ISSN 0006-2979, Biochemistry (Moscow), 2025, Vol. 90, No. 12, pp. 1883-1896 © The Author(s) 2025. This article is an open access publication.
Published in Russian in Biokhimiya, 2025, Vol. 90, No. 12, pp. 1981-1996.
1883
REVIEW
Antibiotics and Cellular Senescence:
An Unexplored Territory
Roman A. Zinovkin
1,a
* and Nataliya D. Kondratenko
1,2
1
A. N. Belozersky Institute of Physico-Сhemical Biology, Lomonosov Moscow State University,
119992 Moscow, Russia
2
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University,
119234 Moscow, Russia
a
e-mail: roman.zinovkin@gmail.com
Received August 26, 2025
Revised November 17, 2025
Accepted November 27, 2025
Abstract— Antibiotics are certainly the most important agents in the fight against human and animal bac-
terial infections. Widespread use of antibiotics has a positive impact on the treatment of infectious diseases
but may be accompanied by serious side effects. Clinical aspects of these side effects are well understood,
but nonspecific molecular targets are not fully recognized. It is generally known that many antibiotics can
damage mitochondria, intracellular organelles responsible for aerobic metabolism as well as regulating a
number of important processes, including cellular redox balance and inflammatory responses. Mitochondrial
dysfunction commonly leads to the development of oxidative stress and inflammation, which are known
stimuli of cellular senescence. On the other hand, the same stimuli could induce death of senescent cells.
Thus, mitotoxic antibiotics could influence both the cellular senescence process and elimination of senescent
cells. The effect of antitumor antibiotics on the induction of cell aging has been studied in detail, but the effect
of antibacterial antibiotics on this process is still essentially unknown. This review aims to draw attention of
the researchers to the possibility of accelerated cellular aging induced by common antibacterial antibiotics
and to discuss potential mechanisms of this process.
DOI: 10.1134/S0006297925602758
Keywords: antibiotics, side effects, cellular senescence, mitochondria, reactive oxygen species
* To whom correspondence should be addressed.
INTRODUCTION
Since their discovery, antibiotics have remained
indispensable tools in the fight against bacterial in-
fections, dramatically reducing infection-related mor-
tality and contributing substantially to the increased
life expectancy worldwide. However, their use is
accompanied by various non-specific effects, physi-
ological features of which are well documented [1].
At least part of these side effects could be attribut-
ed to the evolutionary relationship between bacteria
and mitochondria, which originated from the ancient
alphaproteobacteria [2]. Consequently, many antibi-
otics that target bacterial replication or translation
also induce mitochondrial dysfunction [3]. The down-
stream consequences of mitochondrial dysfunction,
such as oxidative stress and inflammation, could, in
turn, trigger cell cycle arrest and drive cells into a
state of cellular senescence (CS).
Although numerous individual studies and re-
views have addressed antibiotic side effects and the
phenomenon of CS, the relationship between these
two events remains largely unexplored. The primary
exception is antitumor antibiotics, which are known
to induce CS through activation of the cellular DNA
damage response. This review briefly outlines current
understanding of the mechanisms of CS development,
primary and non-specific targets of antibacterial an-
tibiotics, and analyzes the limited available evidence
regarding their ability to promote CS or eliminate se-
nescent cells in human and animal systems.
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CELLULAR SENESCENCE
Cellular aging (senescence) is defined as a sta-
ble cell cycle arrest accompanied by characteristic
phenotypic changes [4] (Fig. 1). CS is intimately in-
volved in the processes such as embryogenesis, tis-
sue regeneration, suppression of carcinogenesis, and
aging. As an antitumor mechanism, CS prevents pro-
liferation of the potentially cancerous cells. Activation
of the tumor suppressor pathways p53/p21CIP1 and
p16INK4A/pRB plays a central role in the development
of CS [5, 6].
Aging cells remain viable, but their metabolic
and transcriptomic activities change, and they devel-
op a complex secretory phenotype (senescence-asso-
ciated secretory phenotype, SASP). This phenotype is
characterized by the synthesis of cytokines and in-
flammatory mediators, proteases, and growth factors
(such as IL-1α, IL-1β, IL-6, IL-8, and MMP) [7]. Senes-
cent cells can be eliminated by immune cells, this
process contributes to the tissue remodeling and re-
generation. However, under certain conditions, aging
cells are not completely removed, which contributes
to the development of pathology [8]. Factors secreted
by the senescent cells can affect neighboring cells in
a paracrine manner and disturb normal tissue func-
tions.
Cellular aging occurs in response to various en-
dogenous and exogenous stimuli. There are two main
types of CS: replicative and stress-induced (Fig. 1).
In the replicative aging, a cell that has divided many
times with shortened telomeres loses its ability to
proliferate, leading to the complete halt in the cell
cycle [9]. The stress-induced aging is caused by a wide
range of factors, such as mitogenic signals, oncogene
activation, radiation, oxidative and genotoxic stress,
epigenetic changes, chromatin disorganization, proteo-
stasis disruption, mitochondrial dysfunction, inflam-
matory responses, tissue damage signals, chemothera-
peutic agents, and nutrient deprivation [10, 11]. Aging
caused by DNA damage is triggered by a wide range of
chemical compounds, as well as ionizing or UV radia-
tion. Depending on the intensity of DNA damage, the
cell may die by apoptosis or progress to CS [12]. More
than fifty compounds have been identified [13] that
induce cellular aging, with the specific mechanism
of cellular aging development varying for different
groups of substances.
The most important physiologically significant
signs of CS are increase in the cell size, increase in
the activity of senescence-associated β-galactosidase
(SA-β-gal), accumulation of autofluorescent granules,
and SASP [13] (Fig.1). The increased autofluorescence
and the SA-β-gal activity result from accumulation
Fig. 1. Main pathways of cellular senescence (CS) induction and characteristics of senescent cells. ROS, reactive oxygen
species; p53, p16Ink4a, p21CIP1, senescence protein markers; SA-β-Gal, senescence-associated beta-galactosidase; IL-1α,
interleukin-1α; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; MMPs, matrix metalloproteinases. Details are
provided in the text.
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ofthe excessive amounts of lysosomal components in
cells. To date, dozens of phenotypes of stress-induced
CS have been described, which partially overlap with
each other [14]. These aging states can differ signifi-
cantly from each other and from the phenotype of
replicative aging. At the same time, it is still unclear
whether the cell cycle arrest constitutes the “true”
CS. Essential characteristics of this “true” CS are also
undefined.
ANTIBIOTICS: CLASSIFICATION
AND MECHANISM OF ACTION
Antibiotics constitute a heterogeneous group of
compounds belonging to various classes of chemical
substances, each characterized by a unique structure
and mechanism of action. Functionally, they are gen-
erally categorized into two types: bacteriostatic an-
tibiotics, which inhibit growth and reproduction of
microorganisms, and bactericidal antibiotics, which
kill bacterial cells. Although the term antibiotics
originally referred exclusively to the substances of
natural origin, it is now used more broadly to in-
clude semi-synthetic and fully synthetic antimicrobi-
al agents [15]. Based on the spectrum of their activi-
ty, antibiotics may be classified as narrow-spectrum,
targeting specific groups of bacteria (e.g., vancomycin
against Gram-positive organisms), or broad-spectrum,
acting against a wide range of bacterial species (e.g.,
tetracyclines, cephalosporins). Furthermore, antibi-
otics can be categorized according to their chemical
structure into classes such as β-lactams, aminoglyco-
sides, macrolides, tetracyclines, phenicols, glycopep-
tides, polymyxins, lincosamides, fluoroquinolones,
and rifamycins, among others [16].
The primary targets of antibiotic action in bacte-
ria include synthesis of the cell wall, proteins, nucleic
acids, mycolic acids, and folic acid (Table 1) [15, 17].
The table also lists ionophores, such as monensin, la-
salocid, and salinomycin, which disrupt intracellular
ion homeostasis [18]. These ionophores are used in
veterinary medicine.
Several bacterial-derived compounds that are
also classified as antibiotics are widely used in can-
cer therapy. These include the anthracyclines (doxo-
rubicin, daunorubicin, epirubicin, and idarubicin),
as well as bleomycin, dactinomycin, and mitomycin.
Their anticancer activity is mediated through multi-
ple mechanisms, including: (i) DNA alkylation (e.g.,
certain anthracyclines); (ii) DNA intercalation (doxo-
rubicin, daunorubicin, actinomycin D); (iii) inhibition
of topoisomerase II (doxorubicin); (iv) induction of
DNA strand breaks (bleomycin) [19]. The resulting
DNA damage leads to cell cycle arrest and ultimately
to tumor cell death [20].
Table 1. Mechanism of action of the main groups of
antibiotics
Classification of antibiotics by mechanism of action
Cell wall synthesis
inhibitors
• penicillins
• cephalosporins
• glycopeptides
• β-lactamase inhibitors
• carbapenems
• β-lactams
• polypeptides
Protein synthesis
inhibitors
30S Subunit inhibitors
• aminoglycosides
• tetracyclines
50S Subunit inhibitors
• macrolides
• phenicols
• lincosamides
• oxazolidinone
• streptogramins
DNA synthesis
inhibitors
• fluoroquinolones
• 5-nitroimidazoles
Folic acid synthesis
inhibitors
• sulfonamides
Ionophores
that disrupt ion
conductivity
• carboxylic polyethers
• linear and cyclic peptides
NON-SPECIFIC TARGETS OF ANTIBIOTICS
Being small molecules (400-1200 Da), antibiotics
have good bioavailability and effectively block vital
bacterial functions in the tissues of the infected or-
ganism. On average, the low-molecular-weight com-
pounds can bind to 6-11 off-target molecules inside
the cell in addition to their primary target [21]. An-
tibiotics can cause side effects of varying severity,
which, according to the current data, are partly due
to their effect on the human microbiota and partly
to their interaction with non-specific cellular targets
[22]. Clinical aspects of antibiotic side effects have
been studied in great detail [1, 23], but nonspecific
intracellular interactions are only partially under-
stood.
As noted above, many antibiotic-associated side
effects arise from the evolutionary relationship be-
tween mitochondria and bacteria; mitochondria are
currently believed to have originated from the ancient
Alphaproteobacteria [2]. Consequently, numerous an-
tibiotics designed to target bacterial replication or
translation also exhibit varying degrees of mitochon-
drial toxicity (Table 2), although not all have been
experimentally shown to interact with nonspecific
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Table 2. Nonspecific mitochondrial targets of selected antibiotics and their associated side effects
Antibiotics
Potential antibiotic
target in mitochondria
Effect at the cellular level
Side effects at the
organismal level
References
Oxazolidinones 50S ribosomal subunit inhibition of megakaryocyte
maturation
thrombocytopenia,
anemia
[28]
reduced COX-II production
in PBMCs
hyperlactatemia [29]
mitochondrial dysfunction
in optic nerve cells
optic neuropathy [30, 31]
Lincosamides 50S ribosomal subunit neuronal apoptosis neurotoxicity [32]
Phenicols 50S ribosomal subunit decreased transferrin receptor
expression and ferritin synthesis
sideroblastic
anemia
[33]
disruption of mitochondrial
protein synthesis and
subsequent impairment
of erythroid cell development
aplastic anemia [34]
Macrolides 50S ribosomal subunit neuronal apoptosis neurotoxicity [32]
cardiomyocyte apoptosis cardiotoxicity [35]
hepatocyte oxidative stress hepatotoxicity [35, 36]
Aminoglycosides 30S ribosomal subunit disruption of mitochondrial
protein synthesis in cochlear
cells
ototoxicity [36, 37]
renal tubular cell mitochondrial
dysfunction
nephrotoxicity [38, 39]
Tetracyclines 30S ribosomal subunit mitochondrial dysfunction
and nerve cell death
neurotoxicity [32]
Fluoroquinolones gyrase/topoisomerase mitochondrial dysfunction
and oxidative stress in tenocytes
tendinopathy [40, 41]
oxidative stress in chondrocytes chondrotoxicity [42]
mitochondrial dysfunction
and oxidative stress
in Müller cells
retinopathy [43]
decreased GLUT1 expression dysglycemia [44]
Nitroimidazoles gyrase/topoisomerase ROS-independent neuronal death neurotoxicity [32]
mitochondrial targets [3]. Principal mechanisms un-
derlying this toxicity include inhibition of respiratory
chain complexes, uncoupling of oxidative phosphory-
lation, disruption of mitochondrial protein transport,
and suppression of key reactions within the tricar-
boxylic acid cycle [24]. Comprehensive discussions of
these nonspecific mitochondrial effects can be found
in several recent review articles [2, 25-27].
In particular, proteins of the mitochondrial 50S
ribosomal subunit display high degree of homology to
their bacterial counterparts, which explains why an-
tibiotics targeting the prokaryotic 50S subunit could
also impair mitochondrial translation [45]. Indeed, all
classes of antibiotics listed in Table 1 that act on the
50S subunit (except clindamycin) have been shown
to inhibit not only bacterial, but also mitochondrial
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protein synthesis [46-51]. For example, XL2, a mem-
ber of the oxazolidinone class, suppresses mitochon-
drial translation by binding to the same A-site on the
ribosome as it does in bacterial cells [52].
In addition to targeting the 50S subunit, some an-
tibiotics also act on the mitochondrial 30S ribosomal
subunit, thereby inhibiting mitochondrial translation.
Adverse effects of certain antibiotics appear to de-
pend on structural features of the mitochondrial 30S
subunit. For example, mutations in the mitochondrial
12S rRNA gene (1555A>G and 1494C>T) are associated
with the significantly increased risk of aminoglyco-
side-induced ototoxicity [53, 54]. These mutations are
thought to render the secondary structure of mito-
chondrial 12S rRNA, a component of the 30S subunit,
more similar to the corresponding region of the bac-
terial 16S rRNA, which constitutes a therapeutic tar-
get of aminoglycosides [37, 55, 56].
Doxycycline, a member of the tetracycline class,
induces a “mitonuclear imbalance” characterized by
disruption of the stoichiometric ratio between mito-
chondrial and nuclear genomes that encode electron
transport chain (ETC) proteins [57]. This imbalance
subsequently leads to mitochondrial fragmentation
and impaired respiratory function [57].
In addition to the impairing mitochondrial rep-
lication, fluoroquinolone antibiotics also disrupt mi-
tochondrial protein synthesis and decrease relative
amount of mitochondrial DNA (mtDNA) [58, 59]. Pro-
teomic analyses in the eukaryotic cell line HEK-293
have identified several additional intracellular tar-
gets of fluoroquinolones. Among these is NUDT1, an
enzyme involved in protecting cells from oxidative
stress by hydrolyzing oxidized nucleotides. Treatment
with ciprofloxacin or levofloxacin reduces NUDT1
levels, thereby lowering cellular resistance to the
fluoroquinolone-induced oxidative stress [60]. Sev-
eral mitochondrial proteins were also identified as
targets, including AIFM1 – a regulator of cell death
and a mediator of metabolite transport across the in-
ner mitochondrial membrane. Ciprofloxacin has been
shown to bind AIFM1, resulting in dysfunction of re-
spiratory chain complexes I and IV. Moreover, both
ciprofloxacin and levofloxacin inhibit IDH2 (isocitrate
dehydrogenase2), further contributing to ETC impair-
ment [60].
Antibiotics that do not target bacterial replication
or translation, such as vancomycin and ceftriaxone
(inhibitors of bacterial cell wall synthesis) also ex-
hibit nonspecific interactions within host tissues. For
example, vancomycin can bind to elastin, a structur-
al protein of the vessel wall, promoting formation of
vancomycin aggregates that exert toxic effects on the
endothelial cells [61]. Ceftriaxone, a cephalosporin
antibiotic, has been shown to interact with Aurora B
kinase, a key regulator of cell cycle and tumor pro-
gression. This unexpected interaction highlights the
potential for exploring anticancer properties of cef-
triaxones [62].
ANTIBIOTICS AND CELLULAR SENESCENCE
Antibiotics used in cancer therapy. As noted
above, several antibiotics are employed as antitumor
agents and, by definition, have the capacity to halt
the cell cycle and induce cellular senescence. These
compounds damage cellular DNA, activate the DNA
damage response, and generate oxidative stress, all
of which contribute to the onset and progression of
cellular senescence.
Anthracyclines form cleavable DNA complexes,
inhibit topoisomerase II activity, and induce oxidative
stress, collectively disrupting both transcription and
DNA replication [63]. They also trigger mitochondrial
dysfunction by inhibiting components of the respira-
tory chain, promoting mitochondrial iron accumula-
tion, and increasing production of reactive oxygen
species (ROS) [64]. Capacity of doxorubicin and other
anthracyclines to induce cellular senescence is well
documented; both their mitochondrial and genotoxic
effects, accompanied by oxidative stress, contribute
to this outcome [65, 66]. Notably, the doxorubicin-in-
duced senescence could proceed through mechanisms
that are either p53-dependent or p53-independent
[67]. Importantly, anthracyclines have been shown to
induce cellular senescence not only in vitro but also
in animal models [68, 69].
Bleomycin induces the genomic DNA strand
breaks [70] and promotes mitochondrial dysfunction,
both of which contribute to the development of cellu-
lar senescence [71]. It triggers a senescent phenotype
characterized by the increased numbers of SA-β-gal
positive cells, morphological alterations, elevated ly-
sosomal content, and reduced proliferative capacity
in the A549 lung adenocarcinoma cells, as well as in
the primary alveolar epithelial cells isolated from the
rats with bleomycin-induced pulmonary fibrosis [72].
In the lung tissue of these animals, elevated levels
of γH2AX-positive cells, activation of p21, and emer-
gence of SASP were also observed [73]. Furthermore,
two bleomycin derivatives, boanmycin and boningmy-
cin, have likewise been reported to induce cellular
senescence [74, 75].
Dactinomycin (actinomycin D), an inhibitor of
RNA synthesis in both prokaryotic and eukaryotic
cells, has been shown to induce cellular senescence
[76, 77]. In the human mesenchymal stem cells, dacti-
nomycin treatment leads to the increased SA-β-gal ac-
tivity and SASP development [77]. Senescence induc-
tion has also been observed in the OCI-AML3 acute
myeloid leukemia cells carrying the mutant form of
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NPM1 gene (NPM1c), where it is accompanied by mi-
tochondrial stress, including mitochondrial fragmen-
tation and elevated ROS production [76]. Moreover,
the conditioned medium from the dactinomycin-treat-
ed cells was found to reduce mitochondrial inner
membrane potential (ΔΨm) and increase ROS levels
in the recipient cells [78].
Mitomycin C induces formation of inter- and
intrastrand DNA crosslinks between guanine resi-
dues, thereby inhibiting both DNA replication and
transcription [79]. It also damages mtDNA [80], thus
contributing to mitochondrial dysfunction [81]. In
the human dermal fibroblasts, mitomycin C triggers
cellular senescence, characterized by the increased
SA-β-gal activity, cell-cycle arrest, development of the
senescence-associated secretory phenotype (SASP),
and elevated ROS levels [82]. In vivo, mitomycin C has
likewise been shown to induce cellular senescence,
as demonstrated in the rabbit trabeculectomy mod-
el [83].
The promising antitumor ionophore antibiotic sa-
linomycin, which also possesses antibacterial proper-
ties, not only induces DNA damage but also promotes
lysosomal iron accumulation and oxidative stress.
These effects lead to the cell-cycle arrest and devel-
opment of cellular senescence in the MDA-MB-231
breast cancer cells [84, 85]. Interestingly, despite its
pro-senescence activity, salinomycin is also capable
of inducing apoptosis in various human tumor cell
types, including MDA-MB-231 cells [84, 86, 87].
The relatively rare antitumor antibiotic lidamy-
cin also appears to induce cellular senescence. Treat-
ment of the BEL-7402 and MCF-7 cells, with lidamycin
leads to the increased cell size and higher propor-
tion of the SA-β-gal-positive cells [88]. Studies with
the BEL-7402 cells further demonstrate that lidamy-
cin could trigger senescence and mitotic catastrophe
either in parallel or sequentially [89]. Reduction in
the telomerase activity and decreased expression of
EZH2 are thought to play key roles in the lidamy-
cin-induced senescence [89, 90].
Antibacterial antibiotics. Influence of antibiot-
ics not traditionally used in cancer therapy on the
development of cellular senescence remains poorly
understood. Chloramphenicol, an inhibitor of both
bacterial and mitochondrial protein synthesis, has
been shown to suppress the mitomycin C-induced
apoptosis while increasing the p21 expression and
the number of SA-β-gal-positive cells [50]. Similar se-
nescence-promoting effects have been observed with
other protein synthesis inhibitors, including doxycy-
cline, clindamycin, and minocycline [50]. Cephalexin,
a cephalosporin antibiotic, does not induce senes-
cence on its own; however, it enhances senescence
in the cells exposed to ionizing radiation, indicating
potential radiosensitizing properties [91].
It can be hypothesized that antibiotics inducing
mitochondrial dysfunction could, under certain con-
ditions, promote the development of cellular senes-
cence (Fig. 2). Mitochondrial dysfunction is known to
trigger inflammatory responses through the release of
mitochondrial damage-associated molecular patterns
(DAMPs), including mitochondrial DNA, mitochondri-
al RNA, and N-formylmethionine-containing proteins
[92, 93]. Inflammation, in turn, is a well-established
driver of cellular senescence (Fig. 1). Moreover, mito-
chondrial dysfunction is almost invariably accompa-
nied by oxidative stress resulting from the impaired
redox processes [94, 95], which further contributes to
the senescence induction [96] (Figs. 1 and 2).
Antibiotics capable of inducing cellular senescence
include oxazolidinones, which impair mitochondrial
function, cause cell cycle arrest, and increase pro-
portion of the SA-β-gal-positive cells [97, 98]. Similar
to salinomycin, oxazolidinones could simultaneously
trigger both senescence and apoptosis, as demonstrat-
ed in the DU145 prostate cancer cells [98]. A recent
review [99] summarizes evidence supporting poten-
tial use of oxazolidinones and their derivatives as
antitumor agents. In addition, the bacteriostatic vet-
erinary antibiotics amoxicillin and chlortetracycline
have been shown to inhibit cell proliferation [100].
Incubation of glioblastoma cells with the fluoro-
quinolone ciprofloxacin induced CS. When exposure
was limited to 10 days, this senescent state was revers-
ible: after ciprofloxacin was removed from the medi-
um, the cells resumed proliferation after a 2-3-day lag
[101]. In contrast, treatment for 15 days or longer re-
sulted in irreversible senescence. Reversibility of the
ciprofloxacin-induced senescence was shown to de-
pend on RelA (p65), a subunit of the NF-κB complex
[101]. However, it remains unclear how ciprofloxacin
and other fluoroquinolones influence senescence in
non-tumor cell lines or in animal models.
Antibiotics as senolytics. Accumulation of se-
nescent cells is known to impair functions of organs
and tissues, in part due to the chronic inflammation
driven by SASP. The use of senolytics, agents that se-
lectively eliminate senescent cells, has been shown
to restore lost or compromised functions [102]. Se-
nolytics can be broadly divided into two major cate-
gories: the first targets pro-survival pathways in the
senescent cells, thereby promoting their apoptosis;
the second amplifies existing cellular stresses with-
in senescent cells, triggering in addition to apoptosis
alternative forms of cell death such as necrosis or
ferroptosis [102].
In addition to the well-established senolytics
such as combination of quercetin with dasatinib [103,
104], senolytic properties have also been found in
several antibiotics. Although the mechanisms under-
lying the senolytic activity of most antibiotics remain
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Fig. 2. Possible pathways of cell senescence induction by antibiotics. Abbreviations: ↓ΔΨm, decrease in mitochondrial trans-
membrane potential; ↓ATP, decrease in ATP level; ↑Ca
2+
, increase in calcium ion concentration; ROS, reactive oxygen species.
Details are given in the text.
largely unexplored, available evidence indicates that
these compounds fall into the second major catego-
ry of senolytics: they enhance pre-existing stresses
in the senescent cells, primarily through mitochon-
drial disruption and/or interference with autophagy
pathways.
The ionophore antibiotic nigericin has been
shown to exert a multifaceted senolytic effect by
depolarizing both the plasma membrane and the
inner mitochondrial membrane, promoting cytoplas-
mic acidification, and inhibiting autophagy. Together,
these disruptions destabilize cellular homeostasis and
ultimately lead to the death of senescent cells [105].
Notably, targeting any one of these processes individ-
ually was insufficient to produce a senolytic effect.
In the study using the A549 cell-based aging
model induced by alisertib and CFI-400945, addi-
tion of the ionophore salinomycin triggered mito-
chondrial dysfunction and oxidative stress, leading
to elimination of the SA-β-gal positive cells through
PANoptosis – a coordinated activation of pyroptosis,
apoptosis, and necroptosis [106]. Effects of salinomy-
cin resembled those observed upon knockdown of
the SLC25A23 gene encoding a mitochondrial carrier
protein that facilitates Ca
2+
uptake [106].
Senolytic activity has also been identified among
the macrolide antibiotics. Azithromycin and roxithro-
mycin were shown to exert senolytic effects in the
MRC5 and BJ fibroblasts in the bromodeoxyuridine-in-
duced senescence model, with azithromycin demon-
strating greater selectivity toward the senescent cells
[107]. This senolytic action appears to be mediated, at
least in part, by the induction of autophagy, although
azithromycin exhibited a concentration-dependent,
bidirectional influence on mitochondrial respiration.
Azithromycin also displayed senolytic properties in
the “aged” endometrial stromal cells isolated from
the patients with ovarian endometriosis [108]. Inter-
estingly, erythromycin showed no senolytic effect in
one study [107], yet demonstrated senolytic activity
in another, that used a hydrogen peroxide-induced se-
nescence model in the BEAS-2B epithelial cells [109].
Roxithromycin also exhibited senolytic effects in the
WI-38 lung fibroblasts in the bleomycin-induced se-
nescence model [110].
Several antibiotics that inhibit bacterial protein
synthesis have also demonstrated senolytic activity.
The veterinary antibiotic valnemulin, for example,
reduced proportion of the senescent cells in the in-
testinal tissue of mice with experimentally induced
ulcerative colitis [111]. Doxycycline, a member of
the tetracycline class, exhibited senolytic effects
in the mouse embryonic fibroblasts derived from
the Hutchinson–Gilford progeria mice model [112].
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Chloramphenicol was shown to prevent the 5-fluo-
rouracil-induced senescence by activating autophagy
[113]. Interestingly, however, another study reported
that both chloramphenicol and doxycycline increased
the number of SA-β-gal positive cells and elevated the
p21 protein levels, suggesting context-dependent ef-
fects on cellular senescence [50].
CONCLUSION
The ability of antitumor antibiotics to induce
stable cell-cycle arrest and cellular senescence both
in vitro and in vivo has long been recognized and is
supported by numerous experimental studies. A clas-
sic example is the anthracycline doxorubicin, which
induces persistent DNA damage, activates the p53/p21
signaling pathway, and triggers hallmark senescence
phenotypes such as SA-β-gal activity and SASP. The
doxorubicin-induced senescent cells have also been
shown to contribute to the late adverse effects of
chemotherapy [114].
Interestingly, the same or structurally similar
agents can exhibit opposing activities – promoting
senescence under some conditions while acting as
senolytics under others. A notable example is the
antibiotic salinomycin: several studies have shown
that it induces hallmark features of CS in tumor
cells (e.g., increased SA-β-gal activity and elevated
p21), whereas more recent findings demonstrate that
it can also function as a senolytic, triggering PANop-
tosis in the pre-existing senescent cells [84, 106]. This
context- dependent duality underscores complexity of
the antibiotic-mediated stress responses and suggests
potential for the two-stage cancer therapeutic strat-
egies in which the chemotherapy-induced tumor se-
nescent cells are subsequently cleared using senolyt-
ics [106].
Mechanistically, many antibiotics, particularly
bactericidal ones such as fluoroquinolones, amino-
glycosides, and certain β-lactams, exert mitotoxic ef-
fects on eukaryotic cells, leading to mtDNA damage,
impaired mitochondrial energy metabolism, and in-
creased ROS production [115]. These disturbances are
closely linked to activation of the cellular senescence
programs, suggesting that the antibiotic-induced mi-
totoxicity may underlie their pro-senescence side ef-
fects. However, prevalence and biological significance
of these effects in vivo remain poorly understood.
To date, there is virtually no direct evidence demon-
strating causal relationship between the antibiotic
exposure and accumulation of the senescent cells in
human tissues.
These knowledge gaps carry important clinical
implications. Long-term side effects of antibiotic use
(persistent changes in the microbiota, metabolic and
immune shifts, musculoskeletal risks, etc.) have been
well documented in both epidemiological and exper-
imental studies. It is plausible that some of these
lasting consequences may, in part, stem from the
antibiotic-induced cellular senescence in critical cell
populations, including fibroblasts, endothelial cells,
and other mesenchymal-derived cells. This hypothesis
warrants further focused investigation.
Taken together, the evidence suggests that al-
most all antibiotics exhibiting pronounced mitotox-
icity or capacity to induce DNA stress in eukaryotic
cells may, under certain conditions, such as specific
dosages, exposure durations, cellular targets, and mi-
croenvironmental contexts, influence cellular aging
processes. This highlights several important direc-
tions for systematic investigation: (i) comprehensive
screening of antibiotic molecules for pro-senescence
and senolytic activities across the diverse primary
and tissue-specific cellular models; (ii) determina-
tion of threshold concentrations and temporal win-
dows at which the pro-senescence effects transition
into overt cytotoxicity; (iii) in vivo studies aimed at
detecting and mapping senescent cell accumulation
following clinically relevant antibiotic regimens; and
(iv) assessment of the contribution of antibiotic-in-
duced cellular senescence to the long-term clinical
outcomes, as well as exploration of whether these
effects could be mitigated using senomorphics or
senolytics.
Convergence of the experimental evidence on mi-
totoxic and pro-senescence effects of multiple antibi-
otics with clinical observations of long-term adverse
outcomes provides a strong rationale for the targeted
investigations into the role of cellular senescence in
antibiotic toxicity. Systematic examination of this is-
sue would not only deepen our understanding of the
fundamental mechanisms underlying antibiotic-asso-
ciated side effects but could also open new strategies
for their prevention and treatment. Such efforts may
ultimately support the design of combination ap-
proaches “antibiotic + senolytics/senomorphics”, when
it is safe and supported by evidence.
Abbreviations
CS cellular senescence
IL interleukin
ROS reactive oxygen species
SA-β-gal senescence-associated beta-galactosi-
dase
SASP senescence-associated secretory phe-
notype
Acknowledgments
The authors would like to thank Evgeniy Sergeevich
Egorov for inspiration, supply of information, and in-
valuable help in the work.
ANTIBIOTICS AND CELLULAR SENESCENCE 1891
BIOCHEMISTRY (Moscow) Vol. 90 No. 12 2025
Contributions
R. A. Zinovkin – concept of the paper and writing the
text. N. D. Kondratenko – writing and editing of the
text.
Funding
The work was financially supported by Russian Sci-
ence Foundation (project no.25-24-00307).
Ethics approval and consent to participate
This work does not contain any studies involving hu-
man and animal subjects.
Conflict of interest
The authors of this work declare that they have
noconflicts of interest.
Open access
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