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The Torch Magazine,
The Journal and Magazine of the
International Association of Torch Clubs
For 95 Years
A Peer-Reviewed
Quality Controlled
Publication
ISSN Print 0040-9440
ISSN Online 2330-9261
Winter
2020
Volume 93, Issue 2
Telescoping
Telomeres
by
Mary Ann F. Kirkpatrick
Your liver is
less than a year old.
Your skin is
less than a month old.
Your stomach is
less than a week and a half old.
Your body is composed of cells, as you
likely know. You probably also know
that the cells in your body today are
not those you were born with; cells
re-create themselves. Telomeres are a
crucial part of that process.
Telomeres are tiny protective caps at
each end of our 46 chromosomes. During
cell division, they ensure that the
genetic information from parent cells
is accurately passed on and that
chromosomes do not fuse with each
other to form mutations. Their
length is controlled by the protein
enzyme telomerase and RNA subunits,
sometimes referred to as a "cellular
immortalizing enzyme"
("Overview"). However, each time
a cell divides, some telomere length
is lost. When it becomes too short,
the chromosome can no longer
replicate, and the cell dies.
Even though telomere length and its
biology are not well-known concepts
for the vast majority of people,
telomeres have a major impact on our
overall health and life quality as we
age. Research findings indicate that
overall telomere length has
implications affecting our health.
Longer length is associated with
longer life expectancy, while shorter
length has been associated with early
onset of conditions such as heart
disease, diabetes, osteoporosis, and
reduced life expectancy.
Indications suggest that lifestyle
choices such as proper nutrition,
exercise, and stress reduction may
promote longer telomeres. Conversely,
short length may have positive
benefits in cancer treatment, where
tumor cells can be deprived of the
immortalizing telomerase, thus
preventing tumor cells from
subdividing.
Telomeres and
Aging
With aging, overall telomere length
tends to decrease: "Telomere length in
humans seems to decrease at a rate of
24.8-27.7 base pairs per year"
(Shammas). Telomere shortening, some
have proposed, may be "a molecular
clock mechanism that counts the number
of times a cell has divided and when
telomeres are short, cellular
senescence (growth arrest) occurs"
("Overview").
Masood A. Shammas of the Harvard
Cancer Institute writes, "Telomere
length, shorter than the average
telomere length for a specific age
group, has been associated with
increased incidence of age-related
diseases and/or decreased lifespan.
Telomere length is affected by a
combination of factors including donor
age, genetic, epigenetic make-up and
environment, social and economic
status, exercise, body weight, and
smoking." For these variables, "Gender
does not seem to have any significant
effect on the rate of telomere loss."
Dr. Shammas
summarizes:
Certain
lifestyle factors such as smoking,
obesity, lack of exercise and
consumption of an unhealthy diet can
increase the pace of telomere
shortening, leading to illness
and/or premature death. Accelerated
telomere shortening is associated
with early onset of many
age-associated health problems,
including coronary heart disease,
heart failure, diabetes, increased
cancer risk, and osteoporosis.
Individuals
whose white blood cell telomeres are
shorter than the corresponding average
telomere length for persons in the
same age group have a three-fold
higher risk of developing myocardial
infarction. In these examples,
oxidative stress is the culprit
causing the telomere
shortening.
Consider this concrete example: women
who smoke a pack of cigarettes per day
for 40 years lose an average of five
more base pairs of telomere per year
than non-smoking women. This
translates into losing 7.4 years of
life. In obese women, an estimated 8.8
years of life are lost (Shammas).
Exposure to similarly harmful agents
likewise leads to oxidative stress and
thus telomere shortening. Traffic
police officers who are exposed to
daily pollution, defined as toluene
and benzene, have shorter telomeres
than office workers who are the same
age. Additionally, coke-oven workers
exposed to polycyclic aromatic
hydrocarbons have significantly
shorter telomeres, as well as more DNA
damage and genetic instability, than a
control group of men. The decrease in
telomere length in the coke-oven
workers significantly correlates with
the number of years the workers were
exposed to harmful agents (Shammas).
As in the case of cigarette smoking,
telomere shortening in coke-oven
workers appears to be dose-related.
Family instability—e.g., family
incarceration, suicide of a family
member, witnessing violence—has also
been linked with shorter telomeres in
children. In a study of 75 African
American families with children ages 5
to 15, researchers found the more
family instability a child had
experienced, the shorter his or her
telomeres were. The researchers "took
into account other factors that could
influence a child’s development, such
as body mass index, age, maternal
education as an indication of
socio-economic status, household
monthly income and more. Almost none
of these factors had any bearing on
telomere length except a few
peculiarities around gender and age"
(Hunt). In this study, remarkably,
family instability appears to affect
girls more than boys (other studies
had shown no gender differences). Boys
who actually witnessed violence appear
to be more affected than those who
experienced other types of family
instability. Interestingly, maternal
education appears to provide a
protective barrier for boys ten years
old or younger. However, the older a
boy is when he experiences family
instability, the shorter his telomeres
appear to be (Hunt).
African-American men tend to have
shorter life expectancies than any
other racial or gender group in the
United States and to have more chronic
diseases compared with the rest of the
population. Older African-American men
who perceive they have experienced
racial discrimination and who also
hold negative in-group racial bias
have shorter telomeres relative to the
rest of the population, even when
other variables are controlled.
Although past discrimination cannot be
eliminated, there is hope that
reducing or eliminating in-group
racial bias could help lengthen their
telomeres and lessen their chronic
disease burden in their later years
(Chae et al.)
Life style changes that lengthen
telomeres may also improve overall
health. In a small, five-year study of
35 men with localized, early-stage
prostate cancer, researchers
investigated the relationship between
comprehensive lifestyle changes and
telomere length and telomerase
activity. Ten of the subjects were
assigned to lifestyle changes that
included a vegetarian diet (high in
fruits, vegetables and unrefined
grains, and low in fat and refined
carbohydrates), a moderate exercise
regimen (walking 30 minutes a day, six
days a week), stress reduction (gentle
yoga-based stretching, breathing
exercises, and meditation) and
increased social support through group
sessions. The group that made
lifestyle changes experienced a
"significant" increase in blood sample
telomere length of approximately 10%.
(Note: the researchers saw the
positive telomere lengthening in blood
rather than prostate tissue.) Further,
the greater the behavioral changes,
the more significant the improvements
in telomere length (Fernandez).
Similar positive results from exercise
have been demonstrated in
post-menopausal women who were primary
caregivers for a family member with
dementia and women with a history of
childhood abuse. The short telomeres
of women who were primary caregivers
had a probable link to holding a
pessimistic outlook, which is
associated with high levels of
pro-inflammatory protein. Pessimism
scores were lower and telomeres were
longer for the caregivers who
exercised regularly. Women with
histories of childhood abuse who did
not exercise had telomeres shorter
than those of women with no history of
abuse. However, "in women who
exercised regularly, there was no link
between childhood abuse and telomere
length, after controlling for body
mass index, income, education and age"
(O’Brien).
Intriguing as these findings are, the
relationship between telomeres and
exercise requires further
investigation. The Mayo Clinic Health
Letter reported the length of time a
person stands is more predictive of
longer telomeres than the amount of
time spent exercising (Mayo Clinic 4).
Earlier studies that showed a
lengthening of telomeres with
exercise, such as the study in which
men walked 30 minutes per day, six
days per week, were investigating the
presence or absence of exercise
and not necessarily studying the type
of exercise.
Entrepreneurs have been quick to
connect the link between nutrition and
telomere length. By simply searching
the web for telomere lengthening
supplements, one can find many
opportunities to purchase supplements
guaranteed to extend telomeres,
reverse aging, cure cancer, and
deplete your bank account. This,
however, is not part of my
discussion—you are on your own with
that one.
Telomerase and
Cancer
In over 85% of cancers, regardless of
the type, telomerase is responsible
for maintaining the length of
telomeres, which allows tumor cells to
proliferate. Therefore, detecting
telomerase may be helpful in
diagnosing certain types of cancer, as
a predictor of outcomes and as a
marker of minimal remaining disease
following standard cancer therapy.
Since most cancer cells must maintain
their telomeres, any treatment or
strategy that prevents telomere
maintenance also prevents precancerous
cells from immortalizing, or forces
immortal cells into a normal pattern
of senescence or cell death, and
therefore is a potentially important
anti-cancer treatment (Shay, "What are
telomeres").
The molecular structure and subunits
of telomerase are well defined, so
researchers can target specific areas
of the enzyme in an effort to
manipulate activity. Short chains of
nucleic acids called oligonucleotides,
researchers have shown, can bind with
a specific region of telomerase RNA
(called the template region), causing
an inactivation of telomerase in
cancer cells. "In addition to
approaches directed at telomerase
RNA," according to a University of
Texas Southwestern website, "other
strategies include specifically
targeting the catalytic reverse
transcriptase subunit or telomerase as
well as its associated proteins.
Identification of the cellular genes
that regulate the telomerase
repression pathway offers an
independent tactic for developing
telomerase antitumor drugs. In this
regard, there is substantial evidence
that a gene on chromosome 3p contains
a telomerase repressor" (Shay, "What
are telomeres").
Findings at the Salk Institute
indicate that yeast telomerase has an
"on/off" switch. This means that
simply having telomerase present may
not keep telomeres from shortening.
Since most cancer cells require
telomerase to allow uncontrolled cell
growth, manipulation of the "off"
switch could potentially keep
telomerase activity below the required
threshold for tumor cell proliferation
("Flip the Telomerase").
In pediatric patients who have
spontaneous remissions from
neuroblastoma 4s and low-grade
gliomas, researchers have learned,
telomerase is not activated.
These children are born with advanced
cancer; however, for those tumors to
grow, a mechanism to maintain telomere
length must be established, and
establishing such a mechanism requires
telomerase. Thus, inhibition of
telomerase in these children could be
a "potent, almost universal,
anticancer therapeutic target" (Shay,
"Short Telomeres").
According to an article by Jerry Shay,
Roger Reddel, and Wooding Wright, "0
to 15% of human cancers lack
detectable telomerase activity, and
many of these use an alternative
lengthening of telomeres (ALT)
mechanism":
Cells
that use ALT to overcome telomere
shortening have many unusual
characteristics such as highly
heterogeneous telomere lengths and
abundant extrachromosomal telomeric
DNA. […] These ALT-expressing tumors
would not be expected to respond to
anti-telomerase therapies, and the
telomerase-expressing tumors could
become resistant by switching to an
ALT mechanism, as has recently been
seen in mice.
Less
is known about ALT structures than is
known about telomerase. A critical
unanswered question to date is whether
or not there is more than one type of
ALT mechanism. Theoretically,
combinations of ALT plus telomerase
inhibitors should be ideal cancer
treatments, but too little is known to
date about ALT.
There are three very different
strategies under investigation for
telomerase-expressing cancer
treatments: telomerase inhibition;
telomerase-targeted immunotherapy; and
telomerase-targeted oncolytic viruses.
Each of these treatment strategies
have been useful for specific types of
cancer. Telomerase inhibition is
useful in small cell lung cancer,
multiple myeloma, and breast cancer,
phase 2. Immunotherapy targeting
telomerase has shown positive results
in mice implanted with human
pancreatic cancer, while phase 3 cells
and virotherapy is showing promise for
lung, prostate and liver cancers. Some
telomerase inhibitors have even been
used in concert with traditional
treatments to suppress growth of new
tumors when post-treatment residual
cancer cells have managed to survive
after multiple rounds of cell
divisions (Ouellette, Wright, and
Shay).
The Long View of
Telomeres
Our understanding of telomeres is
growing but far from complete. If we
had a telescope that could look into
the future of biological research into
telomeres, what might we see?
Biochemically, the telomere is a
rather simple structure, but research
has revealed its importance to our
health and viability. We cannot simply
assume, however, that one could live a
very long healthy life based solely on
the length of our telomeres, so long
as one has a healthy life style, free
from environmental toxins and over
whelming personal stresses. The
telomere story is more complicated.
Researcher Jerry Shay observes:
There
is increasing evidence that
telomeres are heritable, and
mutations in telomere regulatory
genes have a causal role in human
diseases, such as bone marrow
failure and idiopathic pulmonary
fibrosis. These have been referred
to as telomeropathies or telomere
syndromes. It is becoming recognized
that these telomere maintenance
disorders are a spectrum of
diseases, and thus it is too early
to draw general conclusions about
the causative versus correlative
role of telomere biology in most
human disease. ("Short telomeres")
Further complications arise from the
ways telomeres can be measured and
their data compared. Methods of
measurement vary; investigators select
a method based on the specific
research question to be answered, the
material available for analysis, and
the accuracy of the measurements. As
for data comparison, the research
questions may be the same, but the
materials available and/or types of
measurement may be different (Aubert,
Hills, and Lansdorp). For example, in
a meta-analysis involving 36,230
subjects to determine if females have
longer telomeres than males and if the
association becomes stronger with
advancing age, results were
surprising. The overall results
indicated yes, telomere length is
longer in females than males as
expected (since females tend to live
longer), but no differences are found
in studies that do not use the same
methods of determining specific DNA
sequences in the analyses (Gardner et
al.). So, even after a meta-analysis,
the question remains, do females
really have longer telomeres than men?
To further complicate our
understanding, some types of cancer
and disease occur in individuals long
before their telomeres should have
shortened, based on time from birth to
disease presentation, to the point of
losing their protective capability.
Future investigators have plenty of
unanswered questions to address, in
short. However, until more information
is available, I will keep my telescope
trained on my telomeres and try to
live a healthy life style and hope
that I began life with extra-long
telomeres.
Works Cited
Aubert, Geraldine, Hills, Mark, and
Lansdorp, Peter M. "Telomere Length
Measurement-caveats and critical
assessment of the available technologies
and tools." Mutation Research 730,
no. 1-2 (Feb 1, 2012): 59-67.
Doi:10.1016/j.mrfmmm2011.04.003
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460641
Chae, David H., Nuru-Jeter, Amani M.,
Adler, Nancy E., Brody, Gene H., Lin,
Jue, Blackburn, Elizabeth H., and Epel,
Elissa S. "Discrimination, Racial Bias,
and Telomere Length in African-American
Men." American Journal of Preventive
Medicine 46, no. 2 (2014):
103-111.
Fernandez, Elizabeth. "Lifestyle Changes
May Lengthen Telomeres, A Measure of
Cell Aging." September 16, 2013.
https://www.ucsf.edu/news/2013/09/108886/
lifestyle-changes-may-lengthen-telomeres-measure-cell-aging
"Flip the Telomerase On/Off Switch to
Slow Aging." Genetic Engineering
& Biotechnology News.
http://www.genengnews.com/search?q=Salk+Institute.
September 23, 2014.
Gardner, M., Bann, D., Wiey, L, Cooper,
R. et al. (there are 33 authors). Experimental
Gerontology. (March 2014):15-27.
doi:10.1016/j.esger.2013.Epub 2013 Dec
21.
Hunt, Jazelle. "Family instability
affects children’s cells." Pittsburgh
Courier, June 24, 2014.
http://newpittsburghcourieronline.com
Mayo Clinic Health Letter. "Stand up for
your health." February 2015.
O’Brien, Jennifer. "Exercise May Prevent
Impact of Stress on Telomeres, A Measure
of Cell Health."
http://www.ucsf.edu/news/2011/04/9652/
exercise-may-prevent-impact-of-stress
Ouellette, Michael M., Wright, Woodring
E., and Shay, Jerry W. "Targeting
telomerase-expressing cancer cells.
Journal of Cellular Molecular Medicine
15, no. 7 (2011):1447-1448
"Overview of Telomere/Telomerase."
University of Texas Southwestern Medical
Center website.
http://www4.utsouthwestern.edu/cellbio/
shay-wright/research/sw_research.html
Shammas, Masood A. "Telomeres,
lifestyle, cancer, and aging."
http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC3370421/?report=reader
Shay, Jerry W. "Are Short Telomeres
Hallmarks of Cancer Recurrence?" Clinical
Cancer Research. Vol. 20, no. 4
(February 17, 2014):779-781.
doi:10.1158/1078-0432.CCR-13-3198
---. "What are telomeres and
telomerase?"
http://www4.utsouthwestern.edu/cellbio/shay-
wright/intro/facts/sw_facts.html
Shay, Jerry A., Reddel, Roger R., and
Wright, Woodring E. "Cancer and
Telomeres—An ALTernative to Telomerase."
Science Vol. 336. June 15, 2012..
www.sciencemag.org
Author's Biography
Mary Ann F. Kirkpatrick received her
BS degree in pharmacy from the
University of North Carolina. After a
move to Richmond, Virginia, and while
teaching in the School of Pharmacy at
Virginia Commonwealth University, she
earned a MS in gerontology and a PhD
in Urban Services from VCU.
In 2001, Dr. Kirkpatrick moved to
Winchester, Virginia, as the Dean of
Students in the Dunn School of
Pharmacy at Shenandoah University,
where she worked until her retirement
in 2012.
Dr. Kirkpatrick has always been active
in her community and has served as
President of many organizations,
including the Winchester Torch Club.
"Telescoping Telomeres" was delivered
to the Winchester club on April 6,
2016.
She may be reached at mkirkpat@su.edu.
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