Comparing the Role of the p53 Gene and Telomerase Enzyme in 'Accelerated Aging Due to Cancer': A Literature Review

Abstract

Aging is defined as progressive physiological alterations in an organism that lead to senescence. In response to stress, when proliferative-competent cells undergo permanent, irreversible growth arrest (like replicative dividing limit, oncogene activation, oxidative stress, or deoxyribonucleic acid (DNA) damage), it is termed as cellular senescence. Biomarkers p53, telomerase, and other inflammatory cytokines have a vital link with senescence, and directed use of these markers might be useful in manipulating cancer and the aging process. We included studies related to topics ' accelerated aging due to cancer', telomerase's relation to Aging and Cancer, p53's relation to Aging and Cancer, Atherosclerosis and Cancer from Search databases like PubMed and Google Scholar. We relied on peer-reviewed articles and included literature from the last 10 years written in the English language. Degenerative diseases in humans are usually linked to atherosclerosis, and atherosclerosis is associated with short leukocyte telomere length. Cancer itself and its treatment are linked with accelerated aging by causing progressive shortening of telomeres during cell replication, resulting in cell death. Gene p53 is known to have a dual effect that works as a tumor suppressor and has pro-aging side effects. In experimental studies, when p53 overcomes multiple regulatory mechanisms controlling its activity, then only the pro-aging side effects of p53 manifested. This might be a potential key for treating cancer without causing the side-effects of aging. In this review, we aim to explain and summarize the interdependent nature of p53, telomeres, and other conventional mechanisms of aging and cancer like inflammation, oxidative stress, uncontrolled proliferation, angiogenesis, micro ribonucleic acids (RNAs), and apoptosis, with a more synergistic approach that can help in developing new therapeutics and play a potential role in shaping modern human lifespan and revolutionize cancer treatment.

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Received 08/30/2020
Review began 09/16/2020
Review ended 10/01/2020
Published 10/04/2020
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Comparing the Role of the p53 Gene and
Telomerase Enzyme in ‘Accelerated Aging Due to
Cancer’: A Literature Review
Paramvijay Singh Dhalla , Arunima Kaul , Jian Garcia , Anusha Bapatla , Raheela Khalid , Ana S.
Armenta-Quiroga , Safeera Khan
1. Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA 2. Internal Medicine,
California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
Corresponding author: Paramvijay Singh Dhalla, dhallaparamvijay@gmail.com
Abstract
Aging is defined as progressive physiological alterations in an organism that lead to senescence. In response
to stress, when proliferative-competent cells undergo permanent, irreversible growth arrest (like replicative
dividing limit, oncogene activation, oxidative stress, or deoxyribonucleic acid (DNA) damage), it is termed as
cellular senescence. Biomarkers p53, telomerase, and other inflammatory cytokines have a vital link with
senescence, and directed use of these markers might be useful in manipulating cancer and the aging process.
We included studies related to topics ' accelerated aging due to cancer', telomerase's relation to Aging and
Cancer, p53's relation to Aging and Cancer, Atherosclerosis and Cancer from Search databases like PubMed
and Google Scholar. We relied on peer-reviewed articles and included literature from the last 10 years
written in the English language. Degenerative diseases in humans are usually linked to atherosclerosis, and
atherosclerosis is associated with short leukocyte telomere length. Cancer itself and its treatment are linked
with accelerated aging by causing progressive shortening of telomeres during cell replication, resulting in
cell death. Gene p53 is known to have a dual effect that works as a tumor suppressor and has pro-aging side
effects. In experimental studies, when p53 overcomes multiple regulatory mechanisms controlling its
activity, then only the pro-aging side effects of p53 manifested. This might be a potential key for treating
cancer without causing the side-effects of aging. In this review, we aim to explain and summarize the
interdependent nature of p53, telomeres, and other conventional mechanisms of aging and cancer like
inflammation, oxidative stress, uncontrolled proliferation, angiogenesis, micro ribonucleic acids (RNAs),
and apoptosis, with a more synergistic approach that can help in developing new therapeutics and play a
potential role in shaping modern human lifespan and revolutionize cancer treatment.
Categories: Internal Medicine, Oncology
Keywords: p53, telomerase, aging, cancer, metformin, statin, p16ink4a, progeria, atherosclerosis, sasp
Introduction And Background
Aging is defined as the constant physiological changes in an organism leading to senescence, biological
function deterioration, and the capacity to adapt to metabolic stress. 'Senescence' can refer to cellular
senescence or whole organism's senescence. Organismal senescence causes an increase in death rates and/or
a decrease in fecundity associated with increasing age. In other words, aging applies to degenerative
alterations that happen in every organism without any death reference. In contrast, senescence applies to
the developmental stage at which 'close to death' manifestations become evident. Manifestations of the
aging process include graying of hair, increased susceptibility to infection, higher risk of heatstroke or
hypothermia, and musculoskeletal changes. The nine hallmarks of aging are mentioned in Figure 1.
1 2 2 2 2
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Open Access Review
Article DOI: 10.7759/cureus.10794
How to cite this article
Dhalla P, Kaul A, Garcia J, et al. (October 04, 2020) Comparing the Role of the p53 Gene and Telomerase Enzyme in ‘Accelerated Aging Due to
Cancer’: A Literature Review. Cureus 12(10): e10794. DOI 10.7759/cureus.10794

FIGURE 1: Nine Hallmarks of Aging
Accelerated aging in cancer
Some studies have investigated accelerated aging in cancer survivors and concluded that accelerated aging
manifests as frailty, which is a clinical syndrome in which an individual cannot revert to baseline functional
status after a physical insult [1]. Accelerated frailty has been linked to a more striking comorbidity burden in
childhood cancer survivors, which was observed in the brains of adult survivors of pediatric lymphoid
malignancies and adult breast cancer survivors, than in non-cancer control groups. Compiling evidence
supports the hypothesis that cancer itself and its treatment are associated with accelerated aging [1-3].
Aging and cancer have many facets; hence, there are numerous theories, each of which may reveal one or
more aging perspectives. One of the notable theories of aging, which we will review in detail, pivots around
telomeres, which are repeated segments of deoxyribonucleic acid (DNA) seen at the ends of chromosomes.
These decide the maximum life span of a cell because each time a cell divides, many repeats are lost, which
shortens telomere, resulting in cell death. Thus, progressive chromosome shortening occurs during cell
replication and is observed with aging [4]. Various studies have shown that most degenerative and
inflammatory diseases, and many cancers, characterized by oxidative stress, contribute to accelerated
telomere shortening [5-6]. As a prerequisite to cellular senescence, a transcriptional regulator called gene
p53 causes apoptosis or cell cycle arrest, represses stem and progenitor cell populations' mobilization,
resulting in an accelerated aging process. Moreover, p53 also represses unregulated proliferation pathways,
leading to senescence-associated secretory phenotype (SASP) and cellular senescence. This generates
degenerative and pro-inflammatory tissue milieu resulting in aging process suppression. Henceforth, p53
has the potential to both hinder and expedite cellular aging processes [1,7]. In this review, we will discuss
the quantitative expression p16ink4a as a biomarker of aging, used to predict radiation toxicity due to
cancer treatment. We aim to explain and summarize the interdependent nature of p53, telomeres, and other
conventional mechanisms of aging and cancer with a more collaborative approach, which might aid in
understanding these mechanisms from a different perspective.
Review
Method
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We collected free full-text articles as data using PubMed and Google Scholar as our primary databases. We
included studies related to the topics 'accelerated aging due to cancer', telomerase's relation to aging and
cancer, p53's relation to aging and cancer, atherosclerosis, and cancer. We relied on peer-reviewed articles
and included literature from the last 10 years written in the English language. We included all possible types
of studies - mixed studies that covered all kinds of ethnicities from around the world. Participants were
cancer patients of all ages and gender with signs of accelerated aging like atherosclerosis, gray hair,
osteoporosis, and frailty, with biomarkers of aging and cancer like p53 and telomerase enzyme. We excluded
non-peer-reviewed articles, literature before 10 years, and articles written in any other language except
English. Non-cancer patients with frailty or cancer patients without signs of frailty were also excluded.
Discussion
One of the leading causes of death in both developing and developed countries being cancer. There is a
robust biological association between the conventional mechanisms of aging and cancer occurrence. In this
review article, we will explain different theories that discuss the evidence on the vital link between aging
mechanisms and carcinogenesis. These theories are worth considering, which can help understand the
relationship between cancer and the aging process in the general population [8].
Telomerase Enzyme
Telomerase enzyme is a vital enzyme for cell survival that prevents telomere shortening; consequently,
cellular senescence is observed after many cell division rounds. By increasing the expression and
reactivation of the telomerase complex, cancer cells bypass cellular senescence. This is one of the processes
that is required for tumor transformation and progression [9]. Multiple studies have concentrated on
identifying strategies or compounds to inhibit telomerase activity in cancer cells with induction of
senescence and subsequent loss of telomere integrity [9-11].
Mechanisms of Oxidative Stress Accelerating Telomeric Shortening
To demonstrate how oxidative stress accelerates telomere shortening, multiple mechanistic theories have
been suggested. One of the theories proposes that oxidative stress triggers cell death or senescence, and to
compensate that, the survivors undergo more increased cell divisions, resulting in increased telomere
shortening. One of the widely mentioned theories proposes that reactive oxygen species (ROS) causes
single-strand breaks (SSB) at telomeres directly or as intermediates during lesion repair, resulting in
replication fork collapse and telomere loss (Figure 2). Alternatively, lesions that impede telomere replication
can cause an accumulation of unreplicated single-stranded DNA (ssDNA) and manifest as multi-telomeric
foci at chromatid ends termed fragile telomeres (Figure 2) [12-14].
FIGURE 2: Stalling and Blocking of Telomere's Replication Fork
Stalling and Blocking of the Telomeres Replication Fork
The schematic exhibits a description of how telomere losses or telomere fragility arises from DNA lesions
that collapse or stall replication fork progression, respectively. When the DNA replication fork faces SSBs,
it can cause the collapse of the fork, resulting in a double-strand break. Due to uncondensed regions that
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result from accumulated unreplicated ssDNA, fragile telomeres manifest as multi-telomeric foci at a
chromatid end. For detection with a telomeric probe, telomere losses exhibit as chromatid ends lacking
sufficient telomeric DNA. By extending a prematurely truncated telomere, telomerase can suppress
telomere losses. Hence, telomerase's concept of regeneration can be used for the development of
therapeutics (Figure 2).
The Inverse Relation Between Cancer and Atherosclerosis Concerning Telomere Length
Degenerative diseases in humans are mostly linked to atherosclerosis, and atherosclerosis is associated with
short leukocyte telomere length (LTL) [15-17]. Short telomerase also gives protection against cancer
development by diminishing the proliferative activity of stem cells and limiting its regenerative capacity,
which gives rise to age-dependent degenerative conditions like atherosclerosis. To create 'genetic risk
scores' for cancers and atherosclerosis, which is expressed as coronary heart disease, recent studies have
used LTL-GWAS (genome-wide association) study findings [18]. As investigations showing, African
Americans have longer telomere length than in European ethnicity individuals; it is interesting to contrast
and compare the incidence of notable cancers and atherosclerosis between these two ethnicities. The
percentage of cancers like lung (after adjustment for smoking), prostate, pancreas, triple-negative breast
cancer, and its incipience at a younger age were greater in African Americans as compared to European
ethnicity [19-21]. On a contrary note, African Americans exhibited a lower incidence of atherosclerosis.
Hence, emphasizing on the role of telomere length in developing cancers and atherosclerosis more than risk
factors itself [22]. In these studies, the LTL-associated alleles (ZNF208, TERC, TERT, OBFC1, ACTP2, RTEL1,
and NAF1) seen are a risk sign for melanoma, lung cancer, and coronary heart disease. Therefore, when the
alleles' collective effect results in a relatively longer LTL, lung cancer and melanoma risk have risen opposite
to the risk of coronary heart disease, which was reduced. Evidencing the fact that increasing telomere length
increases cancer risk and decreases atherosclerosis, which is shown in Figure 3. The limitations of these
studies are that they don't include other common cancers like breast cancer and colorectal cancer, which
might be linked to LTL-associated alleles, and, if not, which other alleles they are linked to should also be
researched thoroughly (Figure 3) [23].
FIGURE 3: The Inverse Relation Between Cancer and Atherosclerosis
Concerning Telomere Length
p16ink4a Expression Due to Cancer Treatment Influencing Telomere Length
Radiation and chemotherapy can cause progressive and long-term tissue damage by the formation of pro-
inflammatory cytokines [24]. The accelerated development of second malignancies and other comorbidities
was also seen in survivors of childhood cancer treated with radiations. Chemotherapy has a significant effect
on telomere length. Repetitive standard-dose chemotherapy given for solid tumor patients was associated
with telomere shortening in hematopoietic stem cells and peripheral blood mononuclear cells [25]. Between
the ages of 20 and 80, a more robust marker for predicting molecular aging is the dynamic range of p16ink4a
expression, which increases approximately 10-fold. In one study of early-stage breast cancer, in which
females treated with adjuvant chemotherapy had their p16ink4a expression estimated in peripheral blood T
cells immediately after treatment and was raised by approximately one log2 order of magnitude and
continued to be present for one year following treatment [26], which corresponded to approximately a 15-
year increase in chronologic age. Undoubtedly, chemotherapy and radiation therapy accelerate aging;
hence, patients who are most vulnerable to cancer treatment can be identified by several biomarkers of
aging, which are now available and which might minimize treatment-related toxicity by allowing the earlier
testing of the interventions. To predict radiation toxicity in individual cases, studies testing how
quantitative expression biomarkers like p16ink4a might be utilized for developing possible interventions to
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ameliorate radiation effects on patients; therefore, they are required to be researched in more detail [27].
p53 Association With Aging
A rare genetic disorder Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder that
causes de novo point mutation inside exon 11 of the LMNA gene, leading to the accumulation of progerin.
HGPS fibroblasts, which are near-senescent, show reduced levels of Δ133p53α and increased levels of p53β.
Moreover, due to progerin-induced faulty DNA repair and genomic instability, there is an accumulation of
unrepaired DNA and double-strand breaks, which induces cellular senescence [28]. Surprisingly, they found
that due to a tumor protection mechanism controlled by BRD4 (Bromodomain-containing protein 4), cells
from HGPS patients typically do not develop cancer. Hence, research into the unexplored mechanism of
BRD4 and the renewal of Δ133p53α expression can be a crucial link between aging and cancer, which might
aid in cancer prevention [29-31].
p53 Isoforms in Cancer
The role of p53 in cancer formation is paradoxical. The sudden p53 induction in sarcomas and hepatocellular
carcinomas provokes senescence followed by tumor elimination. On the contrary note, cellular senescence
has an ability for tumor promotion, which is presumably related to senescence-associated secretory
phenotype (SASP) factors. Tumors are arrested at the pre-malignant stage due to cellular senescence. SASP
factors are secreted by senescent cells, which promote senescence induction in a paracrine mode (relating to
or denoting a hormone that affects only in the vicinity of the gland secreting it) and further reinforces the
senescence in an autocrine mode (signifying or relating to a cell-produced substance that affects the cell by
which it is secreted) [32]. Through full-length p53 and p53 isoforms, the subsequent model explains the
regulation of aging, age-related disorders, and cellular senescence. Depending on the p53 status and cell
type, multiple stresses stimulate full-length p53 and change various p53 isoforms expressions. The cell-
autonomous effects, like loss of functional cells and regenerative capacity, induce cellular senescence by
changing p53 status like decreased D133p53a and increased p53b. The non-cell-autonomous effect, mainly
SASP, is also seen in senescent cells. Senescence can be reinforced by autocrine SASP; in turn, the induction
of senescence in neighboring cells is achieved by the impact of paracrine SASP and stimulate an immune
response, leading to tumor suppression and aging. Concurrently, tumor progression is caused by SASP,
which also supports fibrosis, angiogenesis, the proliferation of the cells, and tumor invasiveness. Full-length
p53 expressions and various p53 isoforms also regulate this dual outcome through cell-autonomous and
non-cell-autonomous functions. Besides, senescence and age-related outcomes require various p53 isoform
expression for its occurrence. The full-length p53 desirable outcomes are suppressing pre-malignant tumor
cells resulting in tumor suppression, getting rid of damaged cells by stimulating the immune system, and
supporting reparative mechanisms like tissue restoration and wound healing [33-35]. However, the
deleterious effects of full-length p53 comprise prolonged inflammatory reactions, promoting stem cell-like
phenotypes in malignant cells, immune evasion by the tumor, and tumor promotion by inducing
angiogenesis [30,32]. The integration of p53 with anti-growth interventions that enhance survival is shown
in Figure 4.
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FIGURE 4: p53 Isoforms in Cancer
The Integration of p53 With Anti-Growth Interventions That Improve Survival
P53 induces G1 arrest as a part of a stress response, which inhibits mTORC1. G1-arrested cells are enabled
by the pro-growth pathway by introducing these mitogenic signals that change into senescent cells and
manifest as SASP. Cellular senescence represses the cell from developing into cancer; however, the SASP can
trigger cancer development from non-senescent cells by changing the tissue microenvironment.
Furthermore, it also decreases longevity and stimulates tissue degeneration. While p53-deletion promotes
cancer, simple p53 overexpression should reduce cancer. However, a mice experiment revealed that mice
carrying an additional p53 gene within a bacterial artificial chromosome (BAC) exhibited a reduced cancer
incidence, with surprisingly no distinctive exaggerated signs of aging. As ARF elevated p53 levels by
repressing MDM2 and increased gene dosage of p53 collectively with Arf, it resulted in a decline in cancer
rate and improved overall survival. Similarly, increased p53 levels were seen in mice with a hypomorphic
MDM2 allele, showing decreased cancer incidence without adverse side effects [7]. These effects are shown
in Figure 5.
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FIGURE 5: Mitogenic Signals
Therefore, it concludes that enhanced p53-mediated cancer suppression was not toxic to adult mice, and
whenever p53 overwhelms various regulatory mechanisms that modulate its activity, only then pro-aging
side effects of p53 are exhibited. The limitation of the study mentioned above was that it was not conducted
on humans. A broad-based human study on identifying and manipulating these undiscovered regulatory
mechanisms should be done, which might be a potential key to treating cancer without the side effects of
aging [7]. On the other hand, another study done on mice with a reduced level of mdm2 showed a lack of
premature aging phenotype. This suggests that p53 function enhancement is not sufficient to provoke
aging. Hence, more study needs to be conducted to understand the underlying physiology to link p53
expression and aging [36]. Various p53 isoforms abnormal expression was also evidenced in breast cancer,
ovarian cancer, colon carcinoma, head and neck tumors, glioblastoma, melanoma, renal cell carcinoma, lung
cancer, and acute myeloid leukemia, hepatic cholangiocarcinoma, and acute myeloid leukemia [37-39].
Therapeutics Targeting p53 and Myc
A potential approach in pro-senescence therapy is targeting p53 either indirectly or directly and impacting
p53 in the senescence process. Hence, trials involving therapeutics activating p53 and/or its pathway are
currently under work. One of the strategies tested in tumors that retain wild-type p53 is hindering the
MDM2/p53 interaction and improving p53 function. Through the restoration of the p53-mediated tumor
suppression pathway, cancer cell growth arrest and apoptosis were induced while generating minimal
cytotoxicity and side effects, which has led to the discovery of Nutlin, a precise inhibitor of the p53/MDM2
interaction. Moreover, the effectiveness and side effects of Nutlin-3, such as increases in atherosclerosis, are
yet to be established. The signaling pathways involved in the synergistic effects of combining other drugs
could also be used to identify additional targets [9]. 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside
(AICAR) and metformin are compounds that induce adenosine monophosphate-activated protein kinase
(AMPK), resulting in the induction of p53. Additionally, metformin inhibits mTORC1 via AMPK, which
activates the potential insulin- and IGF-signaling pathways, consequently decreasing the harmful impacts of
diabetes mellitus type 2 (including increased risk of cancer). The activation of AMPK and p53 by metformin
has shown to inhibit melanoma invasion (but not migration or proliferation), inhibits growth, and improves
radiation response for non-small cell lung cancer. Like metformin, AICAR also induces AMPK, resulting in
enhancing p53 phosphorylation and promoting p21 to arrest endothelial cells in G0 or G1. Therefore, AMPK-
activating agents can potentially induce p53 and decrease mTORC1 to suppress cancer and possibly other
diseases [40]. As AMPK-activating agents like metformin have shown to inhibit melanoma invasion, it is a
possibility that the p53 gene may have an indirect effect on cancer through the direct effect of IGF-signaling
pathways. Hence, this association should be thoroughly researched upon which might help formulate new
cancer regimes. Other common causes of aging and cancer and their possible therapeutics are mentioned in
Table 1.
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Mechanisms Mediators Effect Relation to Ageing & Cancers Possible Therapeutic interventions
Inflammation
Atherosclerosis antioxidants –
Phospholipase A2- Leukotrienes
pathway- Cyclooxygenase - TNF-α -
Cancer/atherosclerosis IL-6 - TGF-β
A cascade of biochemical events is
triggered due to the harmful stimuli that
induce the migration of leukocytes from
the blood to damaged tissue, resulting in
an inflammatory response that causes
the growth of the atherosclerotic lesion.
In cancer, macrophages and T cells are the predominant inflammato ry cells
since they are accountable for the secretion into the microenvironm ent of
massive amounts of inflammatory cytokines, proangiogenic factors, a nd reactive
oxygen species [41].
Interventions involving anti-
inflammatory molecule's
upregulation like TNF and
interleukin-1 receptor antagonist.
Oxidative
Stress
ROS's primary endogenous source is
the mitochondrial respiratory chain,
associated with enzymatic reactions
catalyzed by the xanthine oxidase,
nitric oxide synthase, and
NADH/NADPH oxidase.
Oxidative stress associated with local
inflammation, tissue remodeling,
endothelial dysfunction, smooth muscle
growth, and plaque formation has also
been associated with the production of
growth factors and mitogens that may
stimulate cell proliferation in early
atheromatous lesion sites.
As a consequence of the failure of the antioxidant systems, which is r esponsible
for their neutralization, promoting the development of inflammatory pro cesses,
there is an imbalance between RNS and ROS contributing to oxidat ive stress.
Which further causes the development of both atherosclerosis and cancer [42].
Interventions involving cell surface
receptors, such as CD44 and
several integrins that interact with
activated macrophages at sites of
inflammation, stimulates cell
adhesion and migration,
consequently, manipulating cancer
and the process of metastasis.
Uncontrolled
Proliferation
Involves regulatory proteins such as
cyclins and CDKs
Macrophages promote the development
of atherosclerotic plaque and, in various
tissues, stimulate the development of
different types of cancer.
Tissue homeostasis is regulated by two of the predominant physiologic al
processes like cell division and programmed cell death, where deregulat ion of
one of them provokes the development of several diseases, including cancer and
atherosclerosis [43].
Interventions target deregulation in
several control points like the G1-S
transition. It is one of the leading
causes of accelerated cell growth
and accumulated mutations.
Angiogenesis
Activators' growth factor - VEGF. FGF,
Cytokines – IL-1, IL-6, IL-8, cathepsin,
copper, oncogenes- c-Myc, r
Endothelin, erythropoietin, nitric oxide
synthase inhibitors cytokines- IL-10,
IL- 12, metalloproteinase, inhibitor,
zinc, oncogenes - p53, Rb endostatin,
interferon-a.
Formation of micro-vessels in an
atherosclerotic lesion contributes to the
development of plaque, the formation of
micro-vessels stimulated by hypoxia, HIF,
and ROS have a role in atherogenesis.
The progression of the primary atherosclerotic lesion requires angiogen esis; it is
known that the expansion of plaque and its risk complications such as rupture or
vascular thrombosis depends on this mechanism. Concerning cance r, tumor
vascular development is also essential for proliferation in processes suc h as
metastatic expansion since cancer cells depend on an adequate su pply of
oxygen and nutrients for this phenomenon to occur, where new bloo d and
lymphatic vessels are formed through angiogenesis and lymphangiog enesis [44].
An example of a medication that
blocks VEGF is bevacizumab
(Avastin), a monoclonal antibody
used in various cancers like colon
cancer. It blocks VEGF from binding
to the receptors on the cells that line
the blood vessels and stop
angiogenesis.
MicroRNAs in
atherosclerosis
and cancer
Both cancer and atherosclerosis
proangiogenic - Let7-f, miR-27b, and
miR-130a Inhibition of cellular
migration, endothelial proliferation,
and angiogenesis - miR-221, miR-222.
miRNAs are a group of highly conserved,
non-coding small RNAs, which play a
crucial role in gene regulation by acting
as repressors or activators. Since a
single miRNA may have various genes as
targets, and several miRNAs may share
the same target [45].
In atherosclerosis and cancer, the presence and regulation of severa l miRNAs
have also been associated with the control of cell proliferation, differen tiation,
and genomic stability, among other functions.
Since miRNAs have been found to
regulate atherosclerosis and Cancer
development, it becomes crucial to
investigate if similar therapeutic
strategies involving miRNAs could
apply to both diseases.
Apoptosis
The extrinsic or death receptor
pathway is triggered by the binding of
Fas and TNFR1 to Fas-L. The intrinsic
pathway is directed by two groups of
molecules, Bcl-2 and Bax.
Apoptosis is characterized by the
morphological and molecular changes in
cells, including cell shrinking, membrane
vesicle formation, and loss of adhesion to
neighboring cells.
The process of apoptosis is considered a determining factor in the reg ression or
progression of atherosclerosis by intervening in the stability of the plaqu e. On the
other hand, apoptosis has been recognized as an important player in c ancer
development since it functions as a molecular tool that cells employ to avoid the
proliferation of damaged cells, hence inhibiting tumor growth [46].
Studies investigating LDLR-
knockout mice have shown the
inactivation of an apoptosis
inhibitor expressed by macrophages
(Spα/Api6), increasing macrophage
apoptosis, and, therefore, inhibiting
atherosclerosis.
TABLE 1: Common Causes of Both Aging and Cancer Formation
TNF-α: tumor necrosis factor-alpha; IL: interleukin; TGF-β: transforming g rowth factor-beta; ROS: reactive oxygen species; CDK: cyclin-dependent
kinases; NADH: nicotinamide adenine dinucleotide + hydrogen; NADPH: nicotinamide adenine dinucleotide phosphate; RNS: reactive nitrogen
species; VEGF: vascular endothelial growth factor; FGF: fibroblast growth factor; RNA: ribonucleic acid; TNFR1: tumor necrosis factor receptor
1; LDLR: low-density lipoprotein receptor; miRNAs: microRNAs; HIF: hypoxia-inducible factor
Source: [45]
Therapeutics Targeting Atherosclerosis
Atherosclerosis has been considered a predisposing risk factor for several malignancies, especially of the
epithelial type (e.g., prostate, colon, ovary, lung), and a marker of aging. For example, tumors treated
with oxazaphosphorines and pyrimidine antagonists decreased the incidence and presence of
atherosclerotic lesions. The probable mechanism behind these effects was the changes in the concentration
of free cholesterol in the plasma membrane of cells affecting the formation of lipid rafts and caveolae. These
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can be directly correlated to the function of crucial receptors, such as the epidermal growth factor receptor
(EGFR), members of the TNF receptor family, and the tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL_ receptor that corresponds well in both cancer development and atherogenesis [47-48].
Combined immunotherapies employing gefitinib or trastuzumab or chemotherapies employing cisplatin or
doxorubicin, when coupled with the use of statins, surprisingly resulted in a higher therapeutic response in
gastrointestinal and lung cancers. Hence, it was concluded that the synergistic induction of cytotoxicity
employing immune- or chemotherapy in conjunction with statins improves the survival rate in patients with
ovarian cancer receiving only statins as a way to prevent an adverse cardiovascular event [47,49], as
atherosclerosis is the leading risk in aging due to cancer and its treatment which increases morbidity and
mortality. A novel therapeutic approach, which should be researched widely, would be the early treatment of
atherosclerosis with statins to prevent future risk of cardiovascular events due to cancer and its treatment.
As statins are readily available, it would be a game-changing strategy and can be manipulated after more in-
depth knowledge of these pathways is available in the future.
Conclusions
In this article, we have discussed various mechanisms such as telomerase enzyme, p53, and other common
mechanisms that indicate that 'accelerated aging' can be caused by cancer and its treatment. The 'double-
edged sword' effects of p53 are tumor suppression with pro-aging side effects and tumor promotion with
anti-aging effects. However, the pro-aging side effects of p53 usually manifest when p53 overwhelms the
many regulatory mechanisms that control its activity. As African American ethnicities have longer telomere
length than European ethnicities, African Americans developed more cancer and less atherosclerosis despite
having more risk factors for atherosclerosis. This could challenge 'the inverse relation theory between cancer
and atherosclerosis concerning telomere length.' Chemotherapy and radiation therapy cause accelerated
aging by affecting telomere length; it has been linked with telomere shortening in hematopoietic stem cells.
Thus, earlier testing of interventions with quantitative measurement of p16ink4a expression might benefit
in minimizing treatment-related toxicity. A new therapeutic strategy researched widely should be the early
treatment of atherosclerosis with statins to prevent future cardiovascular events due to cancer and its
treatment. This paper's limitation was that there was evidence from several experimental mouse studies,
whereas very few human trials have been conducted yet. Finally, we propose platforms for future research
on human telomere and p53 genetics due to its potential role in manipulating the human lifespan, which
might be a possible solution for treating cancer without the side effects of aging.
Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.
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