a key role in the accumulation of
a certain component of telomerase, which works to lengthen telomeres (Nawrot et al.).
The gene called AGTR2, also located on the X chromosome, when stimulated increases
production of nitric oxide, which may help reduce oxidative stress on cells (Nawrot et
al.). The MGST-I enzyme, which protects the cell from oxidative stress, may also be
connected to the X chromosome. The enzyme Mgstl in Drosophlia may be related to a
gene on the X chromosome and is very similar to the MGST-I enzyme in mammals
(Toba & Aigaki, 2000). The similarity of the enzymes suggests that they may possibly
have roots in the same location, the X chromosome. Another telomerase connection to
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the X chromosome lies in the hormone estrogen, which can stimulate hTERT, one
component of telomerase (Nawrot et al.). The correlation of telomere lengths between
mothers and offspring can be explained using mitochondria. Along with working to
control oxidative stress damage, mitochondria also have a maternal connection because
they usually originate from the mother (Nawrot et al.). While several pieces of evidence
support the X chromosome hypothesis, further research is needed before scientists can
become more certain about the relevance of the X chromosome to aging and telomere
length. While telomeres work well to delay and prevent the damages that cause aging,
there is another molecular component used by several cells that gives the cell a form of
immortality.
Another mechanism that works to prevent aging within a cell is ribonucleoprotein
reverse transcriptase, also called telomerase. This substance works to elongate telomeres
and prevent their shortening by using internal RNA (Von Zglinicki, 1998). Telomerase
has two active components. The first component, hTER, is a RNA template for
polymerase activity; the second component, hTERT, is a catalytic subunit that has reverse
transcriptase activity (Poole, Andrews, & Tollefsbol, 2001). In order for a cell to have
telomerase activity, two components of telomerase must be present. While the hTER
component is commonly found in human somatic and embryonic tissue, hTERT is
usually not present in these types of tissue (Poole et al.). As a result, human somatic cells
usually do not have telomerase activity; however, there are several types of cells that do
display this type of aging prevention.
Telomerase activity is very common in germ line cells, unicellular organisms,
some forms of somatic tissue (trophoblasts, hematopoietic cells, and endometrial cells),
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and up to 95% of cancer cells tested (Poole et al., 2001; Von Zglinicki, 1998). As a result
of their telomerase activity, these cells do not experience the telomere shortening
experienced by typical somatic cells. While telomeres are effective in reducing the effects
of continual cellular division, telomerase activity is necessary to produce an immortal
phenotype within a cell (Von Zglinicki). Recent research focused on how to possibly
control the effects of telomerase within a cell. According to this research, telomerase
activity can be greatly decreased by the use of 13-ribosome, which targets the mRNA of
hTERT (Poole et al). The ability to decrease telomerase rate (and increase the aging
process) may prove as useful as the ability to decrease signs of aging. Telomerase
research could have great implications on the field of oncology and other age-related
diseases. For this reason, many researchers are eager to learn more about the combined
effects of telomerase and telomeres on the prevention and acceleration of cellular aging.
However, additional research into the area of aging and genetics has produced several
other mechanisms behind cellular aging.
One major cause of telomere shortening within the cell is oxidative stress.
Denham Harman developed the first likely mechanism for cellular aging involving
oxidative stress: “[C]ontinuous generation of deleterious oxygen free radicals as a byproduct of mitochondrial oxidative metabolism would eventually lead to intolerable
damage and thereby determine cellular life span” (Von Zglinicki, 1998, p. 318). This
theory has become one of the most influential theories in the study of molecular aging
today. Numerous studies have shown that oxidative stress creates damage within
telemetric DNA. Acting as oxidative stress sensors, telomeres may halt the cells cycle
under conditions of mild and chronic damage due to oxidative stress (Von Zglinicki). In
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this way, telomere functioning may act as an indicator of levels of oxidative stress.
Researchers have recently observed that telemetric erosion can be increased in vitro by
use of chronic oxidative stress; in fact, cells undergoing hyperoxia had telomeres of a
similar length to those cells that had reached the Hayflick limit (Von Zglinicki). Other
studies have arrived at similar conclusions involving the increased erosion of telometric
DNA due to oxidative stress (Highfield, 2002; Toba & Aigaki, 2000).
One experiment into the effects of oxidative stress on the aging process involved
the use of fruit flies. By mutating a certain gene (called the “Methuselah gene” by
Seymour Benzer), researchers enabled fruit flies to resist the stresses of radical-forming
herbicides which cause oxidative stress; the life span of those mutated fruit flies
increased by 35% (Highfield, 2002). Other genes may also play a role in coping with
oxidative stress. Research suggests that the previously mentioned enzyme MGST-I helps
protect the cell from oxidative damage (Toba & Aigaki, 2000). Similar studies continued
the use of fruit flies in research into the role of antioxidants in oxidative stress.
Genetically engineered to produce higher levels of antioxidants (which protect against
free radicals and oxidative stress), fruit flies increased their life expectancy from the
typical 45 days to 75-95 days (Highfield). While scientists have been able to manipulate
oxidative stress levels in fruit flies fairly well, additional studies have managed to do the
same for mammals. By deleting a gene called p66shc, researchers created mutant mice
that lived one-third longer than normal, non-mutant mice (Highfield). Science has shown
that oxidative stress plays a key role in the deterioration of telometric DNA, drastically
influencing the rate of damage which causes aging. Along with the implication of
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oxidative stress, the possibility arises for another link to molecular aging: mitochondria,
which may be responsible for several links to molecular aging.
Numerous studies have arrived at the conclusion that mitochondria play an
integral role in regulating cellular damage and aging. Compounds like ROS, which can
be found in mitochondria, are capable of destroying nucleic acids, lipids, proteins, and
many other forms of biomolecules (Osiewacz, 2002). The damage created by ROS may
in part be responsible for cellular aging. A recent study discovered that ROS levels are
lower in the mitochondria of younger organisms (Osiewacz). ROS proves to be a very
damaging threat to the well-being of the cell. As this study has shown, increased damage
of the mitochondrial respiratory system (often caused by ROS) leads to an increase in
ROS production, which in turn leads to increased damage (Oseiwacz). ROS production,
as a result, continues a self-perpetuating cycle of damage that eventually leads to
mitochondria that are incapable of functioning. Mitochondria also contain several
substances that can increase the lifespan of the cell. Scientists have discovered that
longevity of the cell increases in the presence of mitochondrial respiratory chain
inhibitors (e.g. mucidin and potassium cyanide) as well as the substances ethidium
bromide, acridine, and acriflavine (Oseiwacz). Additional observation involving
substances within mitochondria yielded yet other possibilities for mechanisms of
longevity. Kanamycin, neomycin, streptomycin, puromycin, and tiamulin all serve as
inhibitors of mitochondrial ribosomes and may be effective in extending lifespan
(Oseiwacz). While research involving mitochondria and oxidative stress has already
suggested several possible mechanisms for cellular aging, there is yet another theory of
molecular aging that provides additional possibilities for longevity.
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The caloric restriction theory of aging is another major theory of cellular
longevity that has been the focus of several research studies. The basic outline of the
theory is that lowering calorie intake can increase cellular longevity. If individuals cut
their calorie intake by 30%, research suggests that they can increase their lifespan by an
average of 20 years (Highfield, 2002). Scientists at MIT have also found a more specific
connection between calorie restriction and longevity (MIT, 2004). According to MIT
researchers, calorie restriction prolongs lifespan by activating the SIR2 gene which
results in the production of a protein called Sir2 (MIT). While Sir2 is normally restricted
by coenzyme NADH, low calorie diets restrict production of NADH, allowing another
coenzyme, NAD, to activate the Sir2 protein (MIT). Some genes regulating food
metabolism may also play a large role in calorie restriction and increased longevity. A
daf-2 mutation in a nematode worm influenced the worm’s lifespan in a study by Michael
Klass at the University of Colorado (Highfield). Evidence of caloric restriction’s impact
on the longevity of cells is abundant. With multiple mechanisms behind telomere length
and lifespan, including telomerase, oxidative stress, mitochondria, and calorie restriction,
researchers have now begun to investigate the possible applications of the new
information regarding DNA and aging. Once scientists discover more information about
the underlying mechanisms of the cellular aging process, they will be more capable of
using information on the genetics of aging to assist the medical field.
One of the largest concerns about research into the mechanisms of biological
aging is age-related diseases, such as cancer. Scientists have suggested that shorter
telomeres may cause a greater predisposition to age-related disease (Nawrot et al., 2004).
The shorter telomere phenotype is not only more likely to get an age-related disease but
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also more likely to die from an infectious disease. Individuals at the bottom of the 25%
distribution for telomere length had a mortality rate from infections diseases eight times
higher than individuals at the top 75% of the distribution curve (Nawrot et al.). Studies
regarding cancer and aging often include telomerase because of the evidence of its
involvement in cancerous cells and substances. The expression of hTERT is increased
when in the presence of the oncogene c-Myc (Poole et al., 2001). However, oncogenic
proteins are not the only substances involved in the expression of hTERT. The antioncogenic proteins p53 and WT1 also have an effect of hTERT, inhibiting its expression
(Poole et al.). Another substance related to the tumor suppressor p53, p21, may also play
a role in cell division and aging. In non-dividing cells, p53 is activated, blocking cell
division, and levels of p21 increase (Von Zglinicki, 1998). Additional research into the
relationship between aging and cancer would be of great benefit to cancer patients and
that doctors who treat them.
While exact connection between hTERT and cancer is still uncertain, there are
several practical applications for the field of oncology. Upon observing that excessive
cancer preventing protein in mice increases their rate of aging, researchers proposed the
theory that the body creates state of equilibrium between resisting the process of aging
and increasing risk for cancer (Highfield, 2002). If this theory holds true, understanding
this equilibrium will profoundly benefit the field of oncology. Additional applications in
cancer treatment focus specifically on diagnosis. As hTERT is detectable even during the
earliest stages of malignancy in tumors, oncologists could possibly use hTERT levels
when diagnosing cancer (Poole et al., 2001). Needless to say, further information
regarding telomerase and its underlying mechanisms would greatly benefit many areas of
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cancer research. In addition to oncology, information on the genetics of aging also has
several other practical applications.
In the genetic disorder Werner’s syndrome, sufferers undergo significant aging
during adolescence. According to researchers, this syndrome may be the result of a faulty
version of the enzyme helicase, which plays a key role in cell replication by unwinding
DNA strands for duplication; an error in helicase functioning could increase the rate at
which the cell ages (Highfield, 2002). Further research into helicase and DNA replication
could provide information leading to treatments or possible cures of Werner’s syndrome.
In addition, if researchers are able to slow down the erosion of telomeres in cells, they
may be able to slow the effects of aging and decrease risks for age-related diseases (Von
Zglinicki, 1998). Additional research into oxidative stress would also be beneficial.
Currently, researchers are interested to see if antioxidative treatments would be able to
slow the damage to telomeres due to oxidative stress (Von Zglinicki). While telomerase,
especially hTERT, has several possibilities for future treatment against aging, it could
also be very risky. The use of hTERT for cellular immortalization in vivo leads to a high
susceptibility to neoplastic transformation (Poole et al., 2001). Although research into the
genetics of aging is still in its early stages, the possibilities of this field of research are
innumerable, from possible treatments for cancer to the simple idea of helping people live
longer. With the pace at which genetic advancements are advancing, these medical
breakthroughs may one day be possible.
There are few people who would not be interested in the enormous implication of
these studies: the fountain of youth may not just be a myth. It might actually exist within
some of the tiniest particles of the human cell. Research into telomere length, telomerase,
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oxidative stress, and many other molecular components implicated in aging has provided
humanity with incredible new information that may lead to an increase in longevity;
however, in remains to be seen whether “the fountain of youth” will ever be within
scientific grasp. It may be possible in the future, however, to use this new information to
assist the quality of life by treating cancer or just adding on a few more years to the
human lifespan. Much more research is needed before any of these applications can be
realized. However, with a goal as tantalizing as immortality, there is no doubt that
scientists will continue to research the genetics of aging. Perhaps society will never find
the legendary Sorcerer’s Stone. However, even if immortality is impossible and can never
be achieved, people will still dream about it. Books will still be written about it. People
will still chase it. The dream of immortality has been and always will be a large part of
human culture, no matter how impossible that dream may sometimes appear.
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References
Highfield, R. (2002). The Science of Harry Potter. New York: Penguin Books.
MIT helps unlock life-extending secrets of calorie restriction. (2004, January 30).
Genomics & Genetics Weekly, 8-9.
Nawrot, T. S., Saessen, J. A., Gardner, J. P, & Abraham A. (2004). Telomere length and
possible link to X chromosome. The Lancet, 363, 507-510.
Oikawa S., Tada-Oikawa S., & Kawanishi S. (2001). Site-specific damage at the GGG
sequence by UVA involves acceleration of telomere shortening. Biochemistry,
40(15), 4763-4768.
Osiewacz, H. D. (2002). Mitochondrial functions and aging. Gene, 286, 65-71.
Poole, J. C., Andrews L. G., & Tollefsbol, T. O. (2001). Activity, function, and gene
regulation of the catalytic subunit of telomerase (hTERT). Gene, 269, 1-12.
Toba, G., & Aigaki, T. (2000). Disruption of the Microsomal glutathione S-transferaselike gene reduces life span of Drosophlia melanogaster. Gene, 253, 179-187.
Von Zglinicki, T. (1998). Telomeres: Influencing the Rate of Aging. Annals of the New
York Academy of Sciences, 854, 318-327.