Cellular Aging and Senescence in Cancer: A Holistic Review of Cellular Fate Determinants

Abstract

This comprehensive review navigates the complex relationship between cellular aging, senescence, and cancer, unraveling the determinants of cellular fate. Beginning with an overview of cellular aging's significance in cancer, the review explores processes, changes, and molecular pathways influencing senescence. The review explores senescence as a dual mechanism in cancer, acting as a suppressor and contributor, focusing on its impact on therapy response. This review highlights opportunities for cancer therapies that target cellular senescence. The review further examines the senescence-associated secretory phenotype and strategies to modulate cellular aging to influence tumor behavior. Additionally, the review highlights the mechanisms of senescence escape in aging and cancer cells, emphasizing their impact on cancer prognosis and resistance to therapy. The article addresses current advances, unexplored aspects, and future perspectives in understanding cellular aging and senescence in cancer.

Full text

http://dx.doi.org/10.14336/AD.2024.0421
*Correspondence should be addressed to: Dr. Ning Li, Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya
Hospital, Central South University, Changsha, China. Email: liningoms@csu.edu.cn. #These authors contributed equally to this work.
Copyright: © 2024 Tufail M. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ISSN: 2152-5250 1
Review
Cellular Aging and Senescence in Cancer: A Holistic
Review of Cellular Fate Determinants
Muhammad Tufail1#, Yu-Qi Huang1#, Jia-Ju Hu1, Jie Liang1, Cai-Yun He1, Wen-Dong Wan1,
Can-Hua Jiang1,2,3,4, Hong Wu5, Ning Li1,2,3,4*
1Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South
University, Changsha, China. 2Institute of Oral Precancerous Lesions, Central South University, Changsha, China.
3Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha,
China. 4National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University,
Changsha, China. 5State Key Laboratory of Powder Metallurgy, Central South University, Changsha, 410083,
China
[Received April 13, 2024; Revised May 18, 2024; Accepted May 21, 2024]
ABSTRACT: This comprehensive review navigates the complex relationship between cellular aging, senescence, and
cancer, unraveling the determinants of cellular fate. Beginning with an overview of cellular aging's significance in
cancer, the review explores processes, changes, and molecular pathways influencing senescence. The review explores
senescence as a dual mechanism in cancer, acting as a suppressor and contributor, focusing on its impact on therapy
response. This review highlights opportunities for cancer therapies that target cellular senescence. The review further
examines the senescence-associated secretory phenotype and strategies to modulate cellular aging to influence tumor
behavior. Additionally, the review highlights the mechanisms of senescence escape in aging and cancer cells,
emphasizing their impact on cancer prognosis and resistance to therapy. The article addresses current advances,
unexplored aspects, and future perspectives in understanding cellular aging and senescence in cancer.
Key words: Cellular Aging, Senescence, Cancer Progression, Senescence Escape, Therapeutic Strategies
1. Introduction
Cellular aging is the natural process of cells deteriorating
over time, leading to reduced function and increased
susceptibility to disease. Cellular aging has a profound
role in shaping the fate of cells, transcending mere
temporal boundaries to orchestrate a complex symphony
of molecular events. From the intricate dynamics of
telomeres to the precise choreography of genomic
maintenance, the aging process represents a delicate
interplay of molecular intricacies. As cells journey
through time, they accumulate a spectrum of age-related
changes, rendering them susceptible to protective and
detrimental influences [1, 2]. Understanding the paradigm
of cellular aging is pivotal in unraveling the subsequent
chapters on senescence and cancer, as it lays the
foundation for balancing cellular preservation and
transformation.
Exploring cellular aging in cancer unveils the
intricate relationship between these phenomena [3].
Cancer, arising from cellular dysregulation, presents a
significant challenge within the framework of aging cells.
This exploration extends beyond academic realms; it
holds promise in revealing therapeutic strategies targeting
age-associated vulnerabilities in cancer [4, 5]. This
thorough review provides a foundation for reshaping
perspectives on aging-related diseases, particularly
cancer, by offering insights into potential therapeutic
interventions.
At the nexus of cellular aging lies senescence, a stable
cell cycle arrest state with multifaceted implications for
cellular homeostasis. This section examines the dynamic
Early access date: June 7, 2024

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Aging and Disease • Volume 16, Number 3, June 2025 2
interplay between cellular aging and senescence,
examining how the aging process shapes the cellular
landscape, fostering conditions that may either inhibit or
propel senescence. The tapestry extends to the profound
connection between senescence and cancer, where cells
are entangled in a delicate balance of protection and peril
[6]. Understanding this link is paramount, as it reveals the
dual role senescence plays both as a defender against
tumorigenesis and, paradoxically, as a contributor to
cancer progression.
As we navigate this holistic review, the significance
of investigating cellular aging within the context of cancer
comes into sharp focus. Cancer, a manifestation of
cellular dysregulation, represents a formidable challenge
within the framework of aging cells. Unraveling the
intricate relationship between cellular aging and cancer
susceptibility, the role of senescence as a sentinel against
tumorigenesis, and the deviation from this protective
mechanism becomes crucial [7]. This exploration is not
merely an academic pursuit; it promises to uncover
therapeutic strategies targeting age-associated cancer
vulnerabilities [8]. Understanding the determinants of
cellular fate in this holistic manner lays the groundwork
for redefining our perspectives on aging-related diseases,
particularly cancer. We will traverse the realms of
senescence, apoptosis, and cancer therapies, intricately
examining their roles as cellular fate determinants within
the broader context of aging. This holistic review aims to
provide a nuanced understanding of cellular destiny's
molecular intricacies, offering insights that may reshape
our paradigms in both basic cellular biology and the
clinical realm of age-related cancer.
2. Cellular Aging: A Prelude to Senescence and
Cancer
2.1. Processes Involved in Cellular Aging
Cellular senescence is triggered by various cellular
challenges, including DNA damage [9, 10], telomere
shortening [11, 12], and oncogene activation [13]. These
factors initiate a cascade of events that safeguard against
cancer during early life and actively contribute to the
aging process. For instance, the cellular senescence
program is activated when cells undergo DNA damage
due to external factors like radiation or chemicals. This
response halts the replication of damaged cells,
preventing the potential propagation of mutations and,
consequently, acting as a critical defense against cancer
initiation [14, 15]. Telomere shortening, a consequence of
replication-associated telomere shortening, can induce
replicative senescence by activating DNA damage
response signaling pathways. Telomere shortening
triggers replicative senescence by inducing DNA damage
response signaling pathways. This process involves the
activation of two major tumor-suppressor pathways, the
p53/p21Waf1/Cip1 and p16Ink4a/Rb pathways, leading to an
irreversible cell cycle arrest, usually in the G1 phase [16].
On the other hand, oncogene activation drives cellular
senescence by engaging robust tumor suppressive
processes that recognize and counteract inappropriate
proliferative signals. This includes directing cells with
abnormal growth signals toward cell death or an
irreversible cell cycle arrest known as cellular senescence
[17]. DNA damage and telomere shortening emerge as
hallmark features of cellular aging, intricately linked to
the initiation of cellular senescence. Consider the scenario
of telomere shortening with each cell division; the
telomeres, protective caps at the ends of chromosomes,
progressively shorten. This natural biological clock
eventually triggers cellular senescence, limiting the
replicative potential of cells and contributing to the
overall aging landscape within tissues [18, 19].
The tumor-suppressive role of senescence is
noteworthy in its ability to impede cancer progression.
Senescence induces a robust cell cycle arrest, preventing
the uncontrolled division of cells and acting as a sentinel
against the progression from pre-malignant to malignant
states. This mechanism ensures that potentially harmful
cells are halted in their tracks, safeguarding against
tumorigenesis [20]. However, the dual role of senescence
in cancer adds a layer of complexity. While senescence is
a defense mechanism against tumorigenesis, the persistent
presence of senescent cells may paradoxically contribute
to cancer progression [21]. The senescence-associated
secretory phenotype (SASP) is a characteristic feature of
senescent cells, where these cells secrete various factors
such as cytokines, growth factors, and proteases. These
secreted factors can influence the surrounding
microenvironment, promoting inflammation and tissue
remodeling, and potentially contributing to age-related
diseases. The secretory profile of senescent cells, known
as the SASP, can create a pro-inflammatory
microenvironment, fostering conditions conducive to
tumorigenesis. This delicate balance between protective
and potentially harmful effects underscores the nuanced
nature of senescence in cancer development [22, 23].
The interplay between aging and cancer becomes
more apparent through inflammatory connections.
Through the SASP, Senescent cells actively contribute to
tissue degeneration and may promote tumorigenesis by
inducing inflammation. Chronic inflammation induced by
senescent cells in aged tissues exemplifies how these
processes are intertwined, shaping the microenvironment
and influencing aging-related changes and cancer
development [6, 24]. For example, Systemic
inflammation and aging can lead to a condition called
CHIP (clonal hematopoiesis of indeterminate potential),

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which has implications for cancer development. CHIP
refers to a condition characterized by genetically distinct
populations of blood cells derived from a single
hematopoietic stem cell. These cells harbor somatic
mutations commonly associated with hematologic
malignancies but do not meet diagnostic criteria for blood
cancer. CHIP increases with age and is associated with an
elevated risk of developing blood cancers, cardiovascular
disease, and overall mortality.
2.2. The Impact of Cellular Aging on Senescence
As cells undergo aging, the intricate relationship between
cellular aging and the tumor-suppressive role of
senescence becomes evident [25]. Senescence,
functioning as a robust defense mechanism, is crucial in
halting cancer cell proliferation and impeding the
progression from pre-malignant to malignant states. This
dynamic interplay sheds light on how cellular aging
actively contributes to the orchestration of senescence,
forming a critical component in preventing tumorigenesis
[25]. Activated oncogenes, which promote uncontrolled
cell growth, trigger senescence as a countermeasure. This
process is a formidable barrier against cancer
development by preventing the growth of potentially
neoplastic cells [26]. The delicate balance between
cellular aging and the activation of oncogenes highlights
the sophisticated interplay between these processes and
their collective impact on cellular health [27, 28].
The innate immune system targets senescent cells for
elimination, emphasizing its crucial role in regulating the
presence of senescent cells through immune surveillance.
This immune response adds complexity to understanding
how cellular aging influences senescence and,
consequently, shapes the landscape of cancer
development [29, 30]. For example, the interactions
between senescent cells and the immune system are
crucial in regulating cellular aging and cancer
susceptibility. Immune surveillance mechanisms target
senescent cells for elimination, highlighting the
importance of immune responses in controlling the
presence of senescent cells. Factors like the clearance of
senescent cells by immune cells, immune surveillance
promoting senescence induction and clearance, the impact
of the SASP on immune responses, and emerging
senolytic immunotherapy (immunotherapy that targets
and eliminates senescent cells using the immune system
to treat age-related diseases) approaches underscore the
complex relationship between cellular aging, immune
regulation, and cancer development [31].
Table. 1 Senescence in Cancer: Pros and Cons.
Aspect of Senescence
Positive Effect in Cancer
Negative Effect in Cancer
Growth Arrest
Senescence induces a permanent
growth arrest in cancer cells,
preventing uncontrolled proliferation
and metastasis. This halts tumor growth
and can lead to tumor dormancy.
Senescent cells can promote tumor progression
through the secretion of various factors, such as pro-
inflammatory cytokines and growth factors that
stimulate neighboring cancer cells, fostering a pro-
tumorigenic microenvironment and aiding in tumor
survival and spread.
Immune Surveillance
Senescent cancer cells are recognized
and cleared by the immune system,
reducing the tumor burden. This
immune surveillance helps in
controlling cancer growth and
preventing metastasis.
Some senescent cells may evade immune detection
through mechanisms like upregulation of immune
checkpoint molecules, leading to immune tolerance
and allowing tumor cells to escape immune
destruction, contributing to cancer progression.
Tumor Suppression Pathways
Senescence activates tumor-
suppressive pathways, such as p53 and
pRB, inhibiting cancer initiation and
progression. This serves as a natural
barrier against tumorigenesis.
Senescent cells can secrete factors like matrix
metalloproteinases, cytokines, and growth factors
that create a pro-tumorigenic microenvironment,
promoting tumor growth, angiogenesis, and
invasion, ultimately aiding in tumor progression.
Therapy Resistance
Certain cancer treatments, like
chemotherapy and radiation therapy,
can trigger senescence in cancer cells,
halting tumor growth and contributing
to treatment efficacy.
Senescent cells may confer resistance to therapy by
promoting the survival of cancer cells under
treatment-induced stress. They can secrete factors
that enhance cell survival pathways, leading to
therapy resistance and potentially allowing residual
cancer cells to repopulate the tumor.
In therapeutic implications, the discourse focuses on
strategies targeting senescence in cancer therapy.
Notably, therapy-induced senescence emerges as a
promising approach. This strategy aims to prevent tumor
growth by inducing senescence in cancer cells while
minimizing potential side effects. Understanding how
cellular aging influences therapeutic responses provides
valuable insights into novel avenues for cancer treatment,

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ushering in a more nuanced and effective approach to
tackling this complex disease.
3. Senescence: A Double-Edged Sword in Cancer
3.1. Definition and Characteristics of Senescence
Originally characterized as a physiological suppressor
mechanism against tumor cells due to its ability to halt cell
proliferation, senescence plays a pivotal role in the
prevention and progression of cancer (Table. 1). Its initial
role as a tumor suppressor is grounded in the ability to
enforce a halt in cell division, preventing the unchecked
growth of potential malignancies [32]. However, recent
insights have brought forth complexities. Senescent cells
may contribute to oncogenesis through mechanisms like
the SASP [33]. For example, the SASP may create a
microenvironment that promotes tumor recurrence or
progression, demonstrating the dualistic nature of
senescence in cancer.
Senescence establishes intricate connections with
various anticancer therapies, such as chemotherapy,
radiotherapy, and targeted therapies [34]. Its influence is
dual-fold. On one hand, senescence can augment the
effectiveness of treatments by directly inhibiting cancer
cell proliferation or by eliciting an immune response
through bioactive molecules released by senescent cells.
On the other hand, there's a potential downside, where
senescence may compromise patient resilience to
therapies, potentially setting the stage for disease
recurrence post-treatment [34, 35]. For instance,
chemotherapy induces senescence in both tumor and
normal cells. Low doses of chemotherapy can trigger a
senescent state in human cancer cells, while higher doses
may induce apoptosis instead [36]. Furthermore, targeted
therapies can also induce senescence in cancer cells.
Activating oncogenes like HRASV12 can trigger growth
arrest, known as oncogene-induced senescence [36].
Senescent cells exhibit an increased prevalence in the
normal tissues of aged individuals and specific tissue
types like skin and adipose tissue. The presence of
senescent cells in cancer patients holds profound
prognostic implications, influencing outcomes that range
from improved to impaired [37, 38]. The varying effects
of senescence on tumorigenesis and response to therapy
underscore its intricate role in shaping the trajectory of
cancer outcomes [39]. For instance, the prevalence of
senescent cells in the tumor microenvironment may
significantly impact the response to treatment, leading to
diverse outcomes based on the complex dynamics of
senescence in influencing cancer progression and
therapeutic responses.
Viewing cellular senescence as a dynamic, evolving
condition in the context of cancer is paramount [40].
Senescence exhibits both antitumorigenic and
protumorigenic features that can shift over time. The
interactions between senescent cells and the tumor
microenvironment add a layer of complexity to its role in
cancer progression and treatment [41]. As an illustration,
senescent cells may initially contribute to the suppression
of tumors but may later foster conditions conducive to
tumor progression. Recognizing this dynamic nature is
crucial for developing nuanced and effective strategies
that leverage the positive aspects of senescence while
mitigating its potentially detrimental effects on cancer
outcomes [42].
3.2. Senescence as a Tumor Suppressive Mechanism
In Cellular Senescence and Cancer Suppression,
senescence activation responds to various triggers such as
DNA damage, telomere shortening, and oncogene
activation. Its significance lies in acting as a robust barrier
against cancer by initiating growth arrest in damaged
cells. This halts their uncontrolled proliferation, thwarting
the potential transformation into malignant cells (Fig. 1)
[43]. For instance, in response to DNA damage caused by
external factors, the induction of senescence prevents the
replication of genetically compromised cells, thereby
impeding cancer initiation.
The Paradoxical Role of Senescence introduces a
nuanced perspective. While senescence is traditionally
seen as a safeguard by inhibiting the proliferation of
potentially harmful cells, a paradoxical aspect surface.
Senescent cells may exhibit a SASP that,
counterintuitively, promotes tumor growth, invasion,
metastasis, and vascularization. This paradox underscores
the complexity of senescence in the intricate landscape of
cancer biology. An illustrative example is the SASP-
mediated secretion of inflammatory molecules, creating a
microenvironment conducive to tumor progression [2].
Moving to Therapeutic Implications, senescence
induced by chemotherapy, radiotherapy, and targeted
therapies stands out as a beneficial facet of cancer
treatment. It inhibits cell proliferation and stimulates an
immune response against cancer cells [44]. However,
accumulating senescent cells and SASP components may
pose risks over time, necessitating a nuanced approach.
For instance, chemotherapy-induced senescence can
enhance immediate treatment success but may contribute
to long-term complications such as therapy resistance.
Regarding Clinical Relevance, senescent cells
become prevalent in aged tissues and wield significance
in cancer prognosis and treatment outcomes [1].
Identifying senescent cells through specific biomarkers
like senescence-associated β-galactosidase, p21, and
p16INK4A enables researchers to explore the prognostic
implications of senescence in cancer patients [45]. This

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Aging and Disease • Volume 16, Number 3, June 2025 5
identification aids in understanding how the presence of
senescent cells may influence the course of cancer and
response to treatment.
Figure1. This figure illuminates the intricate role of senescence in cancer development, portraying a dual scenario: Protective
Senescence and Promoting Senescence. The initiation triggers of senescence, encompassing DNA damage, telomere shortening,
and oncogene activation, activate a protective response, preventing the propagation of mutations. Senescence acts as a robust tumor
suppressor by halting cell replication, defending against uncontrolled cell division, and acting as a sentinel against cancer initiation
and progression. Additionally, senescence prevents the replication of damaged cells, limiting the potential for mutations and impeding
the progression from pre-malignant to malignant states. On the other hand, the potentially harmful aspects of senescence are depicted.
Senescent cells release the SASP, creating a pro-inflammatory microenvironment. Chronic inflammation in this microenvironment
fosters conditions conducive to tumorigenesis, representing the dark side of senescence. This side illustrates the potential for cancer
development as SASP contributes to cancer progression by altering the microenvironment and providing support for the survival and
growth of cancer cells.
The dynamic nature of senescence in cancer therapy
calls for further research. Understanding the
circumstances under which senescent cells exert
beneficial or detrimental effects on treatment outcomes is
paramount. Strategies involving the selective removal of
senescent cells or the modulation of SASP effects present
promising avenues for enhancing the efficacy of cancer
therapies while minimizing potential risks associated with
senescence-induced tumorigenesis. For example,
exploring therapeutic interventions that selectively target
senescent cells without compromising the overall benefits
of senescence in cancer treatment holds promise for future
advancements in oncology.
3.3. Senescence as a Contributor to Cancer
Development
Initiated by diverse stressors such as DNA damage,
telomere shortening, and oncogene activation, cellular
senescence acts as a stress response mechanism [46]. Its
protective role is evident as it halts the proliferation of
damaged cells, preventing uncontrolled growth (Fig. 1)
[47]. However, the paradox unfolds through the SASP,
where senescent cells release factors promoting tumor
growth, invasion, metastasis, and vascularization [21].
For instance, in response to telomere shortening,
senescence prevents cells from dividing further, averting
potential tumorigenesis [21].
The role of senescence in cancer is both intricate and
controversial. Traditionally recognized as a tumor
suppressor mechanism due to its ability to curb
uncontrolled cell proliferation, recent evidence challenges
this notion [22]. Senescent cells may paradoxically foster
oncogenesis, mainly through SASP-mediated effects [48].
The accumulation of senescent cells and SASP
components over time raises susceptibility to
tumorigenesis, portraying the dual nature of senescence in
cancer biology [21]. An example is seen in oncogene
activation, where senescence may initially act as a defense
but later contribute to a microenvironment conducive to
tumor progression [46].
Senescence induced by chemotherapy, radiotherapy,
or targeted therapies presents a double-edged sword in
cancer treatment outcomes [22]. While it can inhibit cell
proliferation and boost immune responses against cancer
cells, the persistence of senescent cells and SASP
components may lead to unintended consequences such as
tumor recurrence or progression. Strategies that
selectively target or remove senescent cells promise to
optimise cancer therapy outcomes. For instance, in
chemotherapy, inducing senescence may hinder
immediate cancer growth but necessitates a nuanced
approach to mitigate long-term risks [22].
Further research becomes imperative to delineate the
precise conditions under which senescent cells exert
beneficial or detrimental effects on cancer development

Tufail M., et al. Cellular Aging and Senescence in Cancer
Aging and Disease • Volume 16, Number 3, June 2025 6
and treatment outcomes. Strategies focusing on
modulating the effects of SASP or selectively targeting
senescent cells represent promising avenues for
enhancing the efficacy of cancer therapies while
minimizing potential risks associated with senescence-
induced tumorigenesis. For instance, exploring
interventions that selectively target or modulate SASP
components may provide tailored approaches in cancer
therapeutics.
Figure 2. This illustrative figure portrays the dynamic regulation of cellular senescence in a cancer cell through the
pathways. The cancer cell undergoing senescence is highlighted, featuring a pronounced nucleus and chromatin. Sources of DNA
damage, including radiation and chemicals, surround the cell, initiating DDR. ATM and ATR, depicted as vigilant sentinel
proteins, detect damage, transmitting signals downstream to activated gears or switches, CHK1 and CHK2. The bottom section
illustrates DDR-induced cell cycle arrest at checkpoints like G1 and G2, along with active DNA repair. This figure also illustrates
the intricate interplay between the UPR pathway and senescence regulation in cancer cells. cancer cell undergoing senescence is
depicted. The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER) activates the UPR pathway.
Three main sensors of the UPR—PERK, IRE1, and ATF6—detect unfolded proteins and initiate signaling cascades to restore
protein homeostasis. In the middle section, the UPR pathway regulates protein synthesis, folding, and degradation to alleviate ER
stress and prevent the accumulation of misfolded proteins. UPR activation in the context of senescence aims to manage protein
quality control, ensuring proper cellular function and preventing proteotoxic stress-induced senescence. Senescent cells release
SASP factors, including inflammatory cytokines, chemokines, and growth factors, which recruit immune cells and induce
senescence in neighboring cells, contributing to chronic inflammation and cancer progression. Moreover, senescent cells secrete
MMPs as part of the SASP, leading to ECM remodeling characterized by collagen degradation and alterations in tissue structure.
Furthermore, senescent cells modulate angiogenesis within the tumor microenvironment by secreting factors such as VEGF and
FGF, promoting blood vessel formation and tumor growth. Also, Feedback loops between senescence and cancer-promoting
pathways, exemplified by the YAP-LATS2 feedback loop, further influence cancer development.
3.4 Molecular Signaling Pathways Regulating
Senescence in Cancer
In the landscape of cancer, the molecular signaling
pathways orchestrating senescence represent a complex
interplay that profoundly influences tumor development,
progression, and responses to therapeutic interventions
(Fig. 2). Senescence induction in cancer is intricately
regulated by a myriad of triggers, including DNA damage,
telomere shortening, oncogene activation, and other
cellular stressors [49]. These triggers activate several
signaling pathways, such as the DNA damage response
(DDR), cell cycle regulation machinery, apoptosis
regulation, cellular energy metabolism, and the unfolded
protein response (UPR) [46]. The DDR pathway is a
critical cellular mechanism triggered by DNA damage
from various sources [50]. This pathway involves
detecting DNA damage by sensor proteins like ATM and

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ATR, activating downstream effectors such as CHK1 and
CHK2 to halt the cell cycle. Subsequently, DNA repair
processes are initiated to maintain genomic stability [51,
52]. In the context of senescence, DDR activation plays a
crucial role in inducing cell cycle arrest, preventing the
propagation of damaged cells, and promoting senescence
as a tumor-suppressive mechanism [50, 51]. This process
involves the establishment of cellular senescence, where
cells remain alive but permanently unable to further
proliferate, contributing to both aging and cancer research
[53]. The DDR signaling pathway is intricately linked to
cellular senescence through mechanisms involving
oncogene activation, irreparable DNA damage, and the
activation of various proteins like ATM, ATR, p53, and
p21 to regulate cell cycle progression and maintain
genomic integrity [54]. The UPR pathway is a cellular
signaling pathway that responds to the accumulation of
unfolded or misfolded proteins in the endoplasmic
reticulum (ER), a cellular organelle involved in protein
synthesis and folding. The UPR pathway aims to restore
ER homeostasis by increasing the capacity of the ER to
fold and degrade proteins or by reducing the load of
protein synthesis. While the UPR pathway is activated in
response to the accumulation of unfolded or misfolded
proteins in the endoplasmic reticulum. This triggers the
activation of sensors like PERK, IRE1, and ATF6, which
initiate pathways regulating protein synthesis, folding,
and degradation to restore protein homeostasis [55]. In
senescence, UPR activation aims to manage protein
quality control, ensuring proper cellular function and
preventing proteotoxic stress-induced senescence [56].
The UPR pathway represents a critical signaling platform
associated with major senescence hallmarks, highlighting
its role in maintaining cellular integrity and function
during aging and stress-induced conditions [57, 58].
Collectively, these pathways culminate in the initiation of
senescence, a phenomenon that can either impede or,
paradoxically, contribute to cancer progression.
Regulatory feedback loops are mechanisms within
biological systems where the output of a process
influences the input or activity of the same process,
creating a self-regulating cycle. These loops play a
fundamental role in maintaining stability, homeostasis,
and adaptability in various biological processes.
Regulatory feedback loops form a crucial aspect of
senescence's influence on cancer. These loops within key
cellular pathways interplay with immune modulation,
inflammation, extracellular matrix maintenance, and
angiogenesis [59, 60]. In the context of immune
modulation, senescent cells can impact immune
surveillance and clearance mechanisms, leading to their
accumulation within aging tissues. This process is
associated with the pro-inflammatory phenotype, the
SASP, which can have tumor-suppressive functions and
promote immune activation [61]. The mechanism behind
this process involves the secretion of SASP factors by
senescent cells. These factors can induce senescence in
surrounding cells and promote a pro-inflammatory
environment [62]. Moreover, recent studies have
highlighted the role of innate immune responses,
particularly the cGAS–STING pathway, in triggering
SASP induction [63]. The cGAS–STING pathway is a
crucial signaling pathway in the innate immune response
to cytoplasmic DNA. It is critical in detecting and
responding to cellular stress, infection, and DNA damage.
This pathway is crucial for regulating cellular senescence
and the associated pro-inflammatory phenotype.
Understanding and regulating SASP may offer insights
into managing age-associated diseases and cancer
progression [31]. Meanwhile, the senescent cells release
inflammatory factors through the SASP, contributing to
chronic inflammation and influencing cancer
development. Strategies like senolysis aim to eliminate
senescent cells to control SASP effects [62, 63].
Moreover, Senescent cells impact the extracellular matrix
by secreting factors like matrix metalloproteinases, which
play a role in remodeling matrix components such as
collagen. The mechanism involves senescent cells
releasing these enzymes as part of the SASP. Matrix
metalloproteinases are known for their ability to degrade
various components of the extracellular matrix, including
collagen, leading to alterations in tissue structure and
function. This process contributes to the age-related
changes observed in tissues and can have implications for
conditions like cancer progression [63]. Also, Senescent
cells can influence angiogenesis, a process crucial for
tumor growth, by secreting factors that modulate blood
vessel formation and remodeling in the tumor
microenvironment. The mechanism behind this involves
the SASP, where senescent cells secrete a variety of
proteins, cytokines, and growth factors that can alter the
local tissue environment. These secreted factors from
senescent cells induce senescence in surrounding cells and
play a role in promoting chronic inflammation and cancer
progression [5, 63]. Another example is the interruption
of the YAP-LATS2 feedback loop causes ovarian cells to
transition from YAP-induced senescence to malignant
transformation [64]. The YAP-LATS2 feedback loop is a
regulatory mechanism involved in the Hippo signaling
pathway, which plays a critical role in controlling cell
growth, proliferation, and organ size regulation. While the
precise nature of these interactions remains incompletely
understood, their significance in shaping the impact of
senescence on tissue structure and function holds
substantial implications for cancer development and
treatment outcomes.
The SASP emerges as a pivotal mediator of the
effects of senescent cells on cancer progression. SASP

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components can induce or enhance growth arrest in
autocrine and paracrine manners, inhibiting cancer
progression [65]. Autocrine signaling occurs when a cell
releases signaling molecules that bind to receptors on its
surface, essentially signaling itself. This mechanism is
often involved in processes such as cellular growth and
repair. Paracrine signaling, conversely, involves cells
releasing signaling molecules into the extracellular fluid,
affecting nearby cells rather than the cell that secreted
them. This signalling mode is crucial for coordinating
activities among neighboring cells, playing roles in
immune responses and neurotransmission processes.
Simultaneously, however, SASP factors may also
promote cell proliferation, angiogenesis, aging,
tumorigenesis, and metastasis, underscoring the dual
nature of senescence in cancer biology [66]. Examples
include interleukins, chemokines, and matrix
metalloproteinases within the SASP, illustrating its
diverse impact on the tumor microenvironment.
Senescence induced by cancer therapies, such as
radiotherapy and chemotherapy, poses a unique
challenge. While therapy-induced senescence may
initially exhibit a cytostatic clinical response, there is a
risk of these senescent cells reactivating and contributing
to tumor recurrence or progression [49, 67]. The
molecular underpinnings of therapy-induced senescence
are critical for optimizing treatment strategies and
enhancing long-term tumor control. For instance,
understanding the intricate balance between senescence
and cell death pathways could inform therapeutic
regimens to prevent tumor relapse [34, 68].
4. Senescence and Cancer Therapies
4.1. The Role of Senescence in Response to Cancer
Treatments
In the intricate tapestry of cancer therapies, the interplay
between senescence and treatment outcomes emerges as a
complex dynamic that significantly influences the
effectiveness of interventions, tumor response patterns,
and the resilience of patients [66]. Cancer treatments such
as chemotherapy, radiotherapy, and endocrine therapies
exhibit the capability to induce cellular senescence,
imposing a state of stable growth arrest in cancer cells.
This induction of senescence represents a crucial
mechanism through which these treatments exert their
cytostatic effects, effectively inhibiting the proliferation
of cancer cells and, in some cases, enhancing immune
responses against malignant cells [66]. For example,
radiotherapy-induced senescence has been observed in
various cancer types, including breast cancer, where
irradiation triggers the DNA damage response, leading to
the activation of senescence programs.
While therapy-induced senescence contributes to the
initial success of treatments by halting cancer cell growth,
a dual nature of senescence emerges in the context of
cancer therapy. Senescent cells, in addition to their
growth-arrested state, may exhibit pro-aging impacts by
releasing bioactive molecules via the SASP [36]. This
complex process stimulates an immune response against
cancer cells and potentially undermines patient resilience
to cancer therapies. This phenomenon increases the risk
of disease recurrence post-treatment, emphasizing the
need for a nuanced understanding of senescence in the
context of therapeutic interventions [69].
The advent of senotherapies, encompassing senolytic
drugs that selectively target and eliminate senescent cells
or senostatic drugs that inhibit their function, introduces a
novel approach to enhance the efficacy of cancer therapies
(Fig. 3). For instance, compounds like quercetin,
navitoclax, and fisetin are actively under investigation for
their potential roles in improving treatment outcomes by
mitigating the pro-aging impacts of senescent cells [70,
71]. Quercetin, a flavonoid compound, has shown
promise in improving treatment outcomes by targeting
senescent cells. It acts as a senolytic agent, promoting the
selective elimination of senescent cells. The mechanism
of quercetin involves disrupting multiple pathways
associated with senescence, leading to the clearance of
these dysfunctional cells. Quercetin has potent senolytic
effects when combined with dasatinib, enhancing health
and lifespan by eliminating age-related senescent cells
[72, 73]. Navitoclax, another compound under
investigation for its role in mitigating the pro-aging
impacts of senescent cells, induces thrombocytopenia.
This drug targets BCL-2 family proteins, promoting
apoptosis in senescent cells. Navitoclax reduces the
burden of dysfunctional cells by inducing programmed
cell death, which could enhance treatment outcomes in
age-related conditions [74]. Fisetin, a flavonoid similar to
quercetin, exhibits cell-type-specific senolytic properties
by altering multiple pathways associated with senescence.
It has diverse mechanisms of action on senescent cells and
has been shown to promote apoptosis in these cells.
Fisetin's mechanism may involve blocking the PI3K/AKT
pathway, eliminating senescent cells, and potentially
extending health and lifespan. Studies have highlighted
fisetin's ability to induce apoptosis in lung cancer cells
through various mechanisms, including reducing anti-
apoptotic proteins like BCL-2 [75, 76]. These drugs
showcase the evolving landscape of cancer therapeutics,
aiming to refine treatment strategies and mitigate the
challenges of senescence-induced effects [77, 78].

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Aging and Disease • Volume 16, Number 3, June 2025 9
Figure 3. In this figure, the tumor microenvironment is depicted with cancer cells,
senescent cells, and stromal cells. Bidirectional arrows illustrate the interplay between
senescence and cancer cells, indicating factors secreted by both cell types that influence tumor
progression and treatment response. Senotherapeutic agents, including quercetin, navitoclax,
and fisetin are depicted and accompanying descriptions of their mechanisms of action. Arrows
connecting these compounds to senescent cells illustrate their ability to target and eliminate
senescent cells, thereby enhancing treatment efficacy.
Further research becomes imperative to unravel the
intricate mechanisms by which senescence influences
cancer treatment responses and the likelihood of disease
recurrence post-therapy. Understanding the molecular
signaling pathways regulating therapy-induced
senescence and exploring innovative strategies for
targeting senescent cells holds promise for optimizing
cancer therapy outcomes and enhancing patient resilience
to treatments. This evolving landscape opens avenues for
tailored and effective interventions, marking a critical
stride toward personalized cancer therapeutics.
4.2. Senescence as a Barrier to Tumor Progression
Cellular senescence emerges as a formidable barrier in
cancer biology, exerting critical tumor suppressive effects
that impede cancer cell proliferation and thwart malignant
transformation. Senescence, recognized as a tumor
suppressive process, orchestrates a cascade of protective
mechanisms inhibiting cancer cell proliferation and
curtailing the progression from pre-malignant to
malignant states. Triggers such as DNA damage, telomere
shortening, and oncogene activation prompt senescence,

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inducing stable growth arrest in damaged cells [79, 80].
This is a robust defense mechanism against tumorigenesis
early in life, underscoring senescence as a crucial
guardian at the cellular level.
The tumor suppressive effects of senescence extend
into the realm of cancer therapies, where it plays a crucial
effector role in various anti-cancer modalities, including
chemotherapy, radiotherapy, and endocrine therapies.
These treatments induce senescence in cancer cells,
leading to cytostatic effects that effectively halt cell
proliferation. Senescent cells, in turn, release bioactive
molecules via the SASP, potentially stimulating an
immune response against tumors [81, 82]. For example,
chemotherapy-induced senescence has been observed in
breast cancer cells, contributing to the treatment's efficacy
by impeding the uncontrolled growth of cancer cells [83].
While senescence induced by cancer therapies
initially contributes to treatment efficacy, concerns linger
regarding its potential impact on patient resilience to
treatments and the specter of disease recurrence post-
therapy [44]. The pro-aging impacts of senescent cells
released through SASP may pose challenges by
promoting tumor recurrence or progression after therapy
completion [84]. For instance, the SASP-mediated release
of inflammatory cytokines and growth factors may create
a microenvironment conducive to cancer cell survival and
expansion [85].
The emergence of senotherapies presents a promising
avenue for enhancing the efficacy of cancer therapies by
specifically targeting senescent cells [86]. Senolytic drugs
selectively eliminate these cells, while senostatic drugs
inhibit their function. Noteworthy compounds like
quercetin, navitoclax, and fisetin are actively under
investigation for their potential role in interfering with the
pro-aging impacts of senescent cells, thereby improving
treatment outcomes [8, 36]. This innovative approach
promises to refine cancer therapy strategies by mitigating
the potential drawbacks of therapy-induced senescence.
Therefore, the intricate balance of senescence as a
barrier to tumor progression unveils a nuanced
relationship that influences cancer development and
treatment responses. From its fundamental role as a tumor
suppressive process to its implications in therapy-induced
senescence, the multifaceted nature of senescence offers
both challenges and opportunities for refining cancer
therapies and understanding their long-term impact on
patient outcomes.
4.3. Challenges in Harnessing Senescence for
Therapeutic Benefit
Navigating the potential therapeutic benefits of
senescence in the context of cancer treatment presents a
complex challenge due to the dual nature of this cellular
stress response mechanism. Traditionally viewed as a
protective barrier against cancer, senescence induces
stable growth arrest in damaged cells, inhibiting their
proliferation. However, recent discoveries have
introduced a more nuanced perspective, revealing that
senescent cells, particularly through the SASP, may
paradoxically contribute to oncogenesis and tumor
aggressiveness.
The therapeutic implications of senescence are
intricately linked to various anticancer modalities,
including chemotherapy, radiotherapy, and endocrine
therapies [39]. While these treatments induce senescence
in cancer cells, effectively halting their proliferation, the
pro-aging impacts of senescent cells released through
SASP may pose challenges [1]. This phenomenon can
reduce patient resilience to treatments and facilitate
disease recurrence post-therapy, raising important
considerations in managing senescence in cancer therapy
[87].
Addressing the complexities associated with
senescence in cancer therapy necessitates the
development of innovative strategies, and senotherapies
emerge as promising avenues [88]. These therapeutic
approaches aim to target senescent cells for therapeutic
benefit, encompassing senolytic drugs that selectively
eliminate these cells and senostatic drugs that inhibit their
function [1]. Examples such as quercetin, navitoclax, and
fisetin are actively under investigation for their potential
role in enhancing treatment outcomes by mitigating the
pro-aging effects of senescent cells [67, 87].
The impact of senescence on treatment efficacy
further underscores the need for a delicate balance in
leveraging its potential therapeutic benefits. The dual role
of senescence, acting both as a protective mechanism
against cancer and a potential contributor to tumor
progression, emphasizes the intricate nature of this
interplay. Understanding the molecular signaling
pathways regulating senescence induction becomes
paramount, as does exploring innovative strategies to
modulate its effects. For instance, comprehending how
SASP components, including interleukins and growth
factors, influence the tumor microenvironment can inform
strategies to optimize treatment efficacy and patient
outcomes in cancer therapy.
Therefore, while senescence holds promise as a
potential therapeutic tool in cancer treatment, the
challenges associated with its dual nature necessitate a
nuanced and comprehensive approach. Advances in
senotherapies, coupled with an in-depth understanding of
the molecular intricacies governing senescence induction,
are pivotal for overcoming these challenges and
optimizing the therapeutic benefits of senescence in the
complex landscape of cancer therapy.

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4.4. Opportunities for Senescence-Targeted Cancer
Therapies
Exploring senescence as a focal point in targeted cancer
therapies unveils promising opportunities to harness its
intrinsic tumor-suppressive effects. One avenue of
exploration lies in Therapy-Induced Senescence (TIS), an
approach that capitalizes on established cancer treatments
like chemotherapy and radiation to induce senescence in
tumor cells [89, 90]. TIS refers to a phenomenon where
cells undergo senescence due to exposure to certain
therapeutic agents or treatments. These treatments can
include chemotherapy, radiation therapy, targeted
therapy, or immunotherapy for cancer or other diseases.
This strategy halts cancer cell proliferation and serves as
a platform to identify novel targets, biomarkers, and
senotherapeutics. By leveraging TIS, researchers aim to
enhance treatment efficacy while minimizing toxicities
associated with conventional anticancer therapies.
Understanding the intricate molecular pathways
governing senescence in cancer cells is pivotal for
identifying therapeutic targets. Researchers delve into
these pathways to uncover insights that guide the
development of senescence-targeted therapies [91, 92].
This approach can revolutionize cancer treatment through
a "one-two punch" strategy. This involves employing
agents that induce tumor cell senescence followed by
selectively targeting senescent cells, enhancing the
precision and effectiveness of the therapeutic
intervention. For instance, elucidating the signaling
pathways involved in senescence induction may pave the
way for developing targeted drugs that selectively exploit
these pathways to induce senescence in cancer cells (93).
However, the path toward effective senescence-
targeted therapies is challenging [93, 94]. Senolytic
therapies, representing a novel approach, focus on
selectively eliminating senescent cells while preserving
the beneficial effects of senescence [95, 96]. By doing so,
senolytic drugs have the potential to enhance treatment
responses and mitigate therapy-related side effects.
Integrating senolytic therapies into aggressive anticancer
regimens may open new avenues for improving patient
outcomes in cancer therapy. For instance, drugs like
navitoclax have demonstrated senolytic effects by
selectively inducing apoptosis in senescent cells, offering
a glimpse into the potential of targeted elimination in
cancer therapeutics [97].
Characterizing senescent cell heterogeneity based on
cell type, tissue of origin, and the nature of the
senescence-inducing affront is paramount for unraveling
their role in tumorigenesis [98]. This characterization is
pivotal for developing targeted cancer therapies, such as
the "one-two punch" strategy, which aims to exploit the
diverse properties of senescent cells for therapeutic
benefit. For example, understanding how senescent cells
differ in response to distinct anticancer treatments may
guide the development of tailored therapies that capitalize
on these variations for enhanced treatment outcomes [34].
Therefore, the exploration of senescence as a target in
cancer therapies holds immense promise, with avenues
like Therapy-Induced Senescence, molecular pathway
elucidation, senolytic therapies, and comprehensive
characterization of senescent cell heterogeneity offering
opportunities to revolutionize cancer treatment strategies.
Overcoming challenges and addressing knowledge gaps
in this evolving field are crucial for advancing
senescence-targeted therapies and improving outcomes
for cancer patients (Table 2).
Table 2. Role of Senescence in Cancer Therapies and Senotherapeutic Approaches.
Therapy Type
Induction of
Senescence
Role of Senescence
Senotherapeutic Approach
Chemotherapy
Yes
Halts cancer cell proliferation;
enhances immune responses
Senolytic drugs like quercetin, navitoclax, and
fisetin are investigated for selective elimination
of senescent cells
Radiotherapy
Yes
Triggers DNA damage response
leading to senescence
Senolytic drugs targeting senescent cells may
enhance treatment outcomes
Endocrine Therapies
Yes
Induces growth arrest in
hormone-sensitive cancers
Senolytic agents disrupt multiple pathways
associated with senescence, potentially
improving treatment efficacy
Senotherapeutic Drugs
N/A
Target senescent cells or inhibit
their function
Compounds like quercetin, navitoclax, and
fisetin show promise in eliminating senescent
cells, potentially enhancing health and lifespan
Combination
Therapies
N/A
Exploits synergistic effects of
senolytic drugs with standard
therapies
Combinations of senolytic agents with
conventional treatments aim to improve
treatment outcomes by mitigating pro-aging
impacts of senescent cells

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5. Cellular Aging Microenvironment and Tumor
Progression
5.1. SASP and Tumor Microenvironment
Cellular senescence, marked by irreversible cell cycle
arrest and its associated feature, the SASP, intricately
shape the tumor microenvironment, exerting profound
influences on tumor progression. SASP, a hallmark
feature of senescent cells, manifests as the secretion of
diverse factors, including inflammatory cytokines,
chemokines, growth factors, and matrix remodeling
proteins [62]. This multifaceted secretory profile endows
SASP with dual effects in the tumor microenvironment,
exhibiting tumor-suppressive and tumor-promoting
properties contingent upon the specific context and cell
types involved [99]. Through paracrine signaling,
senescent cells can modulate adjacent stromal, immune,
and cancer cells, exerting a profound influence on the
surrounding tissue environment [37].
Within the tumor microenvironment, senescent cells
play a pivotal role in remodeling the neighboring tissues
by altering the behavior of proximal cells [37]. SASP-
mediated effects can trigger senescence surveillance,
suppress tumorigenesis, or inhibit anti-tumor immunity,
fostering tumor progression [100]. Understanding the
context-dependent nature of SASP is paramount for
deciphering its role in shaping the tumor
microenvironment and comprehending its implications
for cancer development. For instance, the SASP of
senescent fibroblasts has been associated with the
promotion of tumor invasion and metastasis, underscoring
the complex and nuanced effects of SASP in cancer
progression [100].
Recent therapeutic advancements have underscored
the potential of targeting SASP components or selectively
eliminating senescent cells as viable strategies in cancer
treatment [101]. Senomorphics, which suppress SASP,
and senolytic drugs, inducing senescent cell death, offer
promising avenues for modulating the tumor
microenvironment. These approaches hold significant
potential for enhancing treatment responses and
mitigating tumor-promoting effects associated with
senescent cells, providing a new dimension to cancer
therapy optimization.
The dynamic nature of cellular senescence in cancer
emphasizes its context-dependent roles that evolve over
time [102]. Senescent cells can reinforce their phenotype
through autocrine signaling, transmitting it to neighboring
malignant and non-malignant cells in paracrine, resulting
in altered tumoral repercussions over time [53].
Recognizing this dynamic interplay is essential for
developing nuanced therapeutic strategies that leverage
the dual nature of cellular senescence for optimal
anticancer interventions. For instance, the persistence of
senescent cells in the tumor microenvironment over time
may contribute to chronic inflammation and immune
suppression, fostering an environment conducive to
cancer progression. Therefore, the interrelation between
cellular senescence, SASP, and the tumor
microenvironment is a multifaceted landscape that
significantly impacts tumorigenesis.
5.2. Impact of Cellular Aging and Senescent Cells on
Cancer Progression
Cellular aging, a multifaceted process encompassing
time-dependent changes at the cellular level, emerges as a
pivotal player in the initiation and progression of cancer.
Cellular aging operates as a robust tumor suppressor
mechanism, employing cell cycle arrest through processes
such as oncogene-induced senescence [103]. This
phenomenon serves as a natural barrier against neoplastic
cell growth, emphasizing the intricate interplay between
cellular aging and the complicated landscape of cancer
development [103]. Additionally, the absence of
telomerase activity in normal tissues, leading to telomere
dysfunction, acts as an anti-cancer mechanism by curbing
indefinite cell expansion and thwarting the development
of neoplastic clones [104]. Activating oncogene-induced
senescence in response to aberrant cellular signaling
pathways is a protective mechanism to prevent the
uncontrolled proliferation of potentially cancerous cells.
For example, oncogene activation or irreparable DNA
damage can induce the activation of ataxia telangiectasia
mutated (ATM) and checkpoint kinase, leading to the
phosphorylation of histone H2AX and p53. This
activation triggers the p53-p21 signaling pathway, which
is crucial in halting the cell cycle and inducing
senescence. Other pathways like NLRP6-NF-κB-
p14ARF-MDM2 and miR-203-ITPKA-MDM2 can also
activate the p53-p21 signaling cascade. In specific cases,
such as breast carcinoma cells with overexpressed
oncogenic ERBB2, senescence can be induced
independently of p53 through upregulation of p21. Loss
of anti-oncogenes like PTEN can also trigger senescence
through various signaling pathways involving Akt-mTOR
-p53 and p19ARF-MDM2-p53. These mechanisms
highlight how oncogene-induced senescence acts as a
safeguard mechanism to prevent the progression of
potentially cancerous cells by promoting cell cycle arrest
and cellular senescence [51, 105].
The SASP introduces a paradoxical dimension to the
role of senescence in cancer progression. Traditionally
viewed as a protective mechanism against cancer, SASP
induces cell cycle arrest and promotes immune
surveillance [62]. However, recent studies reveal its dual
nature. SASP components can counterintuitively foster

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cancer stemness and aggressiveness, contributing to
tumor progression and relapse [106]. This intricate dual
role underscores the complexity of senescence in cancer
pathogenesis and emphasizes the need for a nuanced
understanding to facilitate effective therapeutic
interventions [107]. The secretion of factors like
interleukins and growth factors by senescent cells, known
as the SASP, can have beneficial and harmful effects
[108]. For example, SASP factors can promote tissue
repair, embryonic development, and anti-tumorigenic
properties like attracting immune cells to clear pre-
malignant senescent cells. However, some SASP factors
can also lead to chronic inflammation, fibrogenesis,
tumorigenesis, and impaired insulin sensitivity. In the
context of cancer, the SASP can either aid in cancer
progression or induce growth arrest and apoptosis of
cancer cells, depending on the specific interactions
between senescent cells and cancer cells [63, 109].
The accumulation of senescent cells within the tumor
microenvironment presents profound implications for
cancer progression. Innovative therapeutic strategies
targeting senescent cells or modulating SASP components
offer promising avenues for cancer therapy [110].
Senolytic drugs inducing senescent cell death or
senomorphics suppressing SASP represent pioneering
approaches to manipulate the tumor microenvironment
and optimize treatment outcomes [111]. By harnessing the
dual effects of senescence, researchers aim to refine
therapeutic strategies that leverage the tumour-
suppressive properties while mitigating the tumor-
promoting effects associated with senescent cells [112].
For instance, drugs like dasatinib and quercetin have
shown senolytic effects by selectively eliminating
senescent cells, presenting a potential avenue for
therapeutic intervention [62]. Dasatinib and quercetin
have shown senolytic effects by selectively eliminating
senescent cells, offering a potential therapeutic
intervention. The mechanism involves the synergistic
action of these compounds in targeting and eliminating
senescent cells. Dasatinib, a cancer drug that inhibits the
Src tyrosine kinase, induces apoptosis in senescent cells
by disrupting pro-survival signaling pathways. On the
other hand, quercetin acts by inhibiting the anti-apoptotic
protein Bcl-xL, promoting cell death in senescent cells.
Studies have demonstrated that the combination of
dasatinib and quercetin effectively reduces the burden of
senescent cells in various tissues, including aged mice and
humans with conditions like diabetic kidney disease. This
senolytic therapy targets and eliminates senescent cells
linked to age-related chronic diseases, offering a
promising approach to alleviate age-related pathologies.
The selective elimination of these dysfunctional cells by
dasatinib and quercetin presents a novel strategy for
improving health outcomes and potentially addressing
age-related disorders [113, 114].
5.3. Modulating Cellular Aging and Senescence to
Influence Tumor Behavior
Cellular aging and the presence of senescent cells emerge
as pivotal factors shaping the tumor microenvironment
and influencing tumor behavior. Oncogene-induced
senescence is a critical tumor suppressor mechanism,
erecting a formidable barrier against cancer development
by inducing stable growth arrest in damaged cells [115].
This process is an indispensable anti-cancer mechanism,
preventing the rampant proliferation of potentially
neoplastic cells. To harness this tumor-suppressive
potential, understanding the molecular pathways
governing oncogene-induced senescence becomes
paramount [116]. Exploring targeted therapies that exploit
these pathways offers a promising approach to
influencing tumor behavior and inhibiting cancer
progression [13]. For instance, drugs like MEK inhibitors
have shown efficacy in inducing oncogene-induced
senescence in certain cancer types, presenting a potential
avenue for therapeutic intervention [8]. MEK inhibitors
have demonstrated efficacy in inducing oncogene-
induced senescence in certain cancer types, offering a
potential avenue for therapeutic intervention. For
example, inhibitors of MEK and KRAS kinases have been
shown to induce senescence in pancreatic ductal
carcinoma cells. The associated SASP promotes
angiogenesis, which can influence the tumor
microenvironment. MEK inhibitors, like trametinib,
target the MEK1/2 pathway, leading to cell cycle arrest
and senescence induction in cancer cells. This approach
presents a promising strategy for halting the proliferation
of cancer cells and potentially improving treatment
outcomes in specific cancer types [117, 118].
Telomere shortening, a hallmark of cellular aging,
contributes to cellular senescence by triggering a DNA
damage response leading to cell cycle arrest [119]. The
gradual reduction in telomere length limits the replicative
capacity of somatic cells, culminating in cellular
senescence [120]. Strategies targeting telomere
maintenance mechanisms and interventions preventing
telomere dysfunction present potential avenues for
modulating cellular aging and influencing tumor behavior
in cancer [120]. For example, telomerase-targeting
therapies, such as imetelstat, aim to inhibit telomerase
activity and impede telomere maintenance, offering a
unique approach to modulating cellular aging in cancer
treatment. Imetelstat is a potent telomerase inhibitor that
targets the catalytic subunit of telomerase, thereby
disrupting the enzyme's function in maintaining telomere
length. By inhibiting telomerase activity, imetelstat

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induces telomere shortening in cancer cells, leading to
cellular senescence or apoptosis. This approach is
particularly effective in cancer therapy as it hampers the
unlimited replicative potential of cancer cells by inducing
senescence or cell death. The inhibition of telomerase
activity with imetelstat represents a promising strategy for
targeting cancer cells with high telomerase expression and
offers a novel therapeutic avenue for combating cancer
progression [121, 122].
The SASP adds a layer of complexity to cancer
progression, exhibiting both tumor-suppressive and
tumor-promoting effects [15]. Modulating SASP
components provides an opportunity to influence the
tumor microenvironment and alter tumor behavior. By
specifically targeting SASP factors or developing
interventions that suppress the pro-tumorigenic aspects of
SASP, researchers aim to leverage the beneficial effects
of senescence while mitigating its detrimental impact on
cancer progression. For instance, antibodies against
specific SASP components like IL-6 and IL-8 have shown
promise in preclinical studies, highlighting the potential
for targeted SASP modulation in cancer therapy [123].
Antibodies targeting specific components of the SASP
like IL-6 and IL-8 have shown promise in preclinical
studies, indicating the potential for targeted SASP
modulation in cancer therapy. For instance, IL-6 and IL-8
are key components of the SASP that play roles in tumor
proliferation, invasion, and immunosuppression. Specific
neutralizing antibodies against these factors have
demonstrated efficacy in inhibiting their functions. For
example, targeting IL-6 with a neutralizing monoclonal
antibody (Mab-IL-6.8) has been shown to completely
abolish JAK/STAT signaling and alleviate symptoms of
arthritis in a primate model. Similarly, ABX-IL-8, a
humanized monoclonal antibody against IL-8, acts as an
antagonist impairing IL-8 signaling and attenuating the
growth of certain cancer xenograft models. These
examples highlight the potential of using antibodies to
target specific SASP components like IL-6 and IL-8 as a
strategy to modulate the effects of senescent cells in
cancer therapy [124].
Modifying cellular aging and senescence has
significant therapeutic implications for cancer treatment.
Strategies targeting senescent cells, manipulating SASP
components, or preventing telomere dysfunction offer
innovative approaches to influence tumor behavior and
enhance treatment responses [14, 125]. By
comprehending the intricate interplay between cellular
aging processes and their impact on cancer initiation and
progression, researchers can develop tailored therapeutic
interventions that exploit the dual nature of senescence for
optimal anticancer outcomes [5, 15]. For instance,
combining senolytic drugs, targeting senescent cells, and
SASP-modulating agents may represent a comprehensive
approach to fine-tuning the tumor microenvironment and
improving overall treatment efficacy.
6. Senescence Escape and Cancer Aggressiveness
6.1. Mechanisms of Senescence Bypass in Aging Cells
and Cancer Cells
The phenomenon of senescence escape, wherein cells
circumvent the senescent state, emerges as a critical
determinant in the aggressiveness and progression of
cancer. Telomere maintenance mechanisms constitute one
of the key avenues through which cells elude senescence.
Telomeres, protective structures at the chromosomal ends,
play a pivotal role in triggering cellular senescence [119].
In cancer cells, activating telomerase or engaging
alternative lengthening telomeres (ALT) mechanisms is a
common strategy to counteract telomere shortening-
induced senescence. This allows cancer cells to evade
growth arrest and persist in unbridled proliferation [14].
For instance, telomerase activation is frequently observed
in cancer cells, ensuring the preservation of telomere
length and facilitating continuous cellular division.
Understanding the intricate interplay between these
telomere maintenance mechanisms and senescence
escape is crucial for unraveling the driving forces behind
cancer aggressiveness [14, 126].
The activation of oncogenes represents another
influential mechanism that drives senescence escape.
Oncogene activation can induce replicative stress,
damaging DNA and subsequent cellular senescence [115,
127]. However, cancer cells can acquire additional
mutations that suppress the senescence response triggered
by oncogene activation. Cancer cells gain a proliferative
advantage by bypassing this oncogene-induced
senescence and exhibit increased aggressiveness, thereby
contributing to tumor progression [13, 115]. For instance,
mutations in the TP53 gene are commonly associated with
the evasion of oncogene-induced senescence, allowing
cancer cells to override growth inhibitory signals [13,
128].
The SASP also contributes to promoting senescence
escape and cancer aggressiveness. SASP components
secreted by senescent cells create a pro-inflammatory
microenvironment that fosters tumor growth and
invasiveness. Cancer cells may exploit these
inflammatory signals to enhance their survival and
metastatic potential, evading the senescent cells' growth-
inhibitory effects. Targeting SASP components represents
a potential strategy to disrupt this pro-tumorigenic
signaling cascade and inhibit senescence escape in cancer
cells. For example, drugs that interfere with specific
SASP factors, such as IL-6 inhibitors, have shown
promise in preclinical studies, highlighting the potential

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for disrupting the pro-tumorigenic effects associated with
SASP [15, 125].
Understanding the intricate mechanisms of
senescence escape in aging cells and cancer cells holds
significant therapeutic implications for cancer treatment.
Targeting pathways involved in telomere maintenance,
oncogene activation, or SASP signaling presents
opportunities to prevent senescence bypass and inhibit
cancer aggressiveness. By developing targeted therapies
that specifically disrupt the mechanisms driving
senescence escape, researchers aim to curtail tumor
progression and improve treatment outcomes for cancer
patients. For instance, drugs targeting telomerase, such as
imetelstat, are currently being investigated for their
potential to inhibit telomere maintenance and impede
cancer cell growth.
6.2. Senescence Escape and Metastasis
The phenomenon of senescence escape, wherein cells
elude the senescent state, is a pivotal factor influencing
cancer aggressiveness, particularly contributing to
metastasis. Telomere maintenance mechanisms represent
a critical avenue through which cells bypass senescence,
ultimately influencing metastatic potential [126].
Telomerase activation or ALT empower cells to prevent
growth arrest induced by telomere shortening. In the
context of cancer, the activation of these mechanisms
allows for continuous cell proliferation, fostering tumor
aggressiveness and enhancing metastatic potential. For
example, the upregulation of telomerase is common in
cancer cells, ensuring the maintenance of telomere length
and facilitating persistent cellular division [126]. The
comprehension of how telomere maintenance contributes
to senescence escape is paramount for unraveling the
mechanisms that drive cancer progression and metastasis
[16].
Oncogene activation is another influential factor tied
to metastatic potential. Although activation of oncogenes
can initially trigger cellular senescence as a protective
mechanism against tumorigenesis, cancer cells can
develop strategies to bypass oncogene-induced
senescence. This evasion of growth-inhibitory effects
endows cancer cells with a proliferative advantage,
fueling their capacity to invade surrounding tissues and
disseminate to distant sites, thus fostering metastatic
behavior [127, 129]. The intricate interplay between
oncogene activation, senescence escape, and metastasis
underscores the complexity inherent in the process of
tumor progression.
Senescent cells within the tumor microenvironment
further contribute to metastatic behavior through the
secretion of pro-inflammatory factors and extracellular
matrix remodeling proteins [15, 125]. This unique
secretory profile creates a pro-tumorigenic niche that
supports cancer cell invasion, migration, and colonization
at distant sites. Targeting SASP components or senescent
cells emerges as a potential strategy to disrupt this
metastasis-promoting microenvironment, providing an
avenue to inhibit cancer aggressiveness [14].
The therapeutic implications of understanding how
senescence escape contribute to cancer aggressiveness,
and metastasis are profound, particularly in the realm of
metastatic cancer treatment. Targeting pathways involved
in telomere maintenance, oncogene activation, or SASP
signaling offers promising opportunities to prevent
senescence bypass and inhibit metastatic spread. The
development of tailored therapeutic interventions that
disrupt the mechanisms driving senescence escape in
cancer cells holds the potential to effectively curb
metastatic behavior and improve outcomes for patients
grappling with advanced-stage cancers. For instance,
ongoing research into telomerase inhibitors aims to
leverage telomere maintenance mechanisms as a
therapeutic target to impede metastatic progression in
various cancer types.
6.3. Implications for Cancer Prognosis and Therapy
Resistance
The phenomenon of senescence escape, where cells elude
the senescent state, carries profound implications for
cancer prognosis and the challenge of therapy resistance.
Senescence escape refers to the phenomenon where cells
bypass or overcome the normal process of cellular
senescence, a state of irreversible growth arrest that cells
enter in response to various stressors, such as DNA
damage or shortened telomeres. Senescence escape in
cancer cells emerges as a harbinger of poor prognosis,
primarily due to its role in fostering tumor aggressiveness
and metastasis [1, 130]. Cells adept at bypassing
senescence mechanisms showcase heightened
proliferative capacity, invasiveness, and resistance to cell
death, collectively contributing to more aggressive tumor
behavior [8]. The presence of senescence-escaped cells
within the tumor microenvironment correlates with
advanced disease stages, heightened metastatic potential,
and compromised clinical outcomes [15]. Recognizing
the link between senescence escape and cancer prognosis
becomes paramount for predicting disease progression
and tailoring effective treatment strategies [1, 8]. The
presence of senescence-escaped cells in advanced-stage
melanomas has been linked to increased metastatic
potential, highlighting its importance in predicting disease
outcomes. For example, melanoma cells that evade
senescence mechanisms can exhibit enhanced
aggressiveness and metastatic behavior. These
senescence-escaped cells may acquire characteristics that

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allow them to bypass the growth arrest associated with
senescence, leading to uncontrolled proliferation and
dissemination, ultimately contributing to disease
progression. Understanding the dynamics of these cells is
crucial for developing targeted therapies that can
effectively address their metastatic behavior and improve
treatment outcomes [131].
Senescence escape is a formidable obstacle in cancer
therapy, endowing cells with resistance to conventional
treatments. Cells proficient in evading senescence
mechanisms can withstand the cytotoxic effects of
chemotherapy or radiation therapy, leading to treatment
failure and subsequent disease recurrence. The acquisition
of senescence bypass mechanisms, such as telomere
maintenance or oncogene activation, empowers cancer
cells to endure therapeutic insults and adapt to treatment-
induced stress. Targeting the pathways involved in
senescence escape emerges as a promising approach to
surmount therapy resistance and enhance treatment
outcomes for patients grappling with refractory cancers
[14, 132]. The presence of senescence-escaped cells in
advanced-stage melanomas has been linked to increased
metastatic potential, highlighting its importance in
predicting disease outcomes. For example, melanoma
cells that evade senescence mechanisms can exhibit
enhanced aggressiveness and metastatic behavior. These
senescence-escaped cells may acquire characteristics that
allow them to bypass the growth arrest associated with
senescence, leading to uncontrolled proliferation and
dissemination, ultimately contributing to disease
progression. Understanding the dynamics of these cells is
crucial for developing targeted therapies that can
effectively address their metastatic behavior and improve
treatment outcomes [131].
The SASP contributes significantly to therapy
resistance by creating a pro-inflammatory
microenvironment conducive to cancer cell survival and
proliferation. SASP components actively promote tumor
cell survival, angiogenesis, and immune evasion,
fostering resistance to various treatment modalities,
including chemotherapy, targeted therapy, or
immunotherapy. Strategies aimed at modulating SASP
signaling or directly targeting senescent cells present
potential avenues to overcome therapy resistance and
amplify treatment efficacy in cancer patients. Notably,
manipulating SASP components in breast cancer has
shown promise in sensitizing resistant cells to
chemotherapy, highlighting the therapeutic potential of
addressing senescence-related mechanisms [15, 125].
Understanding the implications of senescence escape
for cancer prognosis and therapy resistance carries
substantial clinical significance in developing novel
treatment strategies. Targeting the pathways involved in
senescence bypass mechanisms or modulating the effects
of SASP on tumor behavior represents a promising
avenue to augment the efficacy of existing therapies and
overcome resistance mechanisms in cancer. Tailored
therapeutic approaches that carefully consider the impact
of senescence escape on treatment outcomes hold promise
for improving patient survival rates and achieving long-
term disease control. For instance, ongoing research into
senolytic drugs aims to selectively eliminate senescent
cells, potentially mitigating therapy resistance and
enhancing treatment responses in various cancers.
7. Impact of Cellular Aging and Senescence on
Various Cancer Types
7.1. Breast Cancer
Senescence is critical in various physiological processes,
including development, tissue repair, and aging.
However, it also has significant implications for the
development and progression of breast cancer. One of the
primary mechanisms underlying cellular aging is telomere
shortening. Telomeres, repetitive DNA sequences located
at the ends of chromosomes, protect the integrity of
genetic material during cell division. With each cell
division, telomeres progressively shorten. When
telomeres become critically short, cells enter a state of
replicative senescence, ceasing further division [83]. This
mechanism is a natural barrier against uncontrolled cell
proliferation, a hallmark of cancer. However, cancer cells
can overcome this barrier through telomerase
reactivation, bypassing senescence, and continuing
unchecked proliferation.
Another aspect of cellular aging impacting breast
cancer is DDR. Senescent cells often exhibit persistent
DNA damage, activating DDR pathways like p53 and
p16INK4a, which promote cell cycle arrest and
senescence in response to DNA damage, preventing the
propagation of harmful mutations [8, 83]. Dysfunctional
DDR signaling can lead to genomic instability and
mutation accumulation, predisposing cells to malignant
transformation. In breast cancer, defects in DDR
pathways are frequent, contributing to tumor initiation
and progression.
Senescent cells also exhibit altered secretory profiles,
known as the SASP. SASP involves the secretion of pro-
inflammatory cytokines, growth factors, and matrix-
remodeling enzymes. While initially facilitating tissue
repair and immune surveillance, chronic SASP signaling
can promote tumor growth and metastasis. In breast
cancer, SASP factors foster a tumor-promoting
microenvironment, stimulating tumor cell proliferation,
angiogenesis, and immune evasion [8, 28].
Interestingly, senescence can exert both tumor-
suppressive and tumor-promoting effects in breast cancer,

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depending on the context. Senescence is a barrier against
tumor initiation by halting the proliferation of damaged
cells. However, senescent cells can promote tumor
progression through paracrine signaling, immune evasion,
and tissue remodeling. The balance between these effects
is influenced by various factors, including tumor stage,
cellular context, and the tumor microenvironment [8, 28].
Hence, cellular aging and senescence play complex roles
in breast cancer, influencing tumor initiation, progression,
and therapy response. Understanding the interplay
between senescence and cancer biology is crucial for
developing novel therapeutic strategies targeting
senescent cells or modulating senescence-associated
pathways to improve breast cancer management.
7.2. Lung Cancer
Cellular aging and senescence play pivotal roles in the
intricate landscape of lung cancer development and
progression. At the core of this relationship lies the
process of telomere shortening. Telomeres, protective
caps at the ends of chromosomes, progressively erode
with each cell division. This erosion acts as a cellular
clock, eventually triggering senescence or apoptosis once
telomeres reach a critical length. However, cancer cells
often exploit mechanisms to circumvent this fate,
maintaining telomere length and enabling indefinite
proliferation [133].
Moreover, cellular senescence, typically a safeguard
against tumorigenesis, can paradoxically fuel cancer
progression. Senescent cells adopt a pro-inflammatory
phenotype, secreting myriad signaling molecules known
as the SASP. In the context of lung cancer, this
inflammatory milieu can promote tumor growth and
metastasis, fostering a microenvironment conducive to
malignancy [134, 135].
DNA damage represents another nexus between
aging and lung cancer. Accumulated DNA lesions,
stemming from endogenous metabolic processes and
exogenous insults like cigarette smoke contribute to
genomic instability. While cells possess intricate DNA
repair mechanisms, aging compromises these processes,
increasing susceptibility to oncogenic mutations and
tumor initiation. Furthermore, the interplay between aging
and immune surveillance is crucial in lung cancer.
Immunosenescence, the age-related decline in immune
function, compromises the body's ability to detect and
eliminate cancer cells. Senescent cells within the tumor
microenvironment further exacerbate immune evasion by
fostering an immunosuppressive milieu through SASP-
mediated recruitment of regulatory T cells and myeloid-
derived suppressor cells [134, 136].
Chronic inflammation induced by environmental
insults perpetuates this lung cycle, accelerating cellular
aging processes and promoting the growth of
premalignant lesions. Lung cancer cells adeptly exploit
vulnerabilities in the aging microenvironment, evading
senescence checkpoints and immune surveillance to
propagate unchecked [136, 137]. Understanding the
intricate interplay between cellular aging, senescence, and
lung cancer is paramount for developing effective
prevention and treatment strategies. By targeting key
pathways involved in these processes, such as telomere
maintenance, DNA repair mechanisms, and immune
modulation, researchers aim to unravel the complexities
of lung cancer pathogenesis and devise innovative
therapeutic interventions.
7.3. Colorectal Cancer
Cellular aging, or senescence, is intricately linked to the
onset and progression of colorectal cancer, a prevalent
malignancy arising from the colon or rectal lining. A key
aspect of cellular aging is telomere shortening, where
protective caps at the ends of chromosomes degrade with
each cell division. This process often culminates in
cellular senescence or programmed cell death. However,
in cancer, including colorectal cancer, cells frequently
activate telomerase, a mechanism that circumvents this
senescence, allowing for uncontrolled proliferation [138,
139].
Moreover, aging cells accumulate DNA damage over
time due to various internal and external factors such as
reactive oxygen species and environmental toxins. This
DNA damage can trigger senescence or programmed cell
death pathways. However, cancer cells often develop
mechanisms to repair DNA damage or bypass cell cycle
checkpoints, enabling their survival and proliferation
despite genomic instability [138, 139]. In colorectal
cancer, mutations in DNA repair genes like APC
contribute significantly to tumor initiation and
progression [138].
Another critical aspect of cellular aging is the SASP.
In colorectal cancer, SASP components contribute to
creating a pro-tumorigenic microenvironment by
promoting inflammation, angiogenesis, and tissue
remodeling. This microenvironment supports the growth
and metastasis of cancer cells, further exacerbating tumor
progression [138, 139].
Immune senescence, a consequence of aging, also
plays a pivotal role in colorectal cancer. The immune
system changes with age, including immunosenescence
and chronic low-grade inflammation. These alterations
compromise the immune system's ability to recognize and
eliminate cancer cells, allowing them to evade immune
surveillance and establish tumors. In colorectal cancer,
immune senescence contributes to tumor immune evasion

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and resistance to immunotherapy, limiting treatment
effectiveness [45, 140].
Furthermore, aging is associated with extensive
epigenetic modifications, such as DNA methylation and
histone modifications. These alterations can dysregulate
gene expression patterns, promoting oncogenic signaling
pathways and silencing tumor suppressor genes in
colorectal cancer cells. Additionally, epigenetic changes
can drive cellular senescence by altering chromatin
structure and transcriptional programs associated with
senescence-associated growth arrest [138, 139].
Understanding the intricate interplay between cellular
aging, senescence, and colorectal cancer is crucial for
developing effective therapeutic strategies. Targeting
senescent cells and mitigating age-related risk factors
associated with colorectal cancer could lead to innovative
treatment approaches, ultimately improving patient
outcomes and quality of life.
7.4. Prostate Cancer
Cellular aging plays a significant role in the development
and progression of prostate cancer. Prostate cancer is the
second most common cancer in men worldwide and is
strongly associated with aging. As men age, their risk of
developing prostate cancer increases, indicating a link
between cellular aging processes and the onset of this
disease.
In the context of prostate cancer, cellular aging and
senescence can have both protective and detrimental
effects. On one hand, senescence acts as a tumor-
suppressive mechanism by preventing the uncontrolled
growth of damaged cells. When cells accumulate DNA
damage or mutations, they can undergo senescence to
avoid becoming cancerous. This prevents the proliferation
of potentially harmful cells and serves as a barrier to
tumor development [141, 142]. However, senescent cells
also secrete various factors collectively known as the
SASP. The SASP includes pro-inflammatory cytokines,
growth factors, and matrix metalloproteinases, among
other molecules. While the SASP can initially contribute
to the clearance of damaged cells and tissue repair,
prolonged secretion of these factors can promote chronic
inflammation and tissue dysfunction, creating a
microenvironment conducive to tumor growth and
progression [28, 142].
In the prostate gland, the effects of cellular aging and
senescence on prostate cancer are multifaceted. With
advancing age, the prostate undergoes structural and
functional changes, including alterations in hormone
levels, inflammation, and accumulation of DNA damage.
These age-related changes can disrupt the balance
between cell proliferation and senescence, tipping the
scales towards oncogenic transformation [141, 142].
Additionally, the prostate microenvironment undergoes
significant remodeling with age, characterized by
increased inflammation and tissue fibrosis. These changes
create fertile ground for the development and progression
of prostate cancer. Senescent cells contribute to this
microenvironmental remodeling through the secretion of
pro-inflammatory cytokines and matrix-degrading
enzymes, further fueling tumor growth and invasion [28,
142].
Furthermore, studies have shown that senescent cells
can evade immune surveillance, allowing them to persist
within the prostate tissue and contribute to the chronic
inflammatory milieu associated with prostate cancer. This
immune evasion facilitates tumor progression and
metastasis, leading to more aggressive forms of the
disease [141, 143]. Therefore, cellular aging and
senescence have a profound impact on prostate cancer
development and progression. While senescence initially
serves as a protective mechanism against oncogenic
transformation, the chronic inflammation and tissue
remodeling associated with senescent cells creates an
environment conducive to tumor growth and metastasis.
Understanding the interplay between cellular aging
processes and prostate cancer biology is crucial for the
development of effective diagnostic and therapeutic
strategies targeting this prevalent disease.
7.5. Gastric Cancer
Gastric cancer emerges from the uncontrolled growth of
cells in the stomach lining, influenced by factors such as
Helicobacter pylori infection, chronic inflammation, diet,
and genetics. Within this context, cellular aging and
senescence play intricate roles, impacting the disease
through multiple mechanisms [144, 145].
Telomere shortening, a hallmark of aging, is observed
in gastric cancer cells, leading to genomic instability and
uncontrolled proliferation. Senescent cells secrete a range
of molecules known as the SASP. In gastric cancer, SASP
components foster chronic inflammation, angiogenesis,
and tumor cell invasion. Furthermore, Oncogene-induced
senescence (OIS) acts as a tumor-suppressive mechanism
to halt the proliferation of potentially cancerous cells.
However, prolonged activation of oncogenes can lead to
senescence bypass mechanisms, enabling cells to evade
senescence and continue proliferating, contributing to
gastric cancer development [1, 144].
Immune surveillance, crucial for cancer prevention,
is altered in cellular senescence. Senescent cells may
evade immune detection by upregulating immune
checkpoint molecules like PD-L1, hindering the anti-
tumor immune response and promoting gastric cancer
progression [1, 146]. Moreover, epigenetic alterations,
including changes in chromatin structure and DNA

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methylation patterns, occur in senescent cells, leading to
aberrant gene expression profiles that promote gastric
cancer development and metastasis [144, 145].
Understanding the interplay between cellular aging,
senescence, and gastric cancer is critical for identifying
new therapeutic targets. Strategies targeting senescent
cells or modulating the tumor microenvironment hold
promise for inhibiting tumor growth and improving
outcomes for patients with gastric cancer.
7.6. Other Cancer Types
Cellular senescence also plays an important role in other
types of cancers. For example, in skin cancer, including
melanoma and non-melanoma types, cellular senescence
induced by factors like UV radiation is a protective
mechanism by triggering the permanent growth arrest of
damaged melanocytes and keratinocytes. However,
senescent cells in the skin microenvironment can also
foster tumor progression by secreting factors that enhance
tumor cell proliferation, angiogenesis, and immune
evasion [147, 148].
Pancreatic cancer presents another scenario where
senescence induction by oncogenic stress initially inhibits
tumor growth by arresting the proliferation of pre-
neoplastic cells. Nonetheless, persistent senescent cells in
the tumor microenvironment can promote inflammation
and fibrosis, creating a supportive niche for tumor
progression, metastasis, and resistance to therapy [36].
Brain cancer, particularly gliomas, exhibits dual
effects of cellular senescence depending on tumor stage
and genetic context. While senescence induction may
initially suppress tumor growth by triggering cell cycle
arrest, it can also contribute to tumor recurrence and
therapy resistance by promoting the survival and
proliferation of senescent tumor cells and activating pro-
tumorigenic signaling pathways [149, 150].
Liver cancer, such as hepatocellular carcinoma
(HCC), demonstrates a similar pattern, where senescence
induced by chronic liver injury and hepatitis viruses can
initially eliminate damaged hepatocytes, thus protecting
against HCC initiation. However, persistent senescent
cells in the liver microenvironment can fuel inflammation,
fibrosis, and compensatory proliferation, ultimately
promoting HCC development and progression [151, 152].
Figure 4. Emerging Senolytic Drugs Targeting Senescence in Cancer Therapy:
Overview of Potential Therapeutic Agents and Their Mechanisms of Action.

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Bladder cancer and renal cell carcinoma (RCC) also
exhibit diverse responses to cellular senescence. In
bladder cancer, senescent cells may initially inhibit tumor
growth by triggering cell cycle arrest and immune-
mediated clearance. However, senescent cells' secretion
of SASP factors can promote tumor progression, invasion,
and resistance to chemotherapy and immunotherapy.
Similarly, in RCC, senescence induction can halt the
proliferation of malignant cells. Still, it may also modulate
the immune response, promote angiogenesis, and
facilitate the establishment of a pre-metastatic niche,
ultimately contributing to tumor progression [153, 154].
In summary, the impact of cellular aging and
senescence on cancer varies widely across different types
of tumors. Understanding these complexities is crucial for
developing targeted therapeutic approaches that exploit
senescence-associated pathways in cancer treatment.
8. Drugs to Target Senescence in Cancer
The field of oncology is witnessing a growing interest in
developing pharmaceutical agents that can selectively
eliminate senescent cells within tumors, a concept known
as "Drugs to Target Senescence in Cancer." Although no
longer dividing, Senescent cells remain metabolically
active and often contribute to tumor growth and therapy
resistance. Compounds like quercetin, navitoclax, and
fisetin have shown senolytic properties by inducing
selective death in senescent cells. These drugs act on
various pathways linked to senescence, including BCL-2
family proteins, the FOXO4-p53 interaction, and cell
adhesion molecules such as E-selectin (Fig. 4). While
preclinical studies have shown promising results, further
research is essential to assess the safety and effectiveness
of these drugs in clinical settings.
8.1. Quercetin
Quercetin, a flavonoid compound, demonstrates
significant promise as a senolytic agent, particularly in
cancer settings. This natural compound can selectively
target and eliminate senescent cells by interfering with
various pathways linked to senescence. Quercetin offers a
focused strategy to impede cancer progression by
disrupting these pathways. Studies have highlighted the
effectiveness of quercetin derivatives, such as QD3, in
sensitizing senescent breast cancer cells induced by
chemotherapy, showcasing a novel approach to combat
cancer by combining pro-senescence and senolytic
activities [155, 156]. The pleiotropic effects of quercetin
on cellular senescence underscore its potential as a
valuable tool in anti-cancer strategies [97]. Additionally,
research has explored the synergistic effects of quercetin
with other compounds like dasatinib to enhance its
senolytic action against cancer cells [157]. These findings
collectively emphasize the promising role of quercetin as
a targeted senolytic agent in cancer therapy, offering new
avenues for combating cancer progression through the
elimination of senescent cells.
8.2. Navitoclax
Navitoclax (ABT-263), a precision drug, is designed to
target BCL-2 family proteins to initiate apoptosis
selectively in senescent cells in cancerous tissues. By
specifically inducing programmed cell death in these
senescent cells, Navitoclax aims to reduce the load of
senescent cells, potentially improving the effectiveness of
treatments for cancer patients. Studies have shown that
Navitoclax effectively eliminates senescent cells in
various contexts, such as human umbilical vein epithelial
cells, human lung fibroblasts, and murine embryonic
fibroblasts, highlighting its senolytic activity [158]. This
targeted approach to triggering apoptosis in senescent
cells underscores the potential of Navitoclax as a valuable
tool in combating cancer progression by reducing the
presence of these resistant cells within tumors [159, 160].
The ability of Navitoclax to induce apoptosis in specific
types of senescent cells offers a promising strategy for
enhancing therapeutic outcomes in cancer treatment by
addressing the challenges posed by these resilient cells.
8.3. Fisetin
Fisetin, a flavonoid compound similar to quercetin, is
recognized for its potent senolytic properties, especially
in cancer [161]. This natural compound stands out for its
ability to induce apoptosis in senescent cells by
modulating diverse pathways linked to senescence,
showcasing cell-type-specific effects. Fisetin's selective
approach in targeting senescent cells highlights its
potential as a valuable asset in cancer therapy by
effectively eliminating these resistant cells within tumors.
Studies have emphasized fisetin's efficacy in inhibiting
cell migration, suppressing metastases, and enhancing the
effects of chemotherapy across various cancer types,
underlining its multifaceted impact on cancer cells [36,
162]. The distinct senolytic activity of fisetin, coupled
with its ability to target specific pathways associated with
senescence, positions it as a promising candidate for
combatting cancer progression through the elimination of
senescent cells, offering new avenues for innovative
cancer treatments [163, 164].
8.4. Dasatinib

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Dasatinib, recognized primarily as a tyrosine kinase
inhibitor, has exhibited significant senolytic effects,
especially in cancer settings, when used in combination
with quercetin. This synergistic combination has shown
potent senolytic properties, effectively targeting and
eliminating age-related senescent cells within cancerous
tissues. The selective removal of these senescent cells
holds promise for enhancing the efficacy of cancer
treatments and potentially extending both patient health
and lifespan. Studies have highlighted the effectiveness of
dasatinib and quercetin in eliminating senescent cells,
emphasizing their potential in anti-cancer strategies by
specifically targeting these resistant cells within tumors
[157]. This targeted approach to senolysis offers a novel
avenue for improving cancer treatment outcomes by
addressing the challenges posed by senescent cells within
the tumor microenvironment. The combination of
dasatinib and quercetin represents a promising strategy
for combating cancer progression through the selective
elimination of these age-related senescent cells,
showcasing the potential for enhancing both the quality of
life and longevity of cancer patients [36].
8.5. Uproleselan
Uproleselan (GMI-1271) is currently being studied for its
senolytic capabilities, specifically emphasising acute
myeloid leukemia (AML). This investigational drug
targets E-selectin, a vital cell adhesion molecule involved
in the interaction between leukemic cells and bone
marrow endothelial cells, aiming to disrupt the leukemic
microenvironment. By disrupting this interaction,
uproleselan shows promise in facilitating the removal of
senescent cells within the context of AML, thereby
potentially enhancing treatment outcomes for individuals
battling cancer. Clinical studies have demonstrated that
uproleselan enhances chemotherapy response, improves
survival rates, and decreases chemotherapy toxicity in
vivo, making it a promising candidate for improving
therapeutic strategies in AML patients [165, 166]. The
ability of uproleselan to target E-selectin and alter the
leukemic microenvironment underscores its potential as a
valuable tool in combating AML by promoting the
clearance of senescent cells and enhancing the efficacy of
existing treatments.
8.6. Piperlongumine
Emerging research suggests that piperlongumine
demonstrates senolytic effects, potentially by selectively
inducing apoptosis in senescent cells, particularly within
cancer contexts. This natural compound has shown
promising results in targeting and eliminating senescent
cells, highlighting its potential for precise intervention in
cancer therapy. While piperlongumine's ability to induce
apoptosis in senescent cells is promising, further
investigations are needed to comprehensively elucidate its
mechanism of action and explore its applications in cancer
treatment. This compound holds significant promise for
offering targeted and effective strategies for combating
cancer by addressing the challenges posed by senescent
cells within tumors [167, 168]. The selective cytotoxicity
of piperlongumine against cancer cells and senescent
cells, coupled with its safety profile in non-senescent and
non-cancerous cells, underscores its potential as a
valuable candidate for further development as a senolytic
agent in cancer therapy.
8.7. FOXO4-DRI peptide
The FOXO4-DRI peptide demonstrates significant
promise in selectively targeting senescent cells for
clearance, especially in the field of cancer research. By
disrupting the interaction between FOXO4 and p53, this
peptide facilitates apoptosis specifically in senescent
cells, providing a focused strategy to counteract the aging
effects of senescence within cancerous tissues. Research
has shown that FOXO4-DRI effectively induces apoptosis
in senescent cells by interfering with the FOXO4-p53
complex [169], eliminating these resistant cells within
tumors [170, 171]. This targeted approach to promoting
apoptosis in senescent cells highlights the potential of
FOXO4-DRI as a valuable tool in cancer therapy by
addressing the challenges posed by these aging cells
within the tumor microenvironment [172]. The ability of
FOXO4-DRI to selectively target senescent cells for
clearance underscores its promise for enhancing treatment
outcomes and potentially extending patient health by
mitigating the pro-aging effects associated with
senescence in cancer contexts [173].
8.8. Methylene Blue
Methylene Blue, traditionally known for its applications
as a dye and treating methemoglobinemia, has
demonstrated senolytic effects in preclinical studies
focused on cancer. This compound has shown the ability
to selectively eliminate senescent cells and improve
healthspan in animal models, indicating its potential for
precise intervention in cancer therapy. Research has
highlighted the senolytic properties of Methylene Blue,
emphasizing its role in targeting and eliminating
senescent cells within tumors, thereby offering a
promising approach to enhancing cancer treatment
outcomes [174, 175]. The selective eradication of
senescent cells by Methylene Blue underscores its
potential as a valuable tool in cancer therapy by
addressing the challenges posed by these aging cells
within the tumor microenvironment [176]. The findings

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from preclinical studies support the notion that Methylene
Blue holds promise for targeted intervention in cancer
treatment by effectively targeting and eliminating
senescent cells, thereby potentially improving therapeutic
strategies and patient outcomes.
9. Emerging Research and Future Directions
The ever-evolving landscape of research on cellular
aging, senescence, and their implications in cancer
initiation and progression is paving the way for a deeper
understanding of the intricate interplay between these
processes.
Cutting-edge research endeavors to integrate various
cellular aging processes, including senescence, apoptosis,
and autophagy, to unravel their collective impact on
cancer development [177]. Autophagy can clear harmful
cellular species associated with senescence and promote
stress coping in cancer cells. Studies suggest that
integrating senescence with apoptosis pathways may offer
synergistic effects in eliminating cancer cells. The
relationship between autophagy and senescence is
complex in cancer, with reports suggesting both tumor-
suppressive and tumor-promoting roles for autophagy.
Autophagy can regulate cellular quality control in both
senescent and normal cells, limiting tumorigenesis [178].
Prolonged senescence can lead to cancer development,
emphasizing the importance of understanding the balance
between beneficial and maladaptive senescence
pathways. Impairment of autophagy contributes to
immunosenescence, leading to chronic inflammation and
age-related diseases. The mechanisms governing the
balance between pro-tumorigenic and anti-tumorigenic
functions of senescence remain unclear, highlighting the
complexity of cellular aging processes in cancer research
[179]. By deciphering the crosstalk between these
pathways and understanding their dynamic regulation in
cancer cells, researchers aim to identify novel therapeutic
targets that exploit vulnerabilities arising from
dysregulated cellular aging mechanisms. For instance,
ongoing studies explore how integrating senescence with
apoptosis pathways may offer synergistic effects in
eliminating cancer cells, potentially leading to more
effective treatment strategies. Understanding how these
processes intersect and influence cellular fate decisions is
crucial for developing comprehensive strategies to
modulate cancer progression.
Recent studies emphasize the sensitivity of the
cellular senescence program to physical differences
within the microenvironment. Investigating how
mechanical cues, extracellular matrix stiffness, and spatial
organization influence senescence induction and escape
provides valuable insights into the role of the tumor
microenvironment in shaping cellular fate [15]. For
example, research has demonstrated that alterations in
extracellular matrix stiffness can influence the expression
of senescence markers in cancer cells, suggesting a role
for physical factors in regulating senescence dynamics.
By considering the impact of physical factors on
senescence, researchers can uncover novel mechanisms
that drive cancer aggressiveness and metastasis,
potentially leading to innovative therapeutic
interventions.
In the realm of cancer treatment, the phenomenon of
therapeutic resistance exhibited by senescent cancer cells
presents a formidable obstacle. These cells often resist
conventional therapies like chemotherapy and radiation
due to altered signaling pathways and diminished
proliferative capacity. Consequently, they become
refractory to treatments primarily targeting actively
dividing cells, necessitating novel therapeutic approaches
that effectively eliminate or neutralize senescent cells
[180, 181].
Moreover, the relationship between tissue aging,
cancer risk, and cellular senescence underscores the
profound impact of aging on cancer susceptibility.
Senescent cell accumulation in aging tissues creates a pro-
inflammatory microenvironment conducive to cancer
initiation and progression, thereby highlighting the
importance of addressing age-related factors in cancer
prevention and treatment strategies [8, 182].
However, amidst these challenges lie potential
opportunities for improved diagnosis and prognosis by
identifying senescence-associated biomarkers. Markers
such as senescence-associated beta-galactosidase (SA-β-
gal) activity and senescence-associated heterochromatin
foci (SAHF) hold promise for diagnosing cancer and
predicting patient outcomes. Their detection in tumor
biopsies could enable clinicians to stratify patients more
effectively, facilitating the development of tailored
treatment approaches targeting individual tumors' specific
molecular characteristics [182].
The tumor microenvironment (TME) emerges as a
pivotal player in the complex landscape of cancer
progression, with the dynamic interplay between
senescent cells and the TME exerting profound influences
on tumor behavior [183, 184]. Notably, senescent stromal
cells within the TME have been implicated in promoting
tumor growth and metastasis through paracrine signaling
mechanisms, underscoring the imperative to target cancer
cells and their microenvironment in therapeutic
interventions. This recognition emphasizes the necessity
of comprehensive treatment strategies that consider the
intricate interactions between tumor cells and their
surrounding milieu.
In the era of precision medicine, the heterogeneity of
senescent cells within tumors presents a formidable
challenge that demands personalized treatment

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approaches. Precision medicine strategies, encompassing
targeted therapies and immunotherapies, promise to
selectively target senescent cancer cells while minimizing
collateral damage to healthy tissues. By leveraging the
molecular diversity of senescent cells, clinicians can tailor
treatment regimens to the specific characteristics of
individual tumors, thereby optimizing therapeutic
efficacy and minimizing adverse effects.
As advancements in cancer therapy continue to
extend the lifespan of cancer survivors, there arises a new
frontier in survivorship care, addressing the long-term
consequences of treatment and accelerated aging. With a
growing population of long-term survivors confronting
the late effects of therapy, strategies to mitigate the
adverse effects of cellular senescence have gained traction
as emerging areas of research. From lifestyle
interventions to pharmacological approaches targeting
senescent cells, efforts are underway to alleviate the
burden of senescence-associated complications and
enhance the quality of life for cancer survivors in the post-
treatment phase. Through a multifaceted approach that
integrates clinical care, research, and patient advocacy,
the journey towards optimizing survivorship outcomes in
the face of cellular senescence unfolds as a vital endeavor
in the oncological landscape.
Figure 5. The figure illustrates the integrated cellular aging processes, emphasizing the roles
of senescence, apoptosis, and autophagy in cancer development. Senescent cells, apoptotic cells,
and autophagic processes are depicted within the cellular context, highlighting their collective
impact on cancer initiation and progression. Additionally, the figure portrays the complex
relationship between senescence and autophagy pathways, demonstrating how autophagy regulates
cellular quality control and influences tumorigenesis. The influence of physical factors, such as
extracellular matrix stiffness and mechanical cues, on senescence induction and escape is
represented, along with alterations in the tumor microenvironment that contribute to cancer
aggressiveness and metastasis. Moreover, the figure visualizes the intricate relationship between
aging, cellular senescence, and cancer progression, showcasing age-related changes at the cellular
level and their implications for tumorigenesis and therapy resistance. Finally, the figure presents
molecular mechanisms involved in senescence induction and escape in cancer cells, alongside
potential diagnostic tools and precision therapies targeting senescent cells or modulating their
secretory phenotype, offering opportunities for early detection and targeted interventions.

Tufail M., et al. Cellular Aging and Senescence in Cancer
Aging and Disease • Volume 16, Number 3, June 2025 24
Future research directions focus on elucidating the
intricate relationship between aging, cellular senescence,
and cancer progression. While cellular aging acts as a
tumor suppressor mechanism under certain
circumstances, it may also enhance cancer development
in a context-dependent manner. Investigating how age-
related changes at the cellular level contribute to
tumorigenesis and therapy resistance provides a
foundation for developing personalized treatment
approaches that consider the impact of aging on cancer
outcomes [185]. For instance, ongoing studies aim to
unravel the role of specific age-related alterations in the
tumor microenvironment that may influence senescence
dynamics and impact cancer behavior. Continued
research will yield insights into leveraging cellular aging
processes for improved cancer prevention and
management.
Advancements in understanding the signaling
pathways involved in senescence induction in cancer cells
offer opportunities for early detection and targeted
interventions. Researchers can develop innovative
diagnostic tools and precision therapies that target
senescent cells or modulate their secretory phenotype by
deciphering the molecular mechanisms that drive
senescence escape and promote tumor aggressiveness.
For example, identifying specific molecular markers
associated with senescence escape may facilitate the
development of diagnostic assays for assessing the risk of
therapy resistance and disease recurrence. These
mechanistic insights pave the way for tailored treatment
strategies that address therapy resistance mechanisms
associated with senescence escape (Fig. 5) [36, 186].
Therapeutic strategies for addressing cellular aging
and senescence in cancer encompass a multifaceted
approach aimed at optimizing treatment outcomes.
Senolytics, including dasatinib, quercetin, navitoclax, and
fisetin, selectively induce apoptosis in senescent cells by
targeting specific survival pathways, offering promising
avenues for intervention supported by preclinical models
and early-phase clinical trials. Immunotherapy presents
another compelling strategy, leveraging the immune
system to recognize and eliminate senescent cancer cells.
Targeting immune checkpoints like PD-1 and CTLA-4
can enhance senescent cell clearance and improve
treatment responses. Combination therapies, integrating
senolytics with conventional chemotherapy or
immunotherapy, offer synergistic effects to overcome
treatment resistance and bolster anti-tumor immune
responses. Lifestyle modifications such as diet, exercise,
and stress reduction are pivotal in modulating cellular
senescence and promoting healthy aging. Integrating
these interventions into cancer care plans improves
treatment tolerability, reduces toxicities, and enhances
cancer patients' overall quality of life.
10. Conclusion
This comprehensive review explores the intricate
interplay between cellular aging, senescence, and their
impact on cancer. Beginning with examining cellular
aging processes, it uncovers the dual nature of senescence
as a tumor suppressor and contributor to cancer
development, governed by complex molecular signaling
pathways. Insights into senescence's role in cancer
therapies highlight its potential as a barrier to tumor
progression, while challenges exist in utilizing it for
therapeutic benefits. The review emphasizes the
importance of the senescence microenvironment,
particularly the SASP, offering strategies to manipulate
cellular aging and senescence for innovative cancer
therapies. Exploration of senescence escape reveals its
critical role in cancer aggressiveness, metastasis, and
therapy resistance, suggesting targeted interventions.
Future directions focus on integrating cellular aging
processes and understanding their relationship with
physical differences, paving the way for tailored
therapeutic strategies and improved cancer outcomes.
Competing interests
There is no competing interest to declare.
Acknowledgments
This work was supported by the National Natural
Sciences Foundation of China (Grant No. 82170974) and
the Central South University Research Program of
Advanced Interdisciplinary Studies (Grant No.
2023QYJC038).
Authors contribution
Muhammad Tufail: Conceptualization, Original Drafting,
Visualization, Writing - Review & Editing. Yu-Qi Huang:
Revisions, Visualization, Writing - Review & Editing.
Jia-Ju Hu: Revisions. Jie Liang: Revisions. Cai-Yun He:
Revisions. Wen-Dong Wan: Revisions. Can-Hua Jiang:
Visualization. Hong Wu: Visualization. Ning Li:
Supervision, reviewed, and Editing. Muhammad Tufail
and Yu-Qi Huang contributed equally to this manuscript.
All authors have reviewed and approved the final
manuscript for publication.

Tufail M., et al. Cellular Aging and Senescence in Cancer
Aging and Disease • Volume 16, Number 3, June 2025 25
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