Cell Calcium 70 (2018) 16–23

Contents lists available at ScienceDirect

Cell Calcium
journal homepage: www.elsevier.com/locate/ceca

Review

Calcium signaling and cellular senescence

Nadine Martin a,b,c,d , David Bernard a,b,c,d,∗
a
Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69373 Lyon, France
b
CNRS UMR 5286, F-69373 Lyon, France
c
Centre Léon Bérard, F-69373 Lyon, France
d
Université de Lyon, F-69373 Lyon, France

a r t i c l e i n f o a b s t r a c t

Article history: Cellular senescence is a stable cell proliferation arrest induced by a variety of stresses including telom-
Received 28 February 2017 ere shortening, oncogene activation and oxidative stress. This process plays a crucial role in many
Received in revised form 3 April 2017 physiopathological contexts, especially during aging when cellular senescence favors development of
Accepted 3 April 2017
age-related diseases, shortening lifespan. However, the molecular and cellular mechanisms controlling
Available online 5 April 2017
senescence are still a matter of active research. In the last decade, there has been emerging literature indi-
cating a key involvement of calcium signaling in cellular senescence. In this review we will initially give
Keywords:
an account of the direct evidence linking calcium and the regulation of senescence. We will then review
Calcium
Senescence our current knowledge on the role of calcium in some senescence-associated features and physiopatho-
Signaling logical conditions, which will shed light on additional ways in which calcium signaling is implicated in
Cancer cellular senescence.
Aging © 2017 Elsevier Ltd. All rights reserved.

Contents

1. Definition of cellular senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

2. Direct evidence of the role of calcium in senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.1. Increase in intracellular calcium levels in senescent cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.2. Calcium-induced mitochondrial dysfunction and ROS production in senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.3. SASP regulation by calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.4. Role of the calcium/NFAT signaling pathway in senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3. Other roles for calcium in the main senescence-associated features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.1. Cell proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.2. Senescence-associated secretory phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4. Role of calcium in senescence-associated physiopathological conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.1. Role of cellular senescence in vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.2. Implication of calcium in some physiopathological responses controlled by senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Abbreviations: 4EBP1, Eukaryotic Translation Initiation Factor 4E Binding Protein 1; ATF3, activating transcription factor 3; ATM, Ataxia Telangiectasia Mutated; ATR, Ataxia
Telangiectasia and Rad3-Related; ARF, alternative reading frame; BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N ,N -tetraacetic acid; CAMK, calmodulin kinase; CDK, cyclin
dependent kinase; CDKN1A/2A, cyclin dependent kinase inhibitor 1A/2A; CHK2, checkpoint 2 kinase; CEBP-␤, CCAAT/enhancer-binding protein beta; CRE, cAMP response ele-
ment; CREB, cAMP responsive element binding protein; DDR, DNA damage response; DUOX, dual oxidase 1; ER, endoplasmic reticulum; IL, interleukin; IKB␣, I-kappa-B alpha;
IKK, I-kappa-B kinase; IP3, inositol-1,4,5-trisphosphate; IP3R, inositol-1,4,5-trisphosphate receptor; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of
rapamycin complex 1; NFAT, nuclear factor of activated T-cells; NF␬B, nuclear factor kappa-light-chain-enhancer of activated B cells; MAM, mitochondria-associated endo-
plasmic reticulum membranes; MCU, mitochondrial calcium uniporter; OIS, oncogene-induced senescence; PDGF, platelet-derived growth factor; PLC, phospholipase C; PKB,
protein kinase B; PML, promyelocytic leukemia protein; PPAR␥, peroxisome proliferator-activated receptor gamma; PTEN, phosphatase and tensin homolog; RB, retinoblas-
toma protein; RHEB1, ras homolog enriched in brain 1; ROS, reactive oxygen species; S6K, ribosomal protein S6 kinase; SAHF, senescence-associated heterochromatin foci;
SASP, senescence-associated secretory phenotype; TRP, transient receptor potential channel; TSC1/2, tuberous sclerosis 1/2.
∗ Corresponding author at: Centre de Recherche en Cancérologie de Lyon, F-69373 Lyon, France.
E-mail address: david.bernard@lyon.unicancer.fr (D. Bernard).

https://doi.org/10.1016/j.ceca.2017.04.001
0143-4160/© 2017 Elsevier Ltd. All rights reserved.

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 N. Martin, D. Bernard / Cell Calcium 70 (2018) 16–23
1. Definition of cellular senescence
Cellular senescence was originally described five decades ago as
the proliferation arrest that accompanies the exhaustion of replica-
tive potential in primary human fibroblasts after extended culture
in vitro. Telomere attrition is the main trigger of this so-called
replicative senescence. However, a number of other stimuli such as
oncogenic signals, oxidative stress and genotoxic agents can also
induce a senescent phenotype, known as premature senescence.
Cellular senescence is thus generally defined as a cellular response
to stresses. Although originally observed in primary human fibrob-
lasts, cellular senescence has now been observed in most human
cell types and in many species [1–4].
The two main features of senescent cells are their stable cell
cycle arrest and their distinct, often pro-inflammatory, secretome
or senescence-associated secretory phenotype (SASP). P53 and RB
(retinoblastoma) are master regulators of senescence implement-
ing the stable cell cycle arrest. Upon stresses, p53 is activated and
induces the expression of genes such as CDKN1A encoding the
cyclin-dependent kinase inhibitor p21. P21 and p16 (CDKN2A),
another inhibitor of cyclin-dependent kinases, then inhibit the
phosphorylation of RB. RB consequently represses the expression
of pro-proliferative genes such as E2F target genes promoting the
cell cycle G1-S transition (Fig. 1) [5,6].
The SASP comprises many pro-inflammatory cytokines and
chemokines, various growth factors and proteases. This secre-
tome is regulated both at the transcriptional level, the expression
of numerous SASP components being induced by transcription
factors such as nuclear factor kappa-light-chain-enhancer of acti-
vated B cells (NF␬B) and CCAAT/enhancer-binding protein beta
(CEBP-␤), and at the translational level by pathways such as
the mammalian target of rapamycin (mTOR) pathway. The SASP
displays autocrine activities reinforcing senescence as well as
several paracrine activities, sometime having opposite effects:
activating the immune system, spreading senescence and/or pro-
moting epithelial-mesenchymal transition, migration and invasion
in neighboring cells (Fig. 1) [7–14].
Besides these two main features, senescent cells acquire other
characteristics. They undergo changes in their morphology, which
often become flat and enlarged. They exhibit senescence-associated
␤-galactosidase activity, which is experimentally used as a marker
of senescence. They display increased levels of reactive oxygen
species (ROS) which could result from altered mitochondrial activ-
ity and lead to DNA damage. They may also accumulate unrepaired
DNA damages, which activate the ATM/ATR-p53-p21-RB DNA dam-
age response (DDR) pathway, as well as senescence-associated
heterochromatin foci (SAHF) repressing pro-proliferative E2F tar-
gets, both participating in the implementation of cell cycle arrest
(Fig. 1) [1,2,5,6].
Calcium critically controls many molecular processes and cel-
lular functions and there is accumulating evidence indicating that
calcium signaling plays a key role in cellular senescence. We will
present the current knowledge on its implication in senescence,
as well as in the main senescence-associated features and in some
physiopathological contexts in which senescence is involved.
2. Direct evidence of the role of calcium in senescence
2.1. Increase in intracellular calcium levels in senescent cells
An elevation of intracellular calcium levels has been observed
in response to different types of senescence-inducing stresses
(telomere shortening, oncogene activation, rotenone or oxidative
stress) and in several cell types. This increase in calcium con-
centration has been attributed to calcium influx though plasma
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17
membrane calcium channels or to calcium release from the endo-
plasmic reticulum (ER) depending on the context. Indeed, it has
been shown that isradipine, a CaV1.3 L-type channel antagonist,
prevents the rise in rotenone-induced calcium that accelerates
senescence in human neuroblastoma SH-SY5Y cells [15]. In human
mammary epithelial cells and primary human fibroblasts, onco-
gene activation and telomere shortening trigger calcium release
from endoplasmic reticulum stores, through the activation of
the PLC/IP3/IP3R pathway [16]. In H2 O2 -induced senescence in
human endometrium-derived stem cells, this IP3R-mediated cal-
cium release from the ER causes the rapid increase in cytosolic
calcium concentration [17]. Treatment with uridine triphosphate
or thapsigargin, which deplete the ER calcium store, significantly
impaired the rise H2 O2 -induced intracellular calcium. High concen-
trations of intracellular calcium are sustained during senescence.
Chelation of this calcium with BAPTA [17] or knockdown of the ER
calcium release channels IP3R [16] foster escape from senescence,
demonstrating that elevation of intracellular calcium levels triggers
cellular senescence.
Interestingly, several oncogenes and tumor suppressors regu-
lating cellular senescence physically interact with IP3Rs and, by
modulating the activity of these channels, exploit calcium signal-
ing [18]. For example, it has been shown that IP3R3 is targeted by
PKB/AKT pro-survival serine/threonine kinase [19]. This oncogene
inhibits IP3R3-mediated ER calcium release by phosphorylating
this channel [20]. The tumor suppressor PML (promyelocytic
leukemia protein), a well know senescence inducer [21], forms
a complex with IP3R3 and PKB/AKT and recruits the PP2A phos-
phatase to counteract PKB/AKT-induced IP3R3 phosphorylation
and inhibition. The resulting increase in ER calcium release is
instrumental in PML-induced apoptosis [22]. It can be hypothesized
that it may also be involved in PML-induced senescence.
2.2. Calcium-induced mitochondrial dysfunction and ROS
production in senescence
Calcium released from the ER in response to senescence-
inducing stresses mainly exerts its effects through reactive oxygen
species (ROS). It has been shown upon oncogene-induced senes-
cence (OIS) in mammary epithelial cells and upon replicative
senescence in primary human fibroblasts that calcium release
from the ER is followed by its accumulation in the mitochondria.
The increase in mitochondrial calcium concentration leads to a
drop in mitochondrial membrane potential and in the enhanced
production of ROS, which triggers senescence. Knockdown of
the mitochondrial calcium uniporter MCU fosters escape from
senescence [16]. The ER and mitochondria can be spatially and func-
tionally coupled through mitochondria-associated ER membranes
(MAMs) which favor the transfer of calcium from the ER to mito-
chondria [23]. A role for these structures in the regulation of cellular
senescence can be speculated but remains to be assessed.
2.3. SASP regulation by calcium
The observed rise in intracellular calcium in response to
senescence-inducing signals regulates the SASP through inter-
leukin 1␣ (IL1␣), a pro-inflammatory cytokine which acts as a key
SASP initiator [24]. IL1␣ is synthesized as a precursor and then pro-
cessed by the calcium-activated protease calpain. In senescent cells,
the rise in intracellular levels of calcium, which is the co-factor of
calpain, activates this protease. This leads to increased IL1␣ pro-
teolytic cleavage and enhanced expression of downstream SASP
cytokines, such as IL6 and IL8.
18 N. Martin, D. Bernard / Cell Calcium 70 (2018) 16–23

TRIGGERS

Telomere Oncogene Oxidave DNA Proteotoxic Other

shortening acvaon stress damage stress stresses

MAIN EFFECTORS

p53 and RB NF B mTOR

pathway pathway pathway

ARF IKK TSC1 TSC2

ATM/ATR

p53

RHEB1
IB
p21 p16
RELA p50

CDKs

mTORC1
RB RELA p50

S6K 4EBP1
E2F

E2F target genes NF B target genes Protein synthesis

FEATURES

Cell morphology Cell cycle SA-secretory Reacve oxygen

changes arrest phenotype (SASP) species (ROS)

SA- -galactosidase Sustained DNA

acvity damage

PHYSIOPATHOLOGICAL EFFECTS

Fig. 1. Main molecular basis of cellular senescence. A wide variety of stresses activate effector pathways implementing cellular senescence. Note that only the main and best
characterized effectors are depicted here and that these pathways intricately interplay. Their activation leads to the establishment of senescence features, among which the
cell cycle arrest and the senescence-associated secretory phenotype (SASP) are the main features causing physiopathological effects.

2.4. Role of the calcium/NFAT signaling pathway in senescence
The calcium-dependent transcription factor NFAT (nuclear
factor of activated T-cells) is activated through the cal-
cium/calmodulin/calcineurin pathway [25]. Upon cytosolic calcium
increase, calmodulin, a calcium sensor protein, binds to calcium
and activates calcineurin. This phosphatase triggers NFAT dephos-
phorylation and its translocation to the nucleus, where it regulates
the expression of its target genes [26]. Several studies have shown
that NFAT plays a crucial role in cellular senescence. Indeed the

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 N. Martin, D. Bernard / Cell Calcium 70 (2018) 16–23 19

Stress
Calcium
channels

Cytosol

Ca2+
IP3R
Endoplasmic
reculum
IP3R

MCU
Mitochondria
Calmodulin Calpain

Calcineurin

ROS NFAT IL1

Nucleus

Cell cycle arrest SASP

CELLULAR SENESCENCE

Fig. 2. Known roles of calcium in cellular senescence. In response to senescence-inducing stresses, intracellular calcium levels increase and promote senescence though
several calcium-dependent mechanisms triggering cell cycle arrest and SASP production. Only direct roles of calcium in senescence are depicted here.

calcineurin/NFAT signaling pathway is critically required for p53-
dependent senescence in skin [27]. NFATc1 directly represses the
expression of ATF3, a transcription factor related to the AP-1
family which inhibits the expression of p53 and other senescence-
associated genes. Impairment of the calcineurin/NFAT pathway
suppresses p53-dependent senescence and promotes tumor for-
mation of H-RASV12 -expressing primary human keratinocytes or
keratinocyte-derived squamous cell carcinoma cells. However, it
has also been shown that NFATc1 activation in prostate epithelium
promotes prostatic intraepithelial neoplasia and prostate adeno-
carcinoma [28]. Moreover, NFATc1 accelerates PTEN null-driven
prostate tumorigenesis. NFATc1 overcomes PTEN loss-induced
cellular senescence by downregulating the cell cycle inhibitor
p21 [28]. Altogether, it seems that the calcineurin/NFAT path-
way displays senescence-promoting or –suppressing functions
depending on the cell type and context. Interestingly, NFATc1
has also been described to activate the expression of the ER cal-
cium release channel IP3R2, which could be an additional way
for the calcineurin/NFAT pathway to impact senescence [29]. Of
course, calcium/calmodulin/calcineurin/NFAT pathway can also
exert effects independently of its effect on cellular senescence, such
as promoting T cell clonal expansion [30].
In addition to these reports which clearly demonstrate a direct
role for calcium signaling in cellular senescence (Fig. 2), there is
extensive literature on the involvement of calcium in features asso-
ciated with senescence. The main implications of calcium in this
context will be reviewed in the next section.
3. Other roles for calcium in the main
senescence-associated features
3.1. Cell proliferation
One of the two functionally crucial features of senescent cells is
their state of stable proliferation arrest. Cell proliferation is directly
linked to cell cycle progression. Calcium signaling plays a key role
throughout the mammalian cell cycle. Intracellular calcium con-
centration is modulated during the G1 phase, G1/S transition and
mitosis [31]. Calcium is important in early G1 for the expression
of genes such as FOS, JUN and MYC and later for RB phospho-
rylation. Antagonists of calmodulin trigger cell cycle arrest in G1
[32]. Calmodulin kinase (CaMK) and calcineurin, downstream tar-
gets of calmodulin, are required for cyclin D1 expression [33,34].
The calcium/calmodulin pathway regulates several transcription
factors such as NFAT or the cAMP responsive element binding
protein (CREB) which target genes that control cell cycle pro-
gression from G1 to S. Direct upregulation of MYC expression by
calcineurin-activated NFATc1 induces an increase in the expression
of MYC target genes, cyclin E and E2F [35]. CREB undergoes calcium-
induced phosphorylation by CAMK2 and 4. Once phosphorylated
CREB binds to the cAMP response element (CRE) on the promoter of
target genes, such as cyclin D1, and recruits co-activators, includ-
ing the histone acetyl-transferases CBP and p300 which activate
gene transcription [36]. CDK2 activity is also increased by cal-
cineurin. In addition, the calcium/calmodulin pathway promotes
RB phosphorylation by enhancing p34 Cdc2 kinase (CDK1) activa-

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20 N. Martin, D. Bernard / Cell Calcium 70 (2018) 16–23
tion [37]. P53, similarly to RB, may also be regulated by calcium.
P53 was shown to bind to several members of the S100 family of
calcium-binding proteins in a calcium-dependent manner. These
interactions can regulate the stability and transcriptional activity
of p53. For instance, S100B binds to p53 in melanoma, reduces
p53 protein levels and thus represses the function of p53 [38]. The
interaction between p53 and some calcium-binding proteins may
thus influence cell cycle progression. However, a comprehensive
analysis of the direct impact of calcium on the two key master regu-
lators of cellular senescence p53 and RB in primary cells is currently
lacking. During mitosis, a rise in cytosolic calcium at the onset of
anaphase, just preceding nuclear envelope breakdown, has been
observed in cultured mammalian fibroblasts and epithelial cells
as well as in embryos [39–41]. Mimicking this cytosolic calcium
increase by artificially injecting calcium into the embryo causes
early nuclear envelope breakdown, whereas chelating it prevents
this breakdown and suspends mitosis [40]. In addition, defects
in calcium- and CAMK2-mediated control of centrosome duplica-
tion (in G1/S) and separation (in G2/M) result in aberrant mitotic
spindles, genetic instability and aneuploidy [42,43]. Modulation of
cytosolic calcium concentration is therefore a crucial regulatory
step for cell cycle progression. Calcium signaling is not only piv-
otal for cell cycle progression but more generally for the survival
and proper functioning of cells. For example, calcium is required
for energy production and acts at several levels in the mitochon-
dria to stimulate ATP synthesis. In addition, calcium controls many
other aspects of cellular metabolism [44]. In conclusion, calcium is
required for cell cycle progression, proliferation and survival.
These latter observations appear to be contradictory with
the pro-senescence effect of calcium described in Section 2.
We can speculate that a spatio-temporal elevation of calcium
concentration might switch the effect of calcium from a pro-
proliferative/survival effect to a cyto-static/toxic effect. Beyond
the literature presented in Section 2, showing an involvement of
calcium in senescence, a rapid rise in mitochondrial calcium lev-
els precedes cell death and contributes to its induction [45,46].
Changes in calcium homeostasis may therefore drive cells to enter
either senescence or cell death, probably depending on the charac-
teristics of the spatio-temporal elevation of calcium concentrations
(site and level of accumulation as well as kinetic and duration of the
increase).
Still in some circumstances increased calcium might not exert
cytostatic/toxic effects if the effector pathways like p53, RB or
caspases are not functional. It is tempting to speculate that it is
what happens in cancer cells, where these pathways are altered
and increased calcium reported. Then in these specific conditions
increased calcium might promote survival, proliferation, migration
and invasion phenotypes (Fig. 3) [47–49].
3.2. Senescence-associated secretory phenotype
Beside the cell proliferation arrest, the other functionally crucial
feature of senescent cells is their distinct pro-inflammatory secre-
tome (SASP). The SASP is regulated at the transcriptional level by
the NF␬B pathway, which induces the expression of SASP compo-
nents such as IL6 and IL8 pro-inflammatory cytokines. Activation
of the NF␬B pathway depends on intracellular free calcium under
certain circumstances. Activation of calmodulin has been shown
to inhibit c-REL and allow RELA to translocate into the nucleus
[50–52].
The SASP is also induced at the translational level by the mTOR
pathway. It has recently been demonstrated that mTORC1 acti-
vation requires lysosomal calcium release through the calcium
channel TRPML1. Lysosomal calcium activates mTORC1 through
calmodulin, which associates with mTORC1 and stimulates its
kinase activity [53]. Calcium and calmodulin have also been shown
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INTRACELLULAR
CALCIUM
TIMELY REGULATED INCREASED
concentraon concentraon
Cells with impaired
senescence and death Normal cells
effector programs
PRO-PROLIFERATIVE and CYTOSTATIC and
PRO-SURVIVAL effects CYTOTOXIC effects
Cell cycle progression
Cellular senescence
Migraon/invasion
Metabolism Cell death
Fig. 3. Dual effects of calcium on cellular life. Calcium has pleiotropic effects on
cellular life depending on its intracellular levels, the regulation of these levels and
the status of the cells.
to promote the secretion of IL1␤, another component of the SASP.
Calmodulin binds to IL1␤ precursors and IL1␤-processing and
–release depends on this calcium-mediated interaction [54].
For the sake of clarity we have only discussed the role of calcium
signaling on cell proliferation and SASP, the two main hallmarks
of senescent cells explaining its role in various physiopatholog-
ical responses. However, calcium signaling plays a key role in
many other senescence-associated features such as DNA damage
response and autophagy, suggesting that calcium may also impact
senescence in many additional ways than the ones we focused on.
4. Role of calcium in senescence-associated
physiopathological conditions
4.1. Role of cellular senescence in vivo
Senescent cells accumulate with age and contribute to age-
related diseases and organismal aging. Although a matter of debate
for many years, this role for senescence has definitely been demon-
strated the last few years by the evidence that elimination of
senescent cells during accelerated or normal aging extends life
span and improves numerous age-associated pathologies such as
atherosclerosis, type II diabetes, glomerulosclerosis, cardiac aging,
lung degenerative diseases, cancer relapse and progression, as well
as immunosenescence [8,55–61].
Senescent cells are also observed in the organism at various
stages of life during which senescence can have beneficial health
effects. Cellular senescence is activated during normal embry-
onic development, where it contributes to embryonic growth and
patterning [62,63]. It is also involved in various responses, from
promoting wound healing [64] to increasing insulin secretion [65].
In the context of tumor initiation, cellular senescence is a major
failsafe program that is activated upon oncogenic stresses, short
telomeres and mutagenic signals, to eliminate cells at risk of
transformation. In benign preneoplastic lesions, oncogene-induced
senescence (OIS) limits the proliferation of these cells and triggers
their clearance by the immune system. OIS is therefore a potent
protective barrier in the initial steps of tumorigenesis [9,66,67].
 N. Martin, D. Bernard / Cell Calcium 70 (2018) 16–23
CELLULAR
SENESCENCE
TIMELY REGULATED CHRONIC
senescence senescence
BENEFICIAL DETRIMENTAL
effects effects
Embryonic development Cancer relapse and progression
Type II diabetes
Atherosclerosis
Wound healing
Glomerulosclerosis
Cardiac aging
Lung degenerave diseases
Tumor suppression Immunosenescence
Fig. 4. Dual effects of cellular senescence on organismal health. Based on its dual
effects, cellular senescence has been proposed to be an example of antagonistic
pleiotropy.
Altogether age-related chronic senescence is thought to exert
detrimental effects on health, whereas timely-regulated senes-
cence is thought to exert beneficial effects (Fig. 4) [57,68,69].
4.2. Implication of calcium in some physiopathological responses
controlled by senescence
Calcium plays a pivotal role in several physiopathological con-
texts in which senescence is involved, suggesting a functional
link between calcium and senescence in vivo. Cellular senescence
is critically implicated in wound healing. Appearance of senes-
cent fibroblasts and endothelial cells is observed soon after skin
wounding. These cells accelerate wound closure by triggering
myofibroblast differentiation through the secretion of platelet-
derived growth factor AA (PDGF-AA) [64]. Calcium is an essential
regulator of wound responses [70]. Epithelial wounds trigger inter-
cellular calcium waves which propagate through the wounded
epithelium. Wounds induce an elevation of cytoplasmic calcium
levels through the opening of plasma membrane channels such
as TRPs or through calcium release from intracellular stores.
This increase in intracellular calcium concentrations induces ROS
production by activating the epithelial NADPH-oxidase DUOX
or by triggering mitochondrial permeability transition. Calcium
also guides the secretion of paracrine mediators and is required
for epithelial sheet motility and integrity. In addition to their
coordinated role during wound healing, migration and invasion
contribute to tumor progression. Senescent cells owing to their
SASP have been proposed to favor cell migration and invasion of
neighboring tissues [8]. In particular, senescent fibroblasts in the
tumor stroma promote, through their SASP, cancer cell migration
[71–73]. Calcium directly controls the cell migration process, by
impacting cytoskeleton organization as well as signaling pathways
[47]. Altogether, this suggests that calcium can promote cell migra-
tion and contribute to the pro-migratory effect of the SASP, thus
impacting neighboring cells.
Cystic fibrosis is a genetic lung disease characterized by
chronic airway inflammation. Levels of senescence markers such
as p16, phospho-histone H2A.X (␥H2A.X) and phospho-checkpoint
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21
2 kinase (phospho-Chk2) are increased in this pathology [74]. An
upregulation of intracellular calcium concentration and a calcium-
dependent activation of the NF␬B pathway, which is a key SASP
regulator, are also observed in cystic fibrosis airway epithelial cells
[75]. These findings suggest that senescence could be implicated
in this disease and that calcium could regulate senescence in this
context.
It has been shown that p16-induced senescence in pancre-
atic ␤ cells enhances insulin secretion, partly through mTOR and
the peroxisome proliferator-activated receptor ␥ (PPAR␥) [65].
␤ cell-specific deletion of the calcineurin regulatory subunit cal-
cineurin b1 provokes age-dependent diabetes in mice due to
decreased ␤ cell proliferation, decreased pancreatic insulin content
and hypoinsulinaemia. Consistently, conditional NFAT activation in
normal adult ␤ cells increases their proliferation and mass, provok-
ing hyperinsulinemia, and induces the expression of genes which
are critical for the endocrine function of ␤ cells [76]. Thus, calcium
signaling and ␤-cell senescence promotes insulin secretion.
Even though senescence appears to promote ␤-cell insulin
secretion, senescence in insulin sensitive organs might render
them insulin resistant. Indeed, high fat diets and obesity, which
are known to result in insulin resistance, promote senescence of
adipocytes and hepatocytes, two cell types responding to insulin to
metabolize circulating glucose. Decreasing senescence by deplet-
ing p53 restores the response to insulin, demonstrating that in
that given context senescence provokes insulin resistance [60,77].
Accumulation of mitochondrial calcium is observed during obesity
and has been shown to promote insulin resistance [78], as does
accumulation of senescent cells, once again supporting a functional
link between calcium, and in particular mitochondrial calcium, and
senescence. However, the role of calcium is not that simple as
cytosolic calcium can both decrease or increase insulin sensitiv-
ity [79,80]. We can speculate that the effect of calcium on insulin
sensitivity depends on its spatio-temporal regulation and then on
its ability to induce or not senescence as previously discussed.
Together, calcium might exert some of its effects on health and
diseases through its ability to control cellular senescence.
5. Concluding remarks
Cellular senescence is a cellular response to a wide variety of
stresses that plays a key role in development, aging and diseases.
Identifying the molecular and cellular mechanisms controlling this
process is currently a key challenge to improve our understanding
of these physiopathological conditions and be able to envision ways
to impact them. In the last decade the concept that calcium signal-
ing is a key regulator of cellular senescence has emerged. Thus,
calcium signaling appears to be an important effector of cellular
senescence.
However, it is very likely that our current knowledge is only the
tip of the iceberg and that many more implications of calcium sig-
naling in cellular senescence will be discovered in the near future.
To date only a few members of the calcium signaling pathway have
been identified as senescence regulators. Calcium signaling impli-
cates many players and signaling cascades. According to the KEGG
pathway database, 180 proteins participate in the calcium signal-
ing pathway. It includes a large variety of proteins, among which
numerous calcium channels from diverse families and calcium-
binding proteins. Assessing the involvement of each of these factors
in cellular senescence would improve our understanding of the
role of calcium signaling in this process. To this end, regulation of
their expression and activity as well as their functional impact on
senescence should be investigated.
With regards to a more applied perspective, dissecting the role
of players of the calcium signaling pathway in senescence may
22 N. Martin, D. Bernard / Cell Calcium 70 (2018) 16–23
reveal targets of interest for medical purposes. This could allow
the identification of new early diagnostic markers and shed light
on innovative therapeutic strategies. Indeed, impacting senescence
can be beneficial in some physiopathological contexts such as
aging and aging-related diseases. A possible avenue for modulating
senescence could be to manipulate calcium levels or calcium sig-
naling. In this context calcium channels would be good druggable
candidates to target.
Acknowledgement
This work has been supported by the Fondation ARC pour la
recherche sur le cancer.
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