Radiation Environment and Medicine 2023 Vol.12, No.1 1–11

Review

Radiation-induced Cell Death:a Multifaceted Sequel Shaping Radiation Effects
Keiji Suzuki*
Department of Radiation Medical Sciences, Atomic Bomb Disease Institute, Nagasaki University,
1-12-4 Sakamoto, Nagasaki 852-8523, Japan
Received 24 May 2022; revised 14 July 2022; accepted 9 August 2022

Exposure of cells to ionizing radiation (IR) results in DNA damage, among which DNA doublestrand breaks (DSBs) are the most deleterious to human health. Although DSBs are efficiently
mended by DSB repair systems, intolerant radiation doses cause unreparable DSBs, which
persistently activate DNA damage signaling pathway. As a result, cell death is executed. A
number of cell death modes have been described, including apoptosis, premature senescence,necrosis, and autophagy. While the mode of cell death is dependent on the stimuli given tocells, apoptosis and premature senescence have been documented in several studies as the two
representative modes of cell death in response to radiation exposure. Particularly, it is becoming
more aware that premature senescence is the common cause of cell death in various nonhematopoietic tissues, including epithelial tissues, mesenchymal tissues, and endothelial andlymphatic cells. Further studies have demonstrated that secretory phenotype is common tosenescent cells, and soluble factors secreted from senescent cells, such as cytokines, chemokines,
growth factors, and matrix remodeling factors, are those deeply involved in the execution of bothacute and late radiation health effects. Moreover, recent evidences have demonstrated a close
connection between radiotherapy-induced senescence and the development of adverse effects.
Current review overviews the modes of cell death caused by radiation exposure, and discusses
the physiology of cellular senescence, molecular mechanisms of radiation-induced prematuresenescence, significance of premature senescence in tissue reaction and late effect. Moreover,recent approaches towards the amelioration of health effects by senolytic chemicals that enableelimination of senescent cells from tissues will be presented.
Key words: Ionizing radiation, cell death, senescence, tissue reaction, late effects

1. Introduction
Deposition of radiation energy to cells brings about
various types of molecular changes, among which
DSBs have been known to be the most critical type of*Keiji Suzuki: Department of Radiation Medical Sciences, Atomic Bomb Disease
Institute, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
E-mail: kzsuzuki@nagasaki-u.ac.jp
https://doi.org/10.51083/radiatenvironmed.12.1_1
Copyright © 2023 by Hirosaki University. All rights reserved.

DNA damage resulting in detrimental health effects.
While DSBs are efficiently repaired by multiple DNA
damage repair systems, such as non-homologous endjoining (NHEJ) and homologous recombination (HR)1),
if radiation dose is intolerable, some DSBs are left
unrepaired while most other DSBs are mended by DSB
repair systems, creating so-called unreparable DSBs. Suchunreparable DSBs persist for a very long time2-5), andthey continuously activate ATM-dependent DNA damage
checkpoint pathway, which gives rise to cell death. In

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Table 1. Major modalities of cell death
Mode
I. Macroscopic morphological classification
Type I : apoptosis

Morphological characterization

Key biochemical characterization

cytoplasmic shrinkage, chromatincondensation, DNA fragmentation,
membrane blebbing

Type II : autophagy

cytoplasmic vacuolization

Type III : necrosis

loss of membrane integrity, swelling ofsubcellular organelles

II. Biochemical and molecular classification
Apoptosis

See apoptosis, apoptotic body

caspases activation, CAD activation
phosphatidylserine exposure

Necroptosis

cell swelling, membrane rupture
moderate chromatin condensation

RIPK1, RIPK3, MLKL activation

Ferroptosis

mitochondria membrane rupture
diminutive mitochondria with crista
reducedtriggered by iron accumulation and lipid
peroxidation, regulated by GPX4

Pyroptosis

rupture of plasma membrane, chromatincondensation, cell swelling, membrane
bubbling

inflammatory caspase (caspase-1, -11) activation
gasdermin D (GSDMD) activation

Autophagy-dependent
cell death

autophagic vacuolization, membrane
blebbing

LC3B-II accumulation, increased lysosomal activity

AnoikisSee apoptosis

loss of integrin-dependent anchorage

Entotic cell death(Entosis)cell-in-cell formation

activation of adhesion proteins, LC3-mediatedphagocytosis

Netotic cell death(NETosis)

chromatin fiber release, membrane
nuclear membrane collapse

NETs formation

Lysosome-dependent
cell death

Lysosome and plasma membrane rupturelysosomal membrane permeabilization

MPT-driven necrosis
See necrosis
rely on cyclophilin D (CYPD)
CAD: caspase-activated DNase, RIPK: ubiquitinate receptor interacting serine/threonine kinase, MLKL: mixed lineage kinase domain like pseudokinase,
GPX: glutathione peroxidase, NET: neutrophil extracellular traps, MPT: mitochondrial permeability transition.

addition to necrosis, which was widely recognized as acell death modality, early observations defined that cells
exposed to ionizing radiation were died predominantly by
apoptosis6). It was demonstrated that radiation-induced
apoptosis was regulated by p53, which is also a key player
for regulating cell cycle progression to keep the integrityof the genome7, 8). Accordingly, a model, in which DSBinduced p53 activation transiently arrests cell cycle to
make a time for repair, has been proposed. In the model,
cells with low level of DSBs are assumed to complete
DSB repair by inducing p53-dependent transient cell cycle
arrest, while cells with unreparable amount of DSBs areforced to die by p53-dependent apoptosis. However, it now
turns out to be clear that apoptosis induction is rather
limited to a certain type of tissue, such as hematopoietic
tissues, and most other epithelial tissues, such as epithelial
tissues, mesenchymal tissues, as well as endothelial andlymphatic cells, show non-apoptotic cell death modalities
in response to ionizing radiation9,10). Considering extensive
advances in recent studies regarding cell death pathway,
it is a right time to renew our knowledge on modes ofcell death caused by radiation exposure. Therefore, thisreview overviews past and present studies with regard tocell death after radiation exposure, and emphasizes thesignificance of radiation-induced premature senescencein tissue reaction and late effects, together with possible
ways to ameliorate radiation health effects by eliminating
senescent cells from tissues.
2. Historical view
Historically, three types of cell death modality, whichwere classified by morphological changes, were proposedin mouse and rat prenatal tissues exposed to embryotoxic
substances11) (Table 1). Type I cell death or apoptosis
is represented by cell shrinkage, plasma membrane
blebbing, nuclear fragmentation, and DNA fragmentation,
leading to the formation of small cytoplasmic vesicles,
known as apoptotic bodies. T ype II cell death orautophagy is manif ested by visible cytoplasmic
vacuolization, which contains subcellular organelles andcytoplasmic materials. Type III cell death or necrosis
is characterized by the loss of membrane integrity andorganelle swelling.
Subsequently, various types of cell death modalities
have been documented, so that the Nomenclature
Committee on Cell Death (NCCD) formulates criteria forthe definition of cell death since 200512). The NCCD has

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Fig. 1. Tissue response to IR. Radiation exposure to tissues brings about premature senescence as well as apoptosisof cells. In non-hematopoietic tissues, premature senescence is predominantly induced in various cells, such as epithelial
cells and fibroblasts/stromal cells, which attracts immune cells to promote tissue regeneration. In case, where higher
doses are delivered, cell death is more profound, resulting in manifestations of tissue dysfunction including chronic
inflammation and fibrosis.

published five position papers so far, and the newest one
was released in 201813). Accordingly, cell death is divided
into accidental cell death (ACD) and regulated cell death(RCD), in which the former is induced by unpredictedinsults and the latter is more physiological and isbiologically controlled. Cell death modalities associatedwith RCD include apoptosis, necroptosis, ferroptosis,
pyroptosis, autophagy-dependent cell death, anoikis,
entotic cell death (entosis), netotic cell death (NETosis),lysosome-dependent cell death, and mitochondrial
permeability transition-driven necrosis14) (Table 1).
Additionally, cell death that stimulates adaptive immune
response in the host is called immunogenic cell death15).
Cellular senescence, as well as mitotic catastrophe,
have not been considered to constitute forms of RCD
by NCCD, however, these two play a pivotal role in thefate of cells in response to ionizing radiation, which isextensively discussed later.
3. Physiology of senescence in normal cells
Cellular senescence has been recognized as a cause of
aging, as senescent cells accumulate in various tissues
in aged humans and mice16-18). Cellular senescence wasoriginally described in cultured normal human diploidcells, which ceased to grow after several rounds of cell
divisions19). Telomere attrition, along with DNA damage
accumulation and epigenetic reactivation of the CDKN2A
locus, are the origin of endogenous factors that cause
cellular senescence20, 21). Although cellular senescenceis predominantly associated with aging, recent findings
have illuminated its role in the embryonic development aswell22).
Cellular senescence is distinct from other nonproliferative states, such as quiescence at G0 phase andterminal differentiation. Irreversible and permanent cell
cycle arrest is one representative feature of senescentcells, but they are still metabolically active. In culture,senescent cells are viable and stay for a quite long time2-5),
and several studies have proven that they secrete several
soluble factors, which exert physiological response intissue microenvironment, including inflammation22-26).
Thus, senescence is primarily beneficial to damaged
tissue because its facilitates tissue remodeling (Fig. 1).
However, in elderly animals, accumulation of senescentcells in tissues gives rise to unfavorable decline inphysiological function of them leading to age-related
pathologies.
Since senescence is induced not only by shortened
telomeres but also by endogenous DNA damage, it isexpected to be a barrier against cancer development. At
the same time, some studies have shown that senescencein bone marrow supports proliferation and survivalof malignant cells. Thus, senescence is a multi-faced
phenomenon that causes pleiotropic effects in a contextdependent manner, which is carefully considered below.
Also, physiological senescence is stem from telomere
attrition, while radiation-induced senescence does not
involve telomere shortening, so that the definition,premature senescence, is used in this review.

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Fig. 2. Two representative cell death modes induced by IR. Exposure of epithelial cells to IR gives rise to various modesof cell death, among which premature senescence and apoptosis are the two major modes. In normal cells, immediatecell cycle arrest persists and senescence phenotypes become obvious, whereas, in cancer cells, it needs a few rounds ofcell cycle before terminal growth arrest is executed. Because cancer cells are forced to divide even with multiple DSBs,
mitotic catastrophe, in which multiple micronuclei, di-nuclei, and giant nuclei are emerged, is taken place. Only after thecell cycle is terminated, cancer cells exhibit common senescence phenotypes including SA-β -gal expression. Apoptosis
induction is preferentially observed in hematopoietic cells, however, in some epithelial cells, like those in the crypts ofsmall intestine, show apoptotic cell death.

4. Molecular bases for senescence induction innormal cells
Telomeres, which constitute the end structure of
mammalian chromosomes, are the molecular clock thatcounts the number of cell divisions27, 28). In fact, DNA
replication machinery is unable to synthesize DNA at its
5ʼ terminal, which is known as end-replication problem,so that telomeres are eroded through successive cell
divisions. Finally, critically shortened telomeres arepresumed to unable to organize protective telomere
structure, so-called T-loop. As a result, the end structuresof telomeres, which are structurally equivalent to DSBs,
are exposed and trigger DNA damage response 28).
Shortened telomeres are sensed by A TM, which
results in phosphorylation and stabilization of p5329).
Accumulated and activated p53 transactivates several
downstream effectors that regulate cellular response
to DSBs30-35). Among the factors responsible for DNA
damage response, p21WAF1/CIP1 protein is an essential one
that controls cell cycle arrest. p21WAF1/CIP1 is a nuclear
protein that inhibits cyclin-dependent kinase (CDK)associated with RB phosphorylation, such as CDK2,
CDK4 and CDK6, and thereby inhibiting cell cycle
progression from G1 to S, which is generally called G1arrest36). Because telomere attrition is not reversible, cell
cycle arrest at G1/S border persists. Eventually, the levelof p21WAF1/CIP1 is decreased, but compensative activation of

the p16INK4A locus continues irreversible cell cycle arrest37).
Thus, senescent cells are not mere G1-arrested cells but
are morphologically, physiologically and biochemicallydifferent from the quiescent cells and the terminallydifferentiated cells. In fact, morphology of senescent cells
is totally different from that of proliferating cells, and they
are really large and flattened (Fig. 2). They sometimes
show bi-nuclei or giant nuclei, and exhibit a unique
enzymatic activity, which is called senescence-associatedβ -galactosidase (SA-β -gal) activity38)(Fig. 2). Initially, SAβ -gal activity was thought to be a unique biochemicalmarker for senescence, however, it now becomes clearthat augmented lysosomal activity is the nature of SA-β-gal activity. In fact, the swell of lysosomes are commonly
observed in senescent cells.
In addition to ATM-p53 axis-dependent DNA damage
response, it has been proposed that multiple pathways
are involved in a full specification of senescence39)(Fig. 3).
For example, cytoplasmic chromatin fragments (CCFs),
which are brought about micronuclear chromatin
fragmentation, and damage-associated molecular patterns(DAMPs) are involved in the secretory phenotype ofsenescence. A role of mTOR has also been discussed indeepening the senescence state40). All these pathways
associated with cellular senescence were complied by
the International Cell Senescence Association (ICSA),
together with the recommendations on how to utilize
responsible molecules as biomarkers18).

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Fig. 3. Pathways involved in the manifestation of late effects/adverse effects of radiation exposure. Exposure of tissues
to intolerable doses of IR results in massive cell death in various types of cells constituting tissue, which mediate releaseof several factors from damaged cells, including damage-associated molecular patterns (DAMPs), high mobility groupbox 1 (HMGB1), and creation of cytoplasmic chromatin fragments (CCFs). The latter is involved in the activation of thecyclic GMP-AMP (cGAMP) synthase (cGAS) - the stimulator of interferon genes (STING) pathway, which potentiates
secretion of soluble factors from senescent cells. At the same time, a group of soluble factors are secreted frompremature senescent cells, and they provoke changes in the local and systemic tissue microenvironment, which mediate
late health effects caused by radiation exposure and adverse effects originated from radiation therapy.

5. Induction of premature senescence by IR in normal
cells
Permanent cell cycle arrest was initially documented
in normal human diploid cells exposed to ionizing
radiation41, 42). Subsequently, several DNA damaging
agents were confirmed to induce premature senescence42).
Because most of the earlier studies used lymphocytes,
apoptosis was believed to be the major cell death modality,
which was the reason why studies towards radiationinduced cell death did not take senescence induction into
consideration. However, accumulating evidences havesufficiently proven that premature senescence is more acommon modality of cell death after radiation exposurein various cell types, including not only fibroblasts, butalso epithelial cells, endothelial cells, myoblasts, and bonemarrow- and adipose-derived stem cells9, 10, 43-46). Thus,
premature senescence has now been integrated into themode of cell death in response to radiation exposure, and
it is indispensable for the comprehensive understandingof both tissue reaction and late effect caused by radiation
exposure47).
Historically, two types of cell death mode have beenutilized in the field of radiation biology and radiation
oncology, one of the definition is interphase cell death,and the other is mitotic cell death. While the former ismediated by apoptosis and necrosis, the latter process
is undescribed until recently but is characterized by
the induction of giant cells, bi-nucleated cells, or bymultiple micronuclei. It is comparable with clonogenic
cell death, whose definition is widely used in the radiation
oncology researchers. It now appears to be clear thatmitotic cell death is equivalent to premature senescence.
In addition, interphase cell death in non-hematopoietic
cells is executed primarily by premature senescence, sothat it is the time to renew our view of cell death modeby introducing recent advances in radiation biology andoncology.
6. Mechanism of IR-induced premature senescencein normal cells
While physiological senescence is brought about
the telomere attrition, radiation-induced prematuresenescence is coupled with persisted cell cycle arrest
caused by unscheduled and persistent chromosomal
breakages4, 5, 37). Upon irradiation, multiple DNA repair
systems execute mending DSBs, however, if theamount of DSBs exceeds the threshold of DSB repair
capacity, some fractions of DSBs are left unrepaired.
Since induction of DSBs simultaneously activates ATMdependent DNA damage signaling pathway, irrespectiveof the initial number DSBs, DNA damage signaling ispersisted as long as unreparable DSBs are remained2).
A T M is a product of t he gene named ata xia telangiectasia mutated, which is mutated in radiation
sensitive disorder, Ataxia-telangiectasia (AT). ATM
belongs to the superfamily of phosphatidylinositol 3-kinase

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related kinases48). ATM is a serine-threonine kinase,whose activity is stimulated by reorganization of higherorder chromatin structure caused by DSBs49). Various
targets have been discovered, which include histone
H2AX, NBS1, BRCA1, p53, CHK2, etc. Once ATM is
activated, these downstream effectors are phosphorylated
and mediate/initiate DNA damage response50-55). Amongthem, p53 plays the central role in DNA damage
response30-35). p53 is a well known tumor suppressor
protein, whose gene is mutated or lost in various kindsof human cancers. p53 is a transcription regulator andactivates or suppresses expression of a group of genes,
whose products are involved in apoptosis induction as wellas cell cycle arrest. p53 is also well-known as a guardianof the genome, so that it efficiently limits propagationof cells with unreparable DSBs after radiation exposure.
Since DNA damage repair systems efficiently eliminate
DSBs, the number of DSBs is decreased instantaneously
after irradiation. Following the completion of DSBs repair,
ATM is dephosphorylated, and DNA damage signaling
is turned off. Conversely, if DSB repair is unable tocomplete, activation of ATM and p53 persists, and cell
cycle arrest continues. This is how permanent cell cycle
arrest is executed.
Unreparable DSBs induce not only G1 arrest but also S
arrest and G2 arrest, the latter two are transient, so thatevery cell subsequently starts to proceed to the next cell
cycle phases. In contrast to S and G2 arrest, G1 arrest is
known to be permanent in normal human cells, so thatcells are persistently arrested in G1 phase, leading topremature senescence. It is evidenced that mitotic cells
at the time of exposure have micronuclei3) in the next G1
phase, In addition, it was also reported that cells mightproceed to the next G1 phase even without cell division,
which results in 4N G1 cells56). Cell cycle terminationis really a dynamic process. While many normal cells
are able to terminal cell cycle immediately, there is
obviously a case, particularly in cancer cells, in which a
few cell cycling are required before cell cycle is finallyterminated2).
7. Induction of premature senescence by IR incancer cells
Irrespective of the evidence that IR-induced prematuresenescence in normal cells requires the p53 function,
which is often abrogated in cancer cells, IR has beenreported to induce premature senescence in various
types of cancer cells46, 57-60). In some cancer cells, residual
p53 activity is still able to execute premature senescencewithin one or two rounds of cell cycle. In most othercancer cells, they need a few more cell cycles before
senescent phenotypes become obvious. In such cancer
cells, cell cycle is progressed even with multiple DSBs, sothat they show mitotic catastrophe, which is manifested
by multiple micronuclei, di-nuclei, or by giant cell
formation (Fig. 2). Besides, as cell cycle is progressed,
DNA is also replicated, resulting in the nuclei with
polyploidy. Although the mechanism, by which cell cycle
is terminated in cancer cells, has not been fully definedyet, premature senescence is a common phenomena, andIR-induced premature senescence is now integrated into
so-called therapy-induced senescence (TIS) as a part61-63).
Premature senescence is manifested by prolonged
growth arrest, increased lysosomal activity, and SA-β -gal
activity, which are common to premature senescence innormal cells, however, morphological change is not sosignificant as in normal cells (Fig. 2). While prematuresenescence is irreversible in normal cells, recent studies
have shown that TIS is reversible64-67), although the its
frequency is quite low, such as 1 in 106 cells. Importantly,
it has been demonstrated that cancer cells in TIS reveal
up-regulation of stem cell markers, suggesting that TIS issomehow associated with reprogramming of cancer cells.
It allows prolonged survival of cancer cells in a dormant
state with stemness, and such cancer cells are assumed tocontribute to recurrence of the diseases68).
So far, most of the studies have been done in vitro,and its demonstration is limited to the studies using
certain biological settings. Thus, the reversibility of TIS
still needs to be proven in various culture systems, andwhether escape from TIS in vivo will happen in reality
has to be determined. Also, it is currently not known
whether IR-induced premature senescence in cancer cells
is reversible or not. Future studies will be necessary todefine whether cancer cells are able to escape from IRinduced premature senescence, as it is indispensable forunderstanding of mechanisms underlying radio-resistanceand accelerated repopulation.
8. Secreted phenotype of senescent cells
While senescent cells cease to divide, they are still
metabolically active and exhibit up-regulation of several
gene transcriptions, most of which encode secretory
soluble factors. Interestingly, such secretory factors
were commonly observed in various cell systems, andthe phenomenon was named senescence-associatedsecretory phenotype (SASP)22-25). Discovery of paracrine
f unction of senescent cells uncovers biologicalmechanisms underlying antagonistic pleiotropy ofsenescence 68, 69). Many of the secretory factors arecommon over different cell types, and most of them are
expected to affect surrounding tissue microenvironment.
Until recently, several factors have been identified,
which are categorized into cytokines, chemokines, otherinflammatory factors, growth factors, matrix remodelingfactors, ligands, and extracellular matrix18-25, 70) (Fig. 3 andKeiji Suzuki / Radiation Environment and Medicine 2023 Vol.12, No.1 1–11

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Table 2. Soluble factors secreted from senescent cells
Factors
IL-1a
IL-6
IL-8
MCP-1
CXCL1
CCL2/5TGF-β1IGFBPs
CSFs
MMPs
PAI-1

Functions
Cytokine
Cytokine
Cytokine
Cytokine
Chemokine
Chemokine
Growth modulator
Growth modulator
Growth modulator
Matrix remodeling factor
Matrix remodeling factor

Cell systems secreted factors
Human endothelial/muscle, fibroblasts epithelial cell
Human fibroblasts, keratinocyte, monocyte melanocyte, epithelial cell
Human fibroblasts
Fibroblasts, liver stellate cell
Human fibroblasts
Human fibroblasts
keratinocyte, epithelial cell
Fibroblasts, epithelial cell, endothelial cell
Fibroblasts
Fibroblasts
Endothelial cell, fibroblasts

Table 2). For example, IL-1α and IL-6 are representative
cytokines for inflammatory response. Ectopic IL-1 α
secretion is suggested to amplify senescence cycle, while
IL-6 is involved in inflammatory response and reproduces
immunosuppressive microenvironment. Growth factors,
such as HGF and bFGF, stimulate proliferation ofneighboring cells, and matrix remodeling factors facilitatereconstitution of tissue structures. Thus, the secretion ofsoluble factors by senescent cells could play pivotal rolesin the cross-talk between senescent cells and surrounding
tissue microenvironment, by which tissue homeostasis
is maintained. Conversely, inability of the clearanceof senescent cells or persistent senescence caused byhigher doses of radiation exposure give rise to chronic
inflammation and fibrosis, which are detrimental tophysiological tissue functions (Fig. 1).
Several lines of evidences have shown that there isno obvious difference in SASP between normal cells andcancer cells, indicating that common mechanisms could
be involved in the initiation and execution of SASP. For
example, DAMPs, high mobility group box 1 (HMGB1),
and CCFs are those released from damaged normal andcancer cells (Fig. 3), which are contributed to potentiationof SASP in both cells. The profiles of secreted factors
are also very similar between normal and cancer cells
exposed to IR. Thus, it is likely that IR-induced prematuresenescence, whether it is induced in normal cells orcancer cells, shares common features of SASP71-73).
9. Crossroad where IR-induced premature senescencemeets tissue reaction and late effect of radiation
Radiation-induced premature senescence is deeply
associated with cell death in many cell types, indicatingthat it had better integrate premature senescence into
the physiological processes leading to the manifestationof radiation effect. For example, while bone marrow
death and intestinal death are predominantly caused by
apoptosis, premature senescence could also be involvedin the manifestation of acute radiation syndrome(ARS). In fact, several studies have demonstrated thatsenescence-associated secretory phenotype is involvedin the manifestation of adverse ef fects following
radiotherapy46, 74-76).
Significance of premature senescence in tissue reaction
is corroborated by the fact that many of the secretory
factors are those mediating inflammatory response, which
is obviously a symptom of ARS. Although further studies
are needed, secretory factors that mediate tissue reaction
could be the potential target to mitigate ARS.
In addition to ARS, several lines of results havesuggested that premature senescence is also involvedin the manifestation of late effects, in particular, cancer
development. It is well established that ionizing radiationinduces cancer, whereas the underlying mechanism
has not been fully elucidated yet47, 77). Although ionizing
radiation is well known to cause targeted effects, which
are arisen in cells directly absorbed radiation energy,
several studies have described that radiation exposure
give rise to non-targeted effects39, 78-83), which is the
manifestation of the consequences of radiation exposurein cells that have never been exposed. For example,
bystander effect is one of the non-targeted effects,
which is mediated by secreted factors and/or throughcell-to-cell communications84). Importantly, many of thesecreted factors associated with bystander effect areapparently identical to those secreted from senescentcells. Considering that premature senescence is surely the
major modality of cell death in many cell types, it is no
doubt that radiation-induced premature senescence plays
an indispensable role in executing non-targeted effects.
Since senescence-associated secretory factors havebeen proven as critical mediators to change tissue
microenvironment and immunogenic microenvironment,
they play a pivotal role in reinforcement of the state ofsenescence. Furthermore, secreted factors are involved intissue reconstruction by stimulating cell growth, matrix
remodeling, and angiogenesis. Particularly, attracting

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immunogenic cells by senescent cell-derived cytokinesand chemokines need to be discussed, since it is essential
for tissue regeneration and is known to be involved
in immunogenic cell death85, 86). While recruitment of
immune cells gives rise to beneficial effects, such as
potentiation of systemic immunity, which is know as
abscopal effect87-89), several literatures demonstrated thatsome secreted factors bring local chronic inflammation
as well as immunosuppressive microenvironment 87-89),
which play a role in propagation of the initiated cancerous
cells. Thus, radiation-induced premature senescence plays
pleiotropic roles, and it is likely that some late effects
might be brought about secreted factors from senescentcells. This idea should be integrated into the mechanismof radiation-induced carcinogenesis. Since manifestationof secretory phenotype of senescence dislike a stochastic
phenomenon, its dose-response should not be linear, andsuch possibility has to be discussed further in detail fromthe radiation protection point of view.
Of note, it has now been clear that several agingrelated diseases are originated from senescence20-22). Since
non-cancer health effects caused by radiation exposure
resemble such pathological processes, radiation-inducedpremature senescence should also be discussed withrespect to non-cancer effects.
10. Elimination of senescent cells and ameliorationof adverse effects
Radiation-induced premature senescence could be
involved in the execution of radiation health effect, so thatremoval of senescent cells is expected to mitigate shortterm as well as long-term radiation effects. Since targeted
elimination of senescent cells from tissues have alreadybeen proven to ameliorate age-related pathologies20, 21, 90-92).
It is practical to consider immediate application oftargeted elimination of premature senescent cells fromradiation protection point of view. So far, the developmentof the unique transgenic INK-ATT AC mouse model,
in which the drug-inducible apoptosis-activator gene
was driven by the p16 INK4a promoter, revealed thatseveral types of age-related diseases were mitigated byeliminating the p16INK4a-positive senescent cells fromold mice. The same results were obtained by anothertransgenic 3MR mice, in which the herpes simplex virusderived thymidine kinase gene was under the controlof p16INK4a promoter. Accordingly, selective removal ofsenescent cells was examined in human cases90-92).
In order to eliminate senescent human cells several
senolytic approaches have been examined 90-92). One
representative approach is to use small chemical
inhibitors targeting proteins involved in apoptosis. The
most promising approach is to use inhibitors of prosurvival BCL family proteins93-95). For example, ABT-

263, which is widely used senolytic drug, inhibits Bcl-2
families, including Bcl-2, Bcl-xL and Bcl-w93, 94), and several
previous studies have shown that ABT-263 effectively
eliminate senescent cells both in vitro and in vivo93-98).
Importantly, several clinical trials have been examined
to improve the efficacy of radiotherapy by eliminating
therapy-induced senescent cells99-109).
Although the mechanism, by which senescent cells
are eliminated by senolytic drugs, is not fully understoodyet, our previous study demonstrated that ABT-263 alone
had little or no effect on growing cancer cells. Since SAβ -gal-positive senescent cells were selectively eradicatedby apoptosis110), western blot analysis was performed,
which demonstrated that expression of apoptosis-related
proteins, such as Bcl-xL, Bcl-2, and Bcl-w were obviously
up-regulated in radiation-induced premature senescentcells. Furthermore, the examination also revealed thatthe levels of Bax and Bad were commonly increased
in senescent cells. Since apoptosis was not evident insenescent cancer cells without ABT-263, and ABT263 alone was not effective to unirradiated cancer cells,
it was suggested that augmented expressions of both
apoptotic and anti-apoptotic factors were critical for
efficient removal of premature senescent cells induced byradiation exposure.
Besides ABT-263, several bioactive compounds havebeen applied for senolysis. For example, the combinationof the Src kinase inhibitor dasatinib and the flavonoid
quecetin (so-called D +Q recipe), which was developed
using a bioinformatical approach, has now been subjected
to clinical trials21, 92). Several other clinical trials areunderway or planned92). Although these clinical trials
are towards the age-related diseases, the same approachshould be applicable to mitigate the adverse healtheffects originated from radiation therapy, and to alleviate
radiation health effects as well.
11. Conclusion
Exposure to ionizing radiation results in induction of
DSBs, which are the most deleterious to human health.
Although DSBs are efficiently mended by DSB repair
systems, receiving intolerable doses of radiation gives rise
to unreparable DSBs, resulting in persistent activation of
ATM-p53 axis-dependent DNA damage signaling pathway
in normal cells. Accordingly, cell death is brought about
tissues/organs, and impermissible levels of cell deathcause tissue reaction. Among cell death modalities
observed after radiation exposure, premature senescencehas now been recognized as a representative consequenceof various non-hematopoietic tissues, including epithelial
tissues, mesenchymal tissues, and endothelial andlymphatic cells. It has also been demonstrated that IRinduced premature senescence is a major cause of

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death of cancer cells. Unexpected secretory phenotype
associated with premature senescence has attracted
enormous interests, as secreted soluble factors, suchas cytokines, chemokines, growth factors, and matrix
remodeling factors are indeed associated with themodification of tissue microenvironment, which is
involved in the execution of radiation late effects as wellas adverse effects after radiation therapy.
Although physiological significance of senescenceinduction and its relevance to radiation health risk havenot been fully described yet, several studies have alreadyshown its potential to promote novel strategies andtechniques against radiation protection seems promising.
Future studies are expected to deepen our knowledgeof biological significance of IR-induced prematuresenescence in tissue reaction and late effects, and promotestudies towards possible ways to ameliorate radiation
health effects by eliminating senescent cells fromexposed tissues. At the same time, deeper understandingsof therapy-induced premature senescence should provide
novel mechanistic insights into the effectiveness ofradiation therapy, which should provide innovative
strategies for cancer radiation therapy in the future.

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Conflict of interest
The author declares that I have no conflict of interest.
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