At a crossroads of cancer risk and aging: the role of telomeres
The risk of overall cancer inevitably increases with advancing age. The cancer incidence rate is not constant within the human life span (it exponentially increases with advancing age). Aging itself is a complex biological process with a poorly understood mechanism of its regulation. The aging proce...
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irk-123456789-322992013-02-13T03:31:03Z At a crossroads of cancer risk and aging: the role of telomeres Gerashchenko, B.I. Reviews The risk of overall cancer inevitably increases with advancing age. The cancer incidence rate is not constant within the human life span (it exponentially increases with advancing age). Aging itself is a complex biological process with a poorly understood mechanism of its regulation. The aging process, as evidenced from the survey of the chances for death for the large cohort of people of various age groups, manifests probably due to a progressive accumulation of diverse adverse changes that increase the risk of death. While an increase of cancer risk due to aging cannot be fully explained, the length of telomeres (biomarker of aging) appears to be important to predict this risk. Cellular senescence, which is believed to be associated with dysfunctional (shortened) telomeres, may contribute to the aging of a whole organism. Here, based on recent literature data, we investigate the possible link between telomere dysfunction associated cellular senescence and tumorigenesis. 2010 Article At a crossroads of cancer risk and aging: the role of telomeres / B.I. Gerashchenko // Experimental Oncology. — 2010. — Т. 32, № 4. — С. 224–227. — Біліогр.: 42 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/32299 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Reviews Reviews Gerashchenko, B.I. At a crossroads of cancer risk and aging: the role of telomeres Experimental Oncology |
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The risk of overall cancer inevitably increases with advancing age. The cancer incidence rate is not constant within the human life span (it exponentially increases with advancing age). Aging itself is a complex biological process with a poorly understood mechanism of its regulation. The aging process, as evidenced from the survey of the chances for death for the large cohort of people of various age groups, manifests probably due to a progressive accumulation of diverse adverse changes that increase the risk of death. While an increase of cancer risk due to aging cannot be fully explained, the length of telomeres (biomarker of aging) appears to be important to predict this risk. Cellular senescence, which is believed to be associated with dysfunctional (shortened) telomeres, may contribute to the aging of a whole organism. Here, based on recent literature data, we investigate the possible link between telomere dysfunction associated cellular senescence and tumorigenesis. |
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Gerashchenko, B.I. |
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Gerashchenko, B.I. |
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At a crossroads of cancer risk and aging: the role of telomeres |
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At a crossroads of cancer risk and aging: the role of telomeres |
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At a crossroads of cancer risk and aging: the role of telomeres |
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At a crossroads of cancer risk and aging: the role of telomeres |
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At a crossroads of cancer risk and aging: the role of telomeres |
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at a crossroads of cancer risk and aging: the role of telomeres |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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At a crossroads of cancer risk and aging: the role of telomeres / B.I. Gerashchenko // Experimental Oncology. — 2010. — Т. 32, № 4. — С. 224–227. — Біліогр.: 42 назв. — англ. |
| series |
Experimental Oncology |
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AT gerashchenkobi atacrossroadsofcancerriskandagingtheroleoftelomeres |
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2025-07-03T12:48:52Z |
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| fulltext |
224 Experimental Oncology 32, 224–227, 2010 (December)
CANCER INCIDENCE RATE AND AGING
In 1825, Gompertz [1] reported that the mortality
increases exponentially with age (Gompertz law
of mortality). At present, this law is still true. Fig. 1
shows the recent data on death rates for specified age
groups (taking into account both sexes of all races)
that were obtained from the survey of the chances for
death in 2006 for the entire population of the United
States (these data are from the National Center for
Health Statistics, USA [2]). The fact that the mortality
increases exponentially with age indicates that the
progressive accumulation of diverse adverse changes
within the life span (these changes increase the risk of
death) is likely to predetermine the rate of aging. As
Harman [3] stated, “the rate of aging is low early in life,
but rapidly increases with age due to the exponential
nature of the process”. Obviously, the aging process
depends upon two components of its regulation: 1)
intrinsic (i.e., genetic); 2) extrinsic, which includes
lifestyle factors and environmental exposures.
Advancing age is known as a high risk factor for
cancer. The relevance of aging to the risk of overall
cancer is likely to be supported by the fact that the
cancer risk exponentially increases with age despite
the age-specific occurrence of some kinds of cancer.
According to the data from the U.S. National Cancer In-
stitute (NCI) Surveillance, Epidemiology, and End Re-
sults (SEER) Program [4, 5], the cancer risk increases
exponentially up to a certain age (70–74 years), then
decelerates (75−84 years) and eventually declines
(≥ 85 years) (Fig. 2). It should be noted that ≈ 60%
of newly diagnosed malignancies and ≈ 70% of all
cancer deaths occur in persons aged ≥ 65 years [4,
5]. More than 70% of the mortality associated with
many cancers including prostate, bladder, colon,
uterus, pancreas, stomach, rectum and lung occurs
in persons aged ≥ 65 years [4−6]. Deceleration and
decline of the cancer incidence rate at older ages is
an interesting but not fully understood phenomenon.
It seems that the large amount of age-associated
changes accumulated by older ages (≥ 75 years; see
Fig. 2) somehow reduces the probability of cancer
occurrence and/or its detection. Driver et al. [7] have
recently proposed that the decrease in incidence of
cancer late in life is largely due to a substantial amount
of undiagnosed disease. On the other hand, it has
been reasonably hypothesized that the age-related
decline of the rate of cell proliferation together with
accumulation of senescent (non-proliferating) cells
may lead to the reduction in the number of newly trans-
formed cells at older ages, thereby contributing to this
aforementioned phenomenon [8]. A late-life mortality
rate plateau that has been theoretically predicted [9,
10] may be relevant to deceleration and decline of the
cancer incidence rate at older ages.
0
2000
4000
6000
8000
10000
12000
14000
Age (years)
De
at
h
ra
te
p
er
1
00
,0
00
p
op
ul
at
io
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9
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25
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9
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–3
4
35
–3
9
40
–4
4
45
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9
50
–5
4
55
–5
9
60
–6
4
65
–6
9
70
–7
4
75
–7
9
80
–8
4
≥
85
Fig. 1. Death rates for specified age groups (both sexes of
all races) obtained from the survey of the chances for death
in 2006 for the entire population of the United States. Elevated
mortality rate in children of the age group of 0−4 years can be
explained by the fact that children under 1 year die quite fre-
quently (death rate: 690.7) [2]
It should be pointed out that in the United States,
for instance, among the causes of death in the current
millennium, malignant neoplasms remain to be second
AT A CROSSROADS OF CANCER RISK AND AGING: THE ROLE OF
TELOMERES
B.I. Gerashchenko
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology,
National Academy of Sciences of Ukraine, Vasylkivska 45, Kyiv 03022, Ukraine
The risk of overall cancer inevitably increases with advancing age. The cancer incidence rate is not constant within the human life
span (it exponentially increases with advancing age). Aging itself is a complex biological process with a poorly understood mecha-
nism of its regulation. The aging process, as evidenced from the survey of the chances for death for the large cohort of people of
various age groups, manifests probably due to a progressive accumulation of diverse adverse changes that increase the risk of death.
While an increase of cancer risk due to aging cannot be fully explained, the length of telomeres (biomarker of aging) appears to be
important to predict this risk. Cellular senescence, which is believed to be associated with dysfunctional (shortened) telomeres,
may contribute to the aging of a whole organism. Here, based on recent literature data, we investigate the possible link between
telomere dysfunction associated cellular senescence and tumorigenesis.
Key words: telomeres, aging, cancer incidence rate, cellular senescence, TIF.
Received: October 1, 2010.
*Correspondence: Fax: +380442581656
E-mail: biger63@yahoo.com
Abbreviations used: 53BP1 — p53 binding protein 1; ATM — ataxia
telangiectasia mutated; TIF — telomere dysfunction-induced focus.
Exp Oncol 2010
32, 4, 224–227
Experimental Oncology 32, 224–227, 2010 (December) 225
after cardiovascular disease (in 2006, cancers were
23.1%, while cardiovascular disease was 26.0% [2]).
Interestingly, according to the annual reports of the
U.S. National Center for Health Statistics [2], the mor-
tality rate for cardiovascular disease steadily declines
(≈ 0.5% every year), while the mortality rate for cancers
remains unchanged, so one can predict that cancers
by 2013 will be the number one cause of death.
0
500
1000
1500
2000
2500
3000
Age (years)
Ca
nc
er
in
ci
de
nc
e
ra
te
pe
r 1
00
,0
00
p
op
ul
at
io
n
0–
4
5–
9
10
–1
4
15
–1
9
20
–2
4
25
–2
9
30
–3
4
35
–3
9
40
–4
4
45
–4
9
50
–5
4
55
–5
9
60
–6
4
65
–6
9
70
–7
4
75
–7
9
80
–8
4
≥
85
Fig. 2. Cancer incidence rates for specified age groups (both sexes
of all races) based on NCI SEER program data of 1994–1998 [4, 5]
TELOMERES: THEIR ROLE IN CELLULAR
SENESCENCE AND TUMORIGENESIS
The fact that the cancer incidence rate progresses
with advancing age indicates that the mechanisms of
tumorigenesis and aging somehow intersect. Dysfunc-
tional (shortened) telomeres appear to play a key role at
the aging-cancer interface. In the beginning of 1990th it
has been reported that the length of telomeres markedly
decreases with advancing age and increasing passage of
cell culture [11, 12]. At present, attrition of telomeres is a
significant molecular biomarker of aging. Telomeres are
known as nucleoprotein structures at the extreme ends of
linear chromosomes, whose length (telomeric length) is a
critical factor in maintaining genomic stability. Telomeric
DNA, which does not contain protein-encoding genes,
is composed of G-rich hexanucleotide repeats that have
(TTAGGG)n sequence. Incomplete and inefficient (due to
accumulation of telomeric DNA damage) end replication
may contribute to telomere shortening [13, 14]. Repair of
DNA (including telomeric DNA) appears to decline with
aging [14, 15]. Telomeres shorten to a certain critical size,
and this event signals cells to enter an irreversible growth
arrest (i.e., cellular senescence) that may contribute to the
aging of a whole organism. In most instances cells become
senescent before they accumulate enough mutations to
be cancerous, (this, in part, can explain deceleration and
decline of the cancer incidence rate at older ages). The
growth arrest induced by shortened telomeres may be a
potent anti-cancer mechanism. It has been reasonably
noted that the starting point for telomere length in somatic
cells is the length of telomeres in germ line cells of the
individual or species, and this parameter is and must be
strictly conserved in order to maintain viability of the spe-
cies [16]. The rate of telomere shortening is not necessarily
a constant function of cell division. In i n vitro maintained
normal human cells the rate of telomere shortening may
vary from 50 to 100 bp per cell division (“normative”
telomere loss [16]) [17]. A permanent loss of telomeric
DNA with each cell division is primarily because of the
lagging strand of DNA synthesis cannot replicate the
extreme 3� end of the chromosome (the “end replica-
tion problem”) [13]. Short telomeres in peripheral blood
leucocytes have been reported to be associated not
only with risks of cancer and cardiovascular disease,
but also with mortality from them [18−20].
The integrity of telomeres is maintained, at least in
part, by the ribonucleoprotein enzyme telomerase [21,
22]. Telomerase activity is present in almost all human
tumors but not in adjacent normal cells [23, 24]. It is
growth-regulated, since it correlates with cell proliferation
in both normal tissues and tumors [25]. The expression
of telomerase activity does not necessarily correlate
with the length of telomeres. In some mitotically active
normal somatic cells telomeres become shorter with
each cell division cycle even though telomerase activity
is still present [26]. Although most tumors do express
telomerase activity, their telomeres are usually not as long
as in normal tissues with lack of cell proliferation [25].
Activation of telomerase that is important in maintain-
ing telomere length stability may be necessary for the
sustained growth of most tumors. Telomerase activity
appears to be a promising diagnostic and prognostic
marker of cancer [25, 27−29]. Nevertheless, telomerase
expression alone is not the inciting event in the trans-
formation to neoplasia. This is based on the fact that
introduction and expression of telomerase do not induce
a transformed phenotype [30, 31].
Although telomerase as well as telomeres plays
an important role at the aging-cancer interface [32,
33], the mechanism that can trigger tumorigenesis
due to aging remains largely unknown. Most normal
cells respond to dysfunctional telomeres by mounting
a senescence response that requires the function of
both pRb and p53, but another possible consequence
of telomere dysfunction (absence of the senescence
checkpoint and p53 function) is genomic instability,
which is believed to be an early event in tumorigenesis
[33, 34]. Thus, cellular senescence may be a “double-
edged sword” in this regard (i.e., pro- and anti-tumor-
igenic roles). Interestingly, dysfunctional telomeres
can induce a DNA damage response that involves
their association with DNA damage response factors
(53BP1, γ-H2AX, Rad17, ATM, and Mre11) [35]. The
domain of telomere-associated DNA damage factors
is often referred as a telomere dysfunction-induced
focus (TIF). TIFs containing multiple DNA damage
response factors have been found to be assembled
in a subset of senescent cells and signaled through
ATM to p53, upregulating p21 and causing G1-phase
arrest [36]. Senescent cells displaying dysfunctional
telomeres (i.e., TIF-positive cells) have been found
to accumulate with increasing age in dermal fibro-
blasts of skin biopsies of aging baboons [37], which
like humans have a relatively long life span and show
age-dependent telomere shortening [38]. It should
be pointed out that the number of TIF-positive cells in
this study accumulated exponentially with increasing
age, reaching a value of 15−20% in very old (25−30 yr)
226 Experimental Oncology 32, 224–227, 2010 (December)
animals [37]. Probably, this finding is the first strong
evidence of progressive (exponential) accumulation
of age-related changes at the cellular level. The expo-
nential character of telomere dysfunction associated
cellular senescence that was observed in primates
is likely to take place in humans and contribute to an
exponential increase of mortality and cancer incidence
rates with advancing age (see Fig. 1 and 2, respec-
tively). In senescent cells, in addition to the damage
to telomeric DNA, the damage may also occur to non-
telomeric main DNA that contains protein-encoding
genes. According to another finding by Herbig et al.
[37], in senescent dermal fibroblasts ≈ 30% of nuclear
foci containing 53BP1 (one of the markers of DNA
double-strand break) do no co-localize with telomeric
DNA. If the double-strand break misrepaired or left un-
rejoined, it can cause transformation or cell death [39].
Telomere dysfunction has been reported to impair
DNA repair [40], a finding that could help explain the
persistence of DNA damage nuclear foci associated
with non-telomeric DNA [37].
Finally, cellular senescence may not be caused due
exclusively to replicative exhaustion. Oxidative stress
appears to increase the rate of telomere shortening
as evidenced from telomere-specific accumulation of
DNA damage induced by reactive oxygen species [41].
Interestingly, accelerated telomere shortening has
been found to be a function of response to life stress,
namely to psychological stress, which is significantly
associated with oxidative damage [42].
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