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Targeting senescent cells: Approaches, opportunities, challenges


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Cellular senescence is a hallmark of aging, whose onset is linked to a series of both cell and non-cell autonomous processes, leading to several consequences for the organism. To date, several senescence routes have been identified, which play a fundamental role in development, tumor suppression and aging, among other processes. The positive and/or negative effects of senescent cells are directly related to the time that they remain in the organism. Short-term (acute) senescent cells are associated with positive effects; once they have executed their actions, immune cells are recruited to remove them. In contrast, long-term (chronic) senescent cells are associated with disease; they secrete pro-inflammatory and pro-tumorigenic factors in a state known as senescence-associated secretory phenotype (SASP). In recent years, cellular senescence has become the center of attention for the treatment of aging-related diseases. Current therapies are focused on elimination of senescent cell functions in three main ways: i) use of senolytics; ii) inhibition of SASP; and iii) improvement of immune system functions against senescent cells (immunosurveillance). In addition, some anti-cancer therapies are based on the induction of senescence in tumor cells. However, these senescent-like cancer cells must be subsequently cleared to avoid a chronic pro-tumorigenic state. Here is a summary of different scenarios, depending on the therapy used, with a discussion of the pros and cons of each scenario.
Content may be subject to copyright. 12844 AGING
Cellular senescence is a stress response mechanism
induced by different types of insults such as telomere
attrition, DNA damage, and oncogenic mutations,
among others [1]. First described in cultured human
diploid fibroblasts after successive rounds of division
[2], its main hallmarks are irreversible growth arrest,
alterations of cell size and morphology, increased
lysosomal activity, expression of anti-proliferative
proteins, resistance to apoptosis, activation of damage-
sensing signaling routes. Another important
characteristic is the regulated secretion of interleukins
(ILs), inflammatory factors, termed the senescence-
associated secretory phenotype (SASP) [3].
As there is ample evidence placing senescent cells as
one of the causes of age-related dysfunctions, it has
been considered to be one of the hallmarks of aging [4].
It was recently demonstrated that elimination of
senescent cells by genetic or pharmacological
approaches delays the onset of aging-related diseases,
such as cancer, neurodegenerative disorders or cardio-
vascular diseases, among others, showing that the
chronic presence of these cells is not essential [5–7].
Conversely, local injections of senescent cells drive
aging-related diseases [8, 9]. This data, together with
that obtained from tissues of patients with different
diseases and ages, has established causality of senescent
cells in some aging-related pathologies [10, 11].
Current therapies targeting senescent cells are focused
on: i) specific killing of these cells by senolytics; ii)
specific inhibition of the secretory phenotype (anti-
SASP strategy); and iii) improving clearance of
senescent cells by the immune system [12]. In addition,
currently available senescence-inducing therapies for AGING 2019, Vol. 11, No. 24
Targeting senescent cells: approaches, opportunities, challenges
Cayetano von Kobbe
Centro de Biología Molecular “Severo Ochoa” (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC),
Universidad Autónoma de Madrid, Madrid
28049, Spain
to: Cayetano von Kobbe; email:
: cellular senescence, senolytics, senomorphics, immunosurveillance, anti-aging therapies
September 27, 2019 Accepted: November 20, 2019 Published: November 30, 2019
von Kobbe. This is an open-access article distributed under the terms of the Creative Commons Attribution
BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author
are credited.
senescence is a hallmark of aging, whose onset is linked to a series of both cell and non-cell
leading to several consequences for the organism. To date, several senescence routes have
which play a fundamental role in development, tumor suppression and aging, among other
positive and/or negative effects of senescent cells are directly related to the time that they remain in
Short-term (acute) senescent cells are associated with positive effects; once they have executed
immune cells are recruited to remove them. In contrast, long-term (chronic) senescent cells
with disease; they secrete pro-inflammatory and pro-tumorigenic factors in a state known
-associated secretory phenotype (SASP). In recent years, cellular senescence has become the center
for the treatment of aging-related diseases. Current therapies are focused on elimination of
functions in three main ways: i) use of senolytics; ii) inhibition of SASP; and iii) improvement of
functions against senescent cells (immunosurveillance). In addition, some anti-cancer therapies are
the induction of senescence in tumor cells. However, these senescent-like cancer cells must be
to avoid a chronic pro-tumorigenic state. Here is a summary of different scenarios, depending on
therapy used, with a discussion of the pros and cons of each scenario. 12845 AGING
cancer stop tumor growth while causing accumulation
of senescent cells [13, 14], which subsequently become
a problem for the organism [15].
This review will summarize the hypothetical scenarios
that each anti-cell senescence approach (described
above) could face, either alone or in combination, with
a discussion of open questions that should be kept in
mind when targeting senescent cells.
Triggers of cell senescence
The onset of senescence in healthy tissue occurs in
response to different internal and external stimuli, such
as telomere attrition, DNA damage (alkylating agents,
radiation), oncogene activation, mitochondrial
dysfunction, and spindle, epigenetic, endoplasmic
reticulum (ER) and proteotoxic stress [16–19]. The
type and duration of the stimulus dictates the final
effect on the senescent cells [20]. These cells display
a characteristic phenotype comprising specific
cell/nuclear morphology (increased size, abnormal
shape and nuclear envelope changes), apoptosis
resistance, chromatin redistribution (senescence-
associated heterochromatin foci and senescence-
associated distension of satellites), epigenetic markers
(e.g. H3K9Me3), lipofuscin accumulation, SASP, and
overexpression of proteins such as p53, p16Ink4a,
p21WAF1, Differentiated Embryo Chondrocyte-expressed
gene 1 (DEC1) and senescence-associated β-Gal (SA-β-
Gal) [13, 21–24]. To date there is no universal marker
for senescence, and identification of senescent cells is
based on the combined detection of two or more
phenotypic aspects mentioned above, such as SA-β-Gal,
p16Ink4a or p21WAF1 [10].
One of the characteristic phenotypic hallmarks of cell
senescence is the secretion of a plethora of factors that
affect their environment (SASP), which also serves as
a call for the immune system to recognize and
eliminate the senescent cells [3, 25]. Among the SASP
factors that seem responsible for attraction of immune
cells are CSF (colony stimulating factor 1), CXCL-1
(chemokine C-X-C motif ligand 1), MCP-1 (monocyte
chemoattractant protein 1) and ICAM-1 (intercellular
adhesion molecule 1) [25]. In this scenario of acute or
short-term senescence, the tissue returns to normal
after a regeneration process [17] (Figure 1, steps 1-4).
The regeneration is a fundamental process to avoid
tissue atrophy and dysfunction. In this scenario of
replacement of senescent cells, we should keep in
mind the different capacity of renewal of some
tissues with respect to others, and the exhausted or
damaged state of stem cells that can lead to
functionally compromised differentiated cells or
carcinogenesis [26].
Implication of cell senescence in disease
Acute senescent cells play a direct role in tumor
suppression, efficient wound healing, embryogenesis,
placental formation, and tissue regeneration, among other
processes [17]. At this point, both their onset and primary
effect are positive for the organism [17, 20].
When senescence-inducing stimuli persist and decrease
the ability of the immune system to recognize and
eliminate senescent cells (by either immunosenescence
or immunosuppression), these cells accumulate. The
continual presence of senescent cells negatively affects
their environment, inducing damage, instability or
senescence in other cells through SASP [1, 27]. Over
time, these “secondary” damaged cells can become
either pro-tumorigenic or senescent, which increases the
cellular instability of the tissue, leading to dysfunction
and disease [27] (Figure 1, steps 5 and 6). In this sense,
some SASP factors play a direct role in fibroblast
activation and uncontrolled fibrotic scarring [28].
Chronic senescent cells (also termed “zombie” cells)
have been associated with the onset of several diseases
[1, 10, 13, 17]. In the last few years there have been
extensive studies to elucidate the causative role of
senescence in the onset of different pathologies [17].
These studies were mainly based on: i) detection of
senescent cells in tissues/organs from patients or animal
models; or ii) improvement in tissue/organ functions
upon removal of senescent cells in mice, by either
genetic or pharmacological interventions. This is a list
of some age-related diseases where cellular senescence
seems to play an important role:
Aging is the main cause of cancer [29], and the
presence of senescent cells in aged tissues or xenograft
models correlates with the incidence of cancer [30,
31]. Their specific removal led to a delay in tumor
formation and reduced metastasis [6]. It is also
important to note that both senolytics and senomorphics
are currently being used in clinical trials for the
treatment of numerous types of cancer, such as leukeia,
lung cancer, melanoma and glioblastoma, among others
Neurodegenerative disorders
Senescent cell accumulation has been detected at sites of
brain pathology [7, 32, 33]. The presence of senescent
astrocytes correlates with the onset of pathologies such as
Parkinson’s and Alzheimer’s disease [34]. Interestingly,
Tau protein induces cellular senescence in neurons, and
specific clearance of senescent astrocytes and microglia, 12846 AGING
reduced Tau-containing neurofibrillary tangle, neuron loss
and ventricular enlargement [7, 8]. Moreover, it has been
proposed a role of senescent cells in multiple sclerosis
Cardiovascular disease
Senescent cells play a key role in atherosclerosis, and
their specific removal reduced progression of the
disease [35]. Moreover, senescent macrophages seem to
contribute to coronary heart disease, and cell senescence
in the aorta increases vascular stiffness [13].
This degenerative disease causes the joints to become
painful and stiff, and accumulation of senescent cells
correlates with its progression [36]. In mouse models,
local injections of these cells induce an osteoarthritis-
like condition [9], whereas their clearance improves
health by attenuating development of post-traumatic
osteoarthritis [37].
Type 2 diabetes
Aging is the main cause of type 2 diabetes, and there is
association between disease progression and detection
of senescent markers. Senescent β-cells affect glucose
homeostasis, although further work is needed to
elucidate the exact role of senescence [20, 38, 39].
Kidney-related diseases
Diseases such as glomerulosclerosis and nephropathies
are associated with an increase of senescent cells [10].
Remarkably, when these cells were removed by genetic
approaches, kidney functions improved [6].
Idiopathic pulmonary fibrosis (IPF)
This chronic lung disease results in scarring, affecting
primarily older adults. Tissues from IPF patients
display some phenotypical characteristics of senescent
cells, and when these cells were removed by
senolytics, pulmonary functions improved [104].
In this disease adipocyte differentiation is disrupted by
senescent cells, causing weight loss, muscle wasting
and loss of body fat, leading to metabolic dysfunction
and loss of adaptive thermogenic capacity [10]. When
senescent cells were removed, tissue homeostasis
recovered [6, 75].
Figure 1. The onset of cellular senescence in normal tissue takes place in response to different stimuli (1). Some SASP factors are involved in
immune cell recruitment, which act in the clearance of the senescent cells (2). Then, to restore the normal tissue, a regeneration process is
necessary (3, 4). When a combination of persistent damage and immune system decay occurs, senescent cells accumulate, creating a pro- 12847 AGING
inflammatory and pro-tumorigenic environment and fibrotic tissue. Over time, this leads to disease, such as cancer progression, insulin
resistance, osteoarthritis, atherosclerosis, and brain pathologies, among others (5, 6). 12848 AGING
Characterized by opacity of the lens of the eye [109],
the lens capsules from patients suffering cataracts show
accumulation of senescent human lens epithelial cells
[105]. Removal of these cells by genetic approaches
decreased the incidence of cataracts in old mice [6].
Liver diseases
The presence of senescent cells correlates with the onset
of liver fibrosis, cirrhosis and non-alcoholic fatty liver
disease. Elimination of these cells reduced liver fat
accumulation [10, 106].
Metabolic syndrome
A collection of metabolic disorders such as increased
blood pressure, high blood sugar, excess body fat
(around the waist) and abnormal cholesterol levels.
Endothelial cell senescence is involved in systemic
metabolic dysfunction and glucose intolerance [13,
Erectile dysfunction
The presence of senescent cells is directly related to
endothelial dysfunction. SASP factors seem mediate
this effect, and importantly, removal of senescent cells
led to improvement of erectile function in mice [40].
Altogether, this data highlights the importance of
targeting these cells in order to delay or cure different
An option to eliminate the negative effects of chronic
senescent cells is to kill them specifically, using
compounds called senolytics (Figure 2), which target
pathways activated in senescent cells [16]. The list of
these senolytic tool compounds is extensive and
continuously growing. In Table 1 are shown the
noteworthy ones. Chronic/periodic administration of
senolytics kills senescent cells that are generated in the
tissues, and the immune system is responsible for
clearing apoptotic bodies for subsequent regeneration
with new cells (Figure 2, steps 1-3). Senolytics target
key proteins mainly involved in apoptosis, such as Bcl-
2, Bcl-XL, p53, p21, PI3K, AKT, FOXO4 and p53. See
Table 1 for references.
Although senolytics are supposed to be specific for
senescent cells, there are always unwanted damage/side
Figure 2. Treatment with senolytics to specifically kill senescent cells (1). Over time, these apoptotic bodies will be cleared by the immune
system (2). Finally, a regenerative process will lead to normal tissue functions (3). Normal cells could be affected by either the lack of
specificity of the senolytics or chronic treatment, leading to tissue dysfunction (4). 12849 AGING
Table 1. List of senolytics and their targets.
Dasatinib (D)
Inhibitor EFNB*-dependent suppression of apoptosis
Quercetin (Q)
PI3K/AKT, BCL-2, p53, p21, Serpine
ABT 737
BCL-W and BCL-XL inhibitor
ABT 263 (Navitoclax; UBX0101)
BCL-2, BCL-XL and BCL-W inhibitors
A1331852, A1155463
FOXO4-related peptide (DRI)
Inhibitor of FOXO4-p53 interaction
Delivery options**
Gal-encapsulated cytotoxics
*AKT; protein kinase B. BCL; B-cell lymphoma. EFNB; ephrin ligand B. FOXO; forkhead box proteins O. PI3K;
phosphatidylinositol 3-kinase. ROS; reactive oxygen species.
**It helps improve senolysis by directed targeting.
effects since the administration is not directed [41]
(Figure 2, step 4). In this regard, a new strategy has
been recently described to specifically target senescent
cells in mice, using nanocapsules containing toxins (or
senolytics) [42]. The outer layer of these nanocapsules
are composed of substrates for enzymes that are
overexpressed in senescent cells. In this way, the toxin
(senolytic) will only be released inside senescent cells,
killing them [42]. Thus, these nanocapsules are a
vehicle to specifically deliver any type of senolytic into
senescent cells in mice. The specificity of the delivery is
important in non-targeted senolytics (natural product
derivatives with less defined biological activities), such
as quercetin and fisetin.
Though there have been numerous reports showing the
benefits of senolytics, it is important to highlight the
recently described effects of dasatinib + quercetin (D + Q)
treatment on lifespan in old animals [43]. Transplant of
senescent cells into healthy mice caused physical
dysfunction, which was reversed by oral administration of
D + Q [43]. Also, clearance of senescent neurons
improved neurological functions in transgenic mice
mimicking Tau aggregation-dependent neurodegenerative
disease [8]. It is also important to note that the treatment
with the peptide FOXO4-DRI restored renal functions in
both old (normal) mice and mice with accelerated aging
[44]. As indicated above, some senolytics are currently
being used in clinical trials for treating different diseases
[16]. In this sense it is important to mention that MDM2
inhibitors, targeting p53, are also in clinical phases as
anti-cancer therapies [45].
Remaining questions
There is reasonable doubt about the fate of the dead
senescent cells, especially when the immune system of
the patient is depressed (by either immunosenescence or
immunosuppression). The accumulation of these
apoptotic bodies may have undesired side effects (i.e.
further release pro-inflammatory factors in an already-
damaged tissue) [10]. Also, as indicated before, the
possible side effects of periodic/chronic treatments
should not be ignored. In fact, toxic effects after systemic
administration of BCL family inhibitors have been
described in patients, such as thrombocytopenia and
neutropenia [41]. It would be desirable that treatments
with senolytics are as sporadic as possible, without
affecting efficacy. Lastly, and as indicated above, the
regeneration process is an important issue to be analyzed
in the tissues where senescence clearance has taken
SASP inhibitors (or senomorphics)
Another strategy to inhibit the functions of senescent cells
is through the specific silencing of SASP [16, 46], the
complex mixture of soluble factors such as cytokines,
chemokines, growth factors, proteases and angiogenic
factors that mediates the paracrine and autocrine functions
of senescent cells [3, 25] (Figure 3). The qualitative and
quantitative composition of this secretome is different
depending on the cell type and the senescence-inducing
stimulus, and becomes fully active a few days after the
persistent stimulus [3, 47, 48]. Senomorphics inhibit
SASP functions by targeting pathways such as p38
mitogen-activated protein kinase (MAPK), NF-κB, IL-1α,
mTOR and PI3K/AKT (Table 2), which act at the level of
transcription, translation or mRNA stabilization [21].
Alternatively, inhibition may be achieved by specific
neutralizing antibodies against individual SASP factors
(protein function inhibition), as is the case for IL-1α, IL-8
and IL-6. 12850 AGING
As IL- plays a direct role in SASP regulation,
targeting either the receptor (IL-1αR) or the ligand (IL-
1α) leads to decreased global SASP expression, with
special emphasis on oncogene-induced senescence
(OIS) [49, 50].
Importantly, the MABp1 antibody (neutralizing anti-
human IL- monoclonal) has proven efficient in
clinical trials against type 2 diabetes, sarcopenia and
inflammation [56–58], diseases in which senescent cells
play an important causative role [10].
IL-8 is a member of the CXC motif chemokine
upregulated in SASP, and is associated with some types
of cancer [50]. ABX-IL-8 is a humanized monoclonal
antibody against IL-8 that acts as an antagonist,
impairing IL-8 signaling. Treatment with ABX-IL-8
attenuates the growth of some cancer xenografts
models [59].
IL-6 is a pleiotropic cytokine also upregulated in SASP
that is involved in tumor proliferation, invasion and
immunosuppression. Specific inhibition of IL-6 by a
neutralizing monoclonal antibody (Mab-IL-6.8)
completely abolished JAK/STAT signaling [50, 77] and
relieved symptoms of arthritis in a primate model
(Olokizumab) [78]. Arthritis has also been causally
associated with the presence of senescent cells [37].
Finally, SASP-silenced/attenuated senescent cells should
be recognized by the immune system for subsequent
clearance and regeneration (Figure 3, steps 2 and 3).
Remaining questions
One doubt about this strategy is how SASP-
silenced/attenuated senescent cells would be cleared.
Given that some SASP factors are involved in the
recruitment of immune cells, SASP inhibition could
make senescent cells effectively “invisible” to the
immune system, therefore remaining chronically within
the tissue. In fact, two senomorphics (apigenin and
kaempferol) showed inhibition in cultured cells of SASP
components involved in immune cell recruitment, such as
CXCL-1 and CSF [65]. What would the influence of
SASP-silenced senescent cells be in the tissue? Perhaps
instead of being dysfunctional, the tissue would be non-
Likewise, as senomorphics require chronic/continuous
treatment, a major problem of these types of SASP
inhibitors is the lack of specificity for senescent cells.
Perhaps inhibition of individual SASP components by
neutralizing antibodies (as described above) would
minimize the potential side effects. As indicated for
senolytics, it would be desirable if over time, the
treatments with senomorphics were as sporadic as
possible without affecting efficacy.
Figure 3. Treatment with senomorphics to inhibit SASP factors in senescent cells (1). Over time, these cells will be removed by immune cells
(2). Finally, a regenerative process will lead to normal tissue functions (3). In aged or immunosuppressed individuals, this strategy would lead
to an accumulation of SASP-silenced/attenuated senescent cells (4). 12851 AGING
Table 2. List of senomorphics and their targets.
SASP inhibitor
SB 203580
p38 MAPK** inhibitor
([60] Reviewed by [12])
UR-135756, BIRB 796
p38 MAPK inhibitor
NF-ƙB inhibitor (IĸB-kinase inhibitor), AMPK and
SIRT1 activator, others
Apigenin, Wogonin, Kaempferol
NF-ƙB inhibitors (IĸB-zeta)
Inhibition of IKK/NF-ƙB, mitochondrial electron
tranport, mitochondrial GPDH, and KDM6A/UTX,
AMPK activator, others
IL-1α/NF-ƙB pathway inhibitors
ROS (free radical scavenger)
mTOR inhibitor, membrane-bound IL-1A translation
inhibition, prelamin A, 53BP1
[73] [74] [110]
Inhibition of JAK1/2 and ROCK
[75, 76]
*For many of the SASP inhibitors listed there have been described several targets.
**53BP1; p53 binding protein 1. AMPK; AMP-activated protein kinase. IKK; IĸB kinase. JAK; Janus kinase. KDM6A/UTX; lysine
demethylase 6A. MAPK; mitogen-activated protein kinase. mTOR; mammalian target of rapamycin. NDGA;
nordihydroguaiaretic acid. NF-ƙB; nuclear factor kappa light chain enhancer of activated B cells. ROS; reactive oxygen species.
Improving immune system function
A third strategy to target senescent cells is to strengthen
the immune system for efficient recognition and
elimination of these cells, a process termed immuno-
surveillance (Figure 4, steps 1-3). The role of the
immune system in the elimination of senescent cells is
fundamental, and a decline in immune function is
associated with an increase in the number of senescent
cells and finally, disease (Figure 4, step 4) [12, 20, 79,
In this regard, there are two strategies: i) improving the
specific anti-senescent cell functions; and ii) general
enhancement of immune functions (to avoid senescence
of immune cells involved in recognition of senescent
Anti-senescent cell functions have been described in NK
cells, macrophages and CD4+ T cells [20, 81]. Since these
functions take place through membrane receptors, one
option is to increase the binding affinity of the involved
receptors. In this sense, the use of chimeric antigen
receptor (CAR) T cells to target specific senescent-related
molecules would be an attractive approach. This strategy
is currently showing extraordinary results as anti-cancer
therapy [82]. Alternatively, specifically increasing the
surface expression of these receptors in senescent cells
could be attempted. NK cells recognize the CD58/ICAM1
receptor present in senescent cells [83]. In the case of
macrophages this recognition is not clear, and may occur
through modified membrane receptors in senescent cells
(glycans, lipids or vimentin), recognized by receptors
present in macrophages such as CD36, IgM, SIRPα, and
leptins. For T cells this process would be mainly mediated
by TCRs [84].
Another possibility is to reduce the number of senescent
immune cells, perhaps by depletion using specific
antibodies recognizing surface markers of senescence,
and in this way “rejuvenate” the immune system [84].
In this sense the recent identification of a targetable
senescent cell surface marker supports this strategy
NK and T cell functions decrease in older individuals.
The constitutive activation of the nutrient-sensing
component adenosine 5´-monophosphate-activated
protein kinase (AMPK) seems to play a central role in
this process [86]. Thus, an alternative approach to
increase functions of these immune cells is to target
AMPK functions, as the p38 MAPK inhibitor does [87].
Another approach would be to inhibit the killer cell
lectin-like receptor G1 (KLRG1, or CD57 in humans),
which increases on NK and T cells of older individuals.
Activation of KLRG1 in NK cells is associated with
activation of AMPK (via protein stabilization), which in
turn would inhibit cell functions. In the case of CD8+ T
cells, this mechanism may involve other inhibitory
receptors, such as programmed death 1 (PD-1) and
cytotoxic T lymphocyte antigen 4 (CTLA-4) [86].
The down-regulation of the CD28 receptor is a hallmark
of human CD8+ T cell senescence. Interestingly these 12852 AGING
senescent T cells have been found not only in old
individuals (aging process), but also associated to
diseases such as cancer and arthrosis [83], which are
aging-related diseases where senescent cells seem to
play a causative role, as discussed above.
This fact reinforces the idea of a pivotal role of immune
cells by delaying the onset of diseases related to the
accumulation of chronic senescent cells. In this regard, a
recent article shows that mice lacking the main cytotoxic
functions of NK and T cells (perforin pathway),
accelerates both senescent cell burden and aging [80].
Some current anti-cancer therapies are based on
immunotherapy, that stimulates the immune system to
recognize and kill disease-associated cells based on
differences in the expression of antigens between
pathogenic and normal cells [88]. Immunotherapy is
currently used not only for different types of cancer, but
also for infectious diseases, Alzheimer’s disease, and
even some types of addictions [89, 90]. Senescent cells
display a characteristic phenotype, which make them
suitable targets for this strategy. Cell and antibody
mediated responses are possible approaches, however,
the specificity of senescent antigens would be the
bottleneck to avoid undesirable side effects [108].
Remaining questions
Improving immune system functions to target senescent
cells could be difficult in scenarios such as immuno-
senescence (in older individuals or patients suffering
from premature aging of the immune system [91]) or
immunosuppression (i.e. patients treated with
corticosteroids or radiation, in cases of organ transplant,
autoimmune disease or cancer). CAR-based strategies
and immune system “rejuvenation” would be
personalized treatments, and thus very time consuming
and expensive. These strategies would rely on specific
(universal) senescence receptors, and a limiting factor
when detecting cell senescence is the lack of universal
markers [13]. Although novel technologies are making
detection of senescent cells in tissues more reliable [92,
93], the use of a combination of different biomarkers is
still necessary for confirmation. Thus, personalized
treatment targeting at least 2 senescence markers would
increase the challenge and difficulty of the process.
Moreover, the described connection between NK and T
cell activation and nutrient-sensing machinery suggests
that dietary interventions could be a promising approach
to maintain a healthy immune system in older
individuals, and thus the ability to efficiently clear
senescent cells. The up-regulation of CD28 (by forced
Figure 4. Improving immune system functions to efficiently remove senescent cells (1). A robust immune system targets senescent cells,
leading to their removal (2). Then a regenerative process will maintain normal tissue functions (3). In situations where the immune system
decays (e.g. immunosenescence or immunodepression), there will be an accumulation of senescent cells, increasing instability in the
tissue/organ (4). 12853 AGING
expression of either the receptor itself or other receptor
related to T cell activation) could be another attractive
approach to delay the senescence process in CD8+ T
cells. Last, but not least, it is important to keep in mind
that a general stimulation of the components of the
immune system might also induce autoimmune diseases
or may also promote some hematopoietic malignancies
[94, 95].
Targeting senescent cancer cells
A way to stop cancer progression is to induce
senescence in tumor cells (TIS; therapy-induced
senescence), through treatments targeting key pathways
activated in highly proliferative cells. These treatments
include DNA damage inducers (e.g. mitoxantrone,
doxorubicin, γ-radiation), and inhibitors of Aurora
kinase A (i.e. MLN8054, alisertib) and CDK4/6
(abemaciclib, palbociclib, ribociclib), among others [14,
96–98]. While stopping tumor growth, TIS becomes a
problem for the organism in the long-term, as cancer
survivors have a higher incidence of age-related
diseases linked to senescence, including cardiovascular
disease, neurodegeneration, sarcopenia and secondary
neoplasia [19]. Cancer cells that escape from TIS (or
“senescence-like” cancer cells) display some features,
such as polyploidy, stemness and aggressiveness. It has
been calculated that only 1 in 106 of senescent cancer
cells escape from TIS. Although it seems to be a rare
event, it occurs [99, 100].
At this point, it is conceivable to imagine a tissue that is
already damaged, not only by tumor cells but also a mix
of pre-tumorigenic and senescent cells, together with
fibrosis and SASP (Figure 5). The newly senescent cells
(from the tumor; TIS) would increase the level of SASP
in the tissue, leading to: i) growth of new tumors (or
sprouts of the former); ii) senescence induction in
neighboring cells; as well as iii) an increase in fibrotic
tissue. This scenario would lead to an exacerbation of
the pathology that was described in the starting point
(step 3).
One solution to this situation would be to combine TIS
(effective therapy to stop the growth of the tumor that is
already present) with one or more of the three anti-
senescent strategies presented above (senolytics,
senomorphics and improved immune function) (Figure
5). Then clearance and tissue renewal processes will be
necessary to restore tissue functions (Figure 5, step 4).
Figure 5. Inducing senescence in tumor cells will lead to an accumulation of senescence burden (1). The pro-inflammatory and pro-
tumorigenic environment (more SASP factors) leads to exacerbation of the pathology (e.g. cancer relapse, fibrosis, inflammation) (2, 3). By
targeting senescent cells with a combination of the approaches currently used, a better final scenario is possible (4). Fibrotic scarring may be
treated by other means, or cured over time. 12854 AGING
Table 3. Comparison of the therapies presented in this review.
High specificity
- Targeted drugs
Sporadic treatments
- Depending on compound efficacy
Low specificity
- Non-targeted compounds
Side effects
- BCL family inhibitors
Increase in apoptotic bodies
Chronic treatments
- Depending on compound efficacy
High specificity
- Targeting individual SASP
Sporadic treatments
- Depending on compound efficacy
Low specificity
- Targeting central pathways
Chronic treatments
- Depending on compound efficacy
Lack of senescent cell clearance?
Side effects
Improving immune
High specificity
- Personalized treatments
- Immunotherapy
Sporadic treatments
Dietary interventions
Time consuming and expensive
- Personalized treatments
Low specificity
- General activation
Side effects
- Autoimmunity?
- Hematopoietic malignancies?
Chronic treatments
Patients affected by immunosuppression and/or
High specificity
- Specific targets
Sporadic treatments
Stops tumor growth
Possibility to combine with other therapies
Low specificity
- General damage (chemo-radiotherapies)
Side effects
- New tumors
- Fibrosis
Chronic treatments
Increasing senescence burden
Remaining questions
Importantly these therapies would rely on the state of the
patient´s immune system, and many patients have been
affected by treatments they have received previously
(immunosuppression), or by age (immunosenescence). In
this sense, it is likely that in some cases it would only be
necessary to inhibit SASP and not specifically induce
death of the senescent cells, to avoid depending on the
immune system for removal of apoptotic bodies.
And what about fibrosis? Fibrotic scarring can resolve
over time, being replaced by new tissue. However, if
this process is not completed (e.g. older people), the
normal function of key organs can be compromised.
Thus, alternative therapies should be kept in mind to
treat senescence-associated fibrosis [101].
Targeting senescent cells has become an alternative
therapy for treating different aging-related diseases.
This therapy can be approached on three levels: i)
specific killing of these cells; ii) inhibition of their
secretory phenotype, therefore making them less
efficient; and iii) improving our immune system for
elimination of senescent cells.
The use of senolytics and senomorphics are showing
promising results, although is still too early to draw
conclusions. It is necessary to improve the specificity of
these compounds, as well as optimize the treatment (i.e.
dosage) to avoid unwanted effects. In this sense, progress
has been made on the specific delivery of drugs into
senescent cells by using nanocapsules. This elegant
approach may overcome the problem of specificity of
senolytic tool compounds when administrated in a chronic
manner [42]. Importantly, senolytics and senomorphics
are found in natural compounds, showing new
(nutraceutical) approaches to treat aging-related diseases,
although in a non-targeted way [102].
The “transformation” of normal cells into senescent
ones is accomplished by a multitude of internal and
external stressors in different physiological situations. 12855 AGING
Cancer cells can become senescent as well after
different therapies, though the new tumor-induced
senescent cells (TIS) generated are harmful in the long
term. In this scenario, the three options presented here
to either eliminate or “silence” the senescent cells are
important to combat TIS. The combination of these pro-
and anti-senescence approaches (TIS + senolytics
and/or senomorphics and/or improved immune system),
will play an important role in the cure of some types of
cancer [98].
In future clinical trials focused on eliminating senescent
cells, it will be important to determine when to initiate
the treatments (age of the patients), the schedule
(continuous, periodic and/or sporadic), as well as the
specific markers to determine the efficacy of the therapy
(see Table 3 for comparison of the therapies presented
in this review). Clinical trials should be supported by
robust preclinical results obtained in proper animal
Senescent cells are the cause of several age-related
diseases, which account for a high percentage of all
causes of death worldwide and an expansion of
morbidity. Likewise, it is estimated that by the year
2045, the number of people older than 60 will surpass,
for the first time in history, the number of people under
the age of 15 [103]. Thus, the approaches presented in
this review highlight the urgent need for new therapies
to delay or cure age/senescence-related diseases.
I am grateful to Adrián V. and Victoria Colombo for
their productive discussions and support. The
professional editing service NB Revisions was used for
technical editing of the manuscript prior to submission.
The author declares that he is co-founder of SenCell
Consejo Superior de Investigaciones Científicas (CSIC).
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... The accumulation of senescent cells is a feature of chronic kidney disease (CKD) and contributes to the progression of the endpoint kidney fibrosis [1]. Acute (short-term) senescent cells can be cleared by the immune system, through chemo-attracting of immune cells, followed by tissue regeneration, while chronic (long-term) senescent cells establish a pro-inflammatory environment and aggravate the disease [2,3]. Senescent cells can be identified by their permanent cell cycle arrest, proliferation limitation and secretion of senescence-associated secretory phenotype (SASP) factors [4]. ...
... Cellular senescence is identified as cell cycle arrest and the limitation of cell proliferation, which is related to kidney disease and fibrosis [41]. Chronic (long-term) senescent cells accumulate and finally aggravate the disease [2,3]. Senescent cells excrete SASP factors, which are key players in the paracrine induction of secondary senescence or senescence transmission [19]. ...
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Kidney fibrosis is the common final pathway of nearly all chronic and progressive nephropathies. One cause may be the accumulation of senescent cells that secrete factors (senescence associated secretory phenotype, SASP) promoting fibrosis and inflammation. It has been suggested that uremic toxins, such as indoxyl sulfate (IS), play a role in this. Here, we investigated whether IS accelerates senescence in conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1), thereby promoting kidney fibrosis. Cell viability results suggested that the tolerance of ciPTEC-OAT1 against IS increased in a time-dependent manner at the same dose of IS. This was accompanied by SA-β-gal staining, confirming the accumulation of senescent cells, as well as an upregulation of p21 and downregulation of laminB1 at different time points, accompanied by an upregulation in the SASP factors IL-1β, IL-6 and IL-8. RNA-sequencing and transcriptome analysis revealed that IS accelerates senescence, and that cell cycle appears to be the most relevant factor during the process. IS accelerates senescence via TNF-α and NF-ĸB signalling early on, and the epithelial-mesenchymal transition process at later time points. In conclusion, our results suggest that IS accelerates cellular senescence in proximal tubule epithelial cells.
... It is a challenge to find a unique marker for fisetin to attach onto senescent cells and enhance fisetin's bio-accessibility, and specific phenotypic aspects might be used for identification of senescent cells (24). So far, there are few delivery strategies for senescent cell targeting, which are mainly focused on nanoparticles (25). ...
... Furthermore, metformin improved vascular function and prolong life span in diabetic patients via its effects on cellular metabolism [110]. The second approach is to neutralize the activity and function of specific SASP factors (such as TGF-β, IL-1β, IL-1α, IL-8, and IL-6) by antibodies [120]. For example, antibodies that neutralize TGF-β can cut off the feedback loop of inflammation, thereby slowing the process of senescence [57]. ...
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Vascular diseases are a major threat to human health, characterized by high rates of morbidity, mortality, and disability. VSMC senescence contributes to dramatic changes in vascular morphology, structure, and function. A growing number of studies suggest that VSMC senescence is an important pathophysiological mechanism for the development of vascular diseases, including pulmonary hypertension, atherosclerosis, aneurysm, and hypertension. This review summarizes the important role of VSMC senescence and senescence-associated secretory phenotype (SASP) secreted by senescent VSMCs in the pathophysiological process of vascular diseases. Meanwhile, it concludes the progress of antisenescence therapy targeting VSMC senescence or SASP, which provides new strategies for the prevention and treatment of vascular diseases.
... Currently available intervention strategies targeting senescence include senolytics, which induce apoptosis in senescent cells [13,14], and senomorphics, which suppress the secretory phenotypes of senescent cells [15,16]. While promising, these strategies are flawed by the lack of specificity and targeting pathways required in healthy cells, potentially causing tissues damage [17,18]; therefore, improving the precision with which senescent cells are targeted has become a primary concern. ...
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DNA damage is the major cause of senescence and apoptosis; however, the manner by which DNA-damaged cells become senescent remains unclear. We demonstrate that DNA damage leads to a greater level of senescence rather than apoptosis in DBC1-deficient cells. In addition, we show that BLM becomes degraded during DNA damage, which induces p21 expression and senescence. DBC1 binds to and shields BLM from degradation, thus suppressing senescence. ML216 promotes DBC1–BLM interaction, which aids in the preservation of BLM following DNA damage and suppresses senescence. ML216 enhances pulmonary function by lowering the levels of senescence and fibrosis in both aged mice and a mouse model of bleomycin-induced idiopathic pulmonary fibrosis. Our data reveal a unique mechanism preventing DNA-damaged cells from becoming senescent, which may be regulated by the use of ML216 as a potential treatment for senescence-related diseases.
... Chronic senescent cells contribute to causing some age-related diseases, including cardiovascular disease, neurodegenerative disorders, cancer, type 2 diabetes, kidney-related diseases, cataracts, liver diseases, and metabolic syndrome. 1 Senescent cell secrete the senescence-associated secretory phenotype (SASP) factor and likely contribute to the linking of senescent accumulation with local and systemic dysfunction and disease. 2,3 The activation of SASP has a beneficial role to eliminated senescent cells and activating immune clearance in acute senescence, otherwise, the released SASP factors sensitize non-senescent neighboring cells to senescence and accumulated according to the declining capacity of senescent cell discarding, especially in elderly people. ...
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Coriander phytoconstituent has pro-apoptotic and anti-inflammatory activities. This study evaluated the activity of Coriander phytoconstituent against the Senescent Cell Anti-Apoptotic Pathways (SCAPs) network nodes that serve as targets for senolytic drugs. Docking simulations were performed using Autodock Vina PyRx (v0.8), Autodock Tools 1.5.6, and visualized by the Discovery Studio Visualizer. The anti-apoptotic protein (BCL-XL, BCL-2, BCLW, and survivin) interaction network was obtained from String The flavonoid compounds showed good binding energy than non-flavonoid compounds. In flavonoid compounds, referring to the binding energy of standard drugs, rutin have a potent affinity to survivin with a binding energy of -7.47 kcal/mol. In addition, the binding energy of galangin-5-methylether, pectolinarigenin, luteolin, apigenin, and 5,6,7-trimethoxyflavone serve higher binding activity to BCL-XL in the ranges -7.73 – -8.64 kcal/mol. Meanwhile, pseudobaptigenin has an affinity to both proteins, survivin, and BCL-XL with the binding energy of -5.71 and -8.64 kcal/mol respectively. Hence, the coriander phytoconstituents could have the potential as a senolytic agent by interfering with the SCAPs, especially BCL-XL and survivin
... Senotherapeutics have been proposed as a new approach for delaying or blunting the progression of diabetes. Senolytic drugs kill senescent cells (68) by overcoming their resistance to apoptosis, while senomorphic agents reduce the secretion of SASPs (69,70) without killing the cells. Senolysis results in improved glucose homeostasis with potential deleterious effects on beta cell mass (6,7). ...
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Senescence in pancreatic beta cells plays a major role in beta cell dysfunction, which leads to impaired glucose homeostasis and diabetes. Therefore, prevention of beta cell senescence could reduce the risk of diabetes. Treatment of nonobese diabetic (NOD) mice, a model of type 1 autoimmune diabetes (T1D), with palmitic acid hydroxy stearic acids (PAHSAs), a novel class of endogenous lipids with antidiabetic and antiinflammatory effects, delays the onset and reduces the incidence of T1D from 82% with vehicle treatment to 35% with PAHSAs. Here, we show that a major mechanism by which PAHSAs protect islets of the NOD mice is by directly preventing and reversing the initial steps of metabolic stress–induced senescence. In vitro PAHSAs increased Mdm2 expression, which decreases the stability of p53, a key inducer of senescence-related genes. In addition, PAHSAs enhanced expression of protective genes, such as those regulating DNA repair and glutathione metabolism and promoting autophagy. We demonstrate the translational relevance by showing that PAHSAs prevent and reverse early stages of senescence in metabolically stressed human islets by the same Mdm2 mechanism. Thus, a major mechanism for the dramatic effect of PAHSAs in reducing the incidence of type 1 diabetes in NOD mice is decreasing cellular senescence; PAHSAs may have a similar benefit in humans.
... To extend the lifespan, senescent cells need to be decreased or suppressed through the senolytics approach. There are many senolytics that have been reported to induce apoptosis of senescent cells and reduce the expression of senescence markers, including a combination of dasatinib and quercetin, BCL2 family inhibitors, SCAPs, FOXO4, and piperlongumine [250][251][252][253][254][255][256][257]. Moreover, HSP90 has been identified as a novel senolytics that can induce apoptosis of senescent cells to improve the health span [258]. ...
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Aging constitutes progressive physiological changes in an organism. These changes alter the normal biological functions, such as the ability to manage metabolic stress, and eventually lead to cellular senescence. The process itself is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These hallmarks are risk factors for pathologies, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Emerging evidence has been focused on examining the genetic pathways and biological processes in organisms surrounding these nine hallmarks. From here, the therapeutic approaches can be addressed in hopes of slowing the progression of aging. In this review, data have been collected on the hallmarks and their relative contributions to aging and supplemented with in vitro and in vivo antiaging research experiments. It is the intention of this article to highlight the most important antiaging strategies that researchers have proposed, including preventive measures, systemic therapeutic agents, and invasive procedures, that will promote healthy aging and increase human life expectancy with decreased side effects.
Objective: Previous in vitro transcriptomic profiling suggests azithromycin exerts its effects in patients with chronic rhinosinusitis (CRS) via modulation of type 1 inflammation and restoration of epithelial barrier function. We wished to verify these postulated effects using in vitro models of epithelial repair and in vivo transcriptional profiling. Study design: Functional effects of azithromycin in CRS were verified using in vitro models of wounding. The mechanism of the effect of azithromycin was assessed in vivo using transcriptomic profiling. Setting: Academic medical center. Methods: Effects of azithromycin on the speed of epithelial repair were verified in a wounding model using primary nasal epithelial cells (pNEC) from CRS patients. Nasal brushings collected pre-and posttreatment during a placebo-controlled trial of azithromycin for CRS patients unresponsive to surgery underwent transcriptomic profiling to identify implicated pathways. Results: Administration of azithromycin improved the wound healing rates in CRS pNECs and prevented the negative effect of Staphylococcus aureus on epithelial repair. In vivo, response to azithromycin was associated with downregulation in pathways of type 1 inflammation, and upregulation of pathways implicated in the restoration of the cell cycle. Conclusion: Restoration of healthy epithelial function may represent a major mode of action of azithromycin in CRS. In vitro models show enhanced epithelial repair, while in vivo transcriptomics shows downregulation of pathways type 1 inflammation accompanied by upregulation of DNA repair and cell-cycle pathways. The maximal effect in patients with high levels of type 1-enhanced inflammation suggests that azithromycin may represent a novel therapeutic option for surgery-unresponsive CRS patients.
Quercetin is a widely known and biologically active phytochemical and exerts therapeutic effects against atherosclerosis. The removal of senescent plaque macrophages effectively slows the progression of atherosclerosis and decreases the plaque burden. Still, whether quercetin alleviates atherosclerosis by inhibiting the senescence of plaque macrophages, including the potential mechanisms, remains unclear. ApoE-/- mice were fed with a normal chow diet or high-fat diet (HFD) supplemented or not with quercetin (100 mg/kg of body weight) for 16 weeks. An accumulation of senescent macrophages was observed in the plaque-rich aortic tissues from the mice with HFD, but quercetin supplementation effectively reduced the amount of senescent plaque macrophage, inhibited the secretion of key senescence-associated secretory phenotype (SASP) factors, and alleviated atherosclerosis by inhibiting p38MAPK phosphorylation and p16 expression. In vitro, SB203580 (a specific inhibitor of p38 MAPK) significantly inhibited oxidized low-density lipoprotein (ox-LDL)-induced senescence in mouse RAW264.7 macrophages, as evidenced by decreased senescence-associated markers (SA-β-gal staining positive cells and p16 expression). Furthermore, quercetin not only effectively reversed ox-LDL-induced senescence in RAW264.7 cells but also decreased the mRNA levels of several key SASP factors by suppressing p38 MAPK phosphorylation and p16 expression. The p38 MAPK agonist asiatic acid reversed the effects of quercetin. In conclusion, these findings indicate that quercetin suppresses ox-LDL-induced senescence in plaque macrophage and attenuates atherosclerosis by inhibiting the p38 MAPK/p16 pathway. This study elucidates the mechanisms of quercetin against atherosclerosis and supports quercetin as a nutraceutical for the management of atherosclerosis.
Cellular senescence is a tumor-suppressive program that promotes tissue homeostasis by identifying damaged cells for immune-mediated clearance. Thus, the ability to evade senescence and the ensuing immune surveillance is a hallmark of cancer. Reactivation of senescence programs can result in profound immune-mediated tumor regressions or sensitize tumors to immunotherapy, although the aberrant persistence of senescent cells can promote tissue decline and contribute to the side effects of some cancer therapies. In this review, we first briefly describe the discovery of senescence as a tumor-suppressive program. Next, we highlight the dueling good and bad effects of the senescence-associated secretory program (SASP) in cancer, including SASP-dependent immune effects. We then summarize the beneficial and deleterious effects of senescence induction by cancer therapies and strategies in development to leverage senescence therapeutically. Finally, we highlight challenges and unmet needs in understanding senescence in cancer and developing senescence-modulating therapies. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see for revised estimates.
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Purpose: Mitochondrial glycerophosphate dehydrogenase (mGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin (MF) in the liver. There are no data on the expression and role of mGPDH as a metformin target in cancer. In this study, we evaluated mGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental design: We analyzed mGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer-derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on mGPDH expression were determined by qRT-PCR and western blot. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and mGPDH expression in metastatic thyroid cancer mouse models. Results: We show for the first time that mGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that mGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of mGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high mGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth inhibitory effects of metformin in vitro and in vivo. Conclusion: Our study established mGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin.
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Small molecules spark NK cell response Immunotherapy is a powerful treatment for certain cancers. Yet for those patients that do not respond, simultaneous strategies that mobilize the immune system and directly target malignant cells may be more effective. Ruscetti et al. report that combining two clinically approved cancer drugs promoted immune surveillance and killing of KRAS-mutant lung tumors in mice (see the Perspective by Cornen and Vivier). The two small molecules—a mitogen-activated protein kinase inhibitor and a cyclin-dependent kinase 4/6 inhibitor—induced natural killer (NK) cell recruitment and elimination of senescent lung cancer cells, which did not occur when either agent was used alone. Science , this issue p. 1416 ; see also p. 1355
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H460 non-small cell lung, HCT116 colon and 4T1 breast tumor cell lines induced into senescence by exposure to either etoposide or doxorubicin were able to recover proliferative capacity both in mass culture and when enriched for the senescence-like phenotype by flow cytometry (based on β-galactosidase staining and cell size, and a senescence-associated reporter, BTG1-RFP). Recovery was further established using both real-time microscopy and High-Speed Live-Cell Interferometry (HSLCI) and was shown to be accompanied by the attenuation of the senescence-associated secretory phenotype (SASP). Cells enriched for the senescence-like phenotype were also capable of forming tumors when implanted in both immunodeficient and immunocompetent mice. As chemotherapy-induced senescence has been identified in patient tumors, our results suggest that certain senescence-like phenotypes may not reflect a terminal state of growth arrest, as cells that recover with self-renewal capacity may ultimately contribute to disease recurrence.
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Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues. However, senescent cells accumulate in tissues in advanced age, where they might promote tissue degeneration and malignant transformation. The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown. Here we show that Prf1−/− mice with impaired cell cytotoxicity exhibit both higher senescent-cell tissue burden and chronic inflammation. They suffer from multiple age-related disorders and lower survival. Strikingly, pharmacological elimination of senescent-cells by ABT-737 partially alleviates accelerated aging phenotype in these mice. In LMNA+/G609G progeroid mice, impaired cell cytotoxicity further promotes senescent-cell accumulation and shortens lifespan. ABT-737 administration during the second half of life of these progeroid mice abrogates senescence signature and increases median survival. Our findings shed new light on mechanisms governing senescent-cell presence in aging, and could motivate new strategies for regenerative medicine.
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Senescent cells accumulate with age in multiple tissues and may cause age‐associated disease and functional decline. In vitro, senescent cells induce senescence in bystander cells. To see how important this bystander effect may be for accumulation of senescent cells in vivo, we xenotransplanted senescent cells into skeletal muscle and skin of immunocompromised NSG mice. 3 weeks after the last transplantation, mouse dermal fibroblasts and myofibres displayed multiple senescence markers in the vicinity of transplanted senescent cells, but not where non‐senescent or no cells were injected. Adjacent to injected senescent cells, the magnitude of the bystander effect was similar to the increase in senescence markers in myofibres between 8 and 32 months of age. The age‐associated increase of senescence markers in muscle correlated with fibre thinning, a widely used marker of muscle aging and sarcopenia. Senescent cell transplantation resulted in borderline induction of centrally nucleated fibres and no significant thinning, suggesting that myofibre aging might be a delayed consequence of senescence‐like signalling. To assess the relative importance of the bystander effect versus cell‐autonomous senescence, we compared senescent hepatocyte frequencies in livers of wild‐type and NSG mice under ad libitum and dietary restricted feeding. This enabled us to approximate cell‐autonomous and bystander‐driven senescent cell accumulation as well as the impact of immunosurveillance separately. The results suggest a significant impact of the bystander effect for accumulation of senescent hepatocytes in liver and indicate that senostatic interventions like dietary restriction may act as senolytics in immunocompetent animals.
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Objectives: Large granular lymphocyte (LGL) leukemia is a rare type of lymphoproliferative disease caused by clonal antigenic stimulation of T cells and natural killer (NK) cells. Methods: In this review, we focus on the current knowledge of the immunological dysfunctions associated with LGL leukemia and the associated disorders coexistent with this disease. Novel therapeutic options targeting known molecular mechanisms are also discussed. Results and discussion: The pathogenesis of LGL leukemia involves the accumulation of gene mutations, dysregulated signaling pathways and immunological dysfunction. Mounting evidence indicated that dysregulated survival signaling pathways may be responsible for the immunological dysfunction in LGL leukemia including decreased numbers of neutrophils, dysregulated signal transduction of NK cells, abnormal B-cells, aberrant CD8+ T cells, as well as autoimmune and hematological abnormalities. Conclusion: A better understanding of the immune dysregulation triggered by LGL leukemia will be beneficial to explore the pathogenesis and potential therapeutic targets for this disease.
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Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence is a homeostatic biological process that has a key role in driving ageing. There is evidence that senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and may predispose a person to the appearance of a neurodegenerative condition or may aggravate its course. Research into senescence has long been hindered by its variable and cell-type specific features and the lack of a universal marker to unequivocally detect senescent cells. Recent advances in senescence markers and genetically modified animal models have boosted our knowledge on the role of cellular senescence in ageing and age-related disease. The aim now is to fully elucidate its role in neurodegeneration in order to efficiently and safely exploit cellular senescence as a therapeutic target. Here, we review evidence of cellular senescence in neurons and glial cells and we discuss its putative role in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis and we provide, for the first time, evidence of senescence in neurons and glia in multiple sclerosis, using the novel GL13 lipofuscin stain as a marker of cellular senescence.
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Cellular senescence, which is characterized by an irreversible cell-cycle arrest1 accompanied by a distinctive secretory phenotype2, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16INK4A have been found to actively drive naturally occurring age-related tissue deterioration3,4 and contribute to several diseases associated with ageing, including atherosclerosis5 and osteoarthritis6. Various markers of senescence have been observed in patients with neurodegenerative diseases7-9; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPTP301SPS19 mouse model of tau-dependent neurodegenerative disease10 accumulates p16INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.
Senescence, a durable form of growth arrest, represents a primary response to numerous anticancer therapies. Although the paradigm that senescence is "irreversible" has largely withstood the findings of tumor cell recovery from what has been termed "pseudo-senescence" or "senescence-like arrest," a review of the literature suggests that therapy-induced senescence in tumor cells is not obligatorily a permanent cell fate. Consequently, we propose that senescence represents one avenue whereby tumor cells evade the direct cytotoxic impact of therapy, thereby allowing for prolonged survival in a dormant state, with the potential to recover self-renewal capacity and contribute to disease recurrence.
Urban particulate matter air pollution induces the release of pro-inflammatory cytokines including interleukin-6 (IL-6) from alveolar macrophages, resulting in an increase in thrombosis. Here, we report that metformin provides protection in this murine model. Treatment of mice with metformin or exposure of murine or human alveolar macrophages to metformin prevented the particulate matter-induced generation of complex III mitochondrial reactive oxygen species, which were necessary for the opening of calcium release-activated channels (CRAC) and release of IL-6. Targeted genetic deletion of electron transport or CRAC channels in alveolar macrophages in mice prevented particulate matter-induced acceleration of arterial thrombosis. These findings suggest metformin as a potential therapy to prevent some of the premature deaths attributable to air pollution exposure worldwide.