Cellular senescence was formerly described by Hayflick and colleagues, after witnessing that normal diploid cells in culture had a limited number of cell divisions and entered a permanent cell cycle arrest (Hayflick and Moorhead, 1961). Hayflick observed that the nondividing cells remained viable for many weeks and suggested that this proliferative halt and finite lifetime in vitro represented aging at the cellular level (Hayflick, 1965). Several decades later, Hayflick’s proposal was corroborated by attributing this proliferation limit to a progressive telomere shortening after propagation of cells in culture, which is now known as replicative senescence (Harley et al., 1990). The link between replicative senescence and aging was further reinforced when an age-dependent accumulation of cells exhibiting senescence markers in vivo was revealed (Dimri et al., 1995). Two years later, a landmark study demonstrated that the expression of active mitogenic oncogenes (such as Ras) induced senescence in primary cells regardless of the age (Serrano et al., 1997). This process was coined oncogene-induced senescence (OIS) and introduced the concept of senescence working as a tumour-suppressive mechanism to prevent aberrant proliferation after an oncogenic stimulus. Since then, it has been established that cellular senescence can be induced by a wide range of different stress signals, such as oxidative stress (Chen et al., 1995), chemotherapy (Schmitt et al., 2002), induced-pluripotent stem (iPS) cell reprogramming (Krizhanovsky and Lowe, 2009), irradiation (Le et al., 2010), or cytokine treatment (Braumüller et al., 2013). It became then clear that senescence and aging are not synonymous and that senescent cells (SCs) can be triggered by several stressful insults independently of organismal age (Rodier and Campisi, 2011; Figure 1).

Figure 1

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Importantly, SCs stopped being regarded as just undead or zombie cells that refuse to die. Though one might say they walk a fine line between life and death, it is now clear that SCs are much more than what was initially thought. In fact, they suffer numerous phenotypic changes and remain metabolically active cells with a complex secretory phenotype, through which they can modify the surrounding microenvironment (Muñoz-Espín and Serrano, 2014; Figure 1). Strikingly, SCs have recently emerged as beneficial players in various physiological processes, from embryonic development to cellular reprogramming and tissue injury responses such as wound healing and tissue repair (Rhinn et al., 2019).

Senescence: the good, the bad, and the ugly

The discovery of additional cellular senescence features and biological roles provided a shifting view from a simple cell autonomous stress response to a dynamically active mobilization of environmental signalling cues with local or systemic repercussions for tissue function and, ultimately, organismal life. Some of these repercussions are beneficial while others are detrimental (Figure 2). In some contexts, these seemingly paradoxical roles are challenging to reconcile, justifying the apparent chaotic nature of this yet undeciphered phenomenon.

Figure 2

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Aging

In zebrafish, rodents, primates, and humans, SCs are found in many tissues throughout life (Campisi, 2005; Dimri et al., 1995; Jeyapalan et al., 2007; Kishi, 2004). Though relatively rare in young organisms, they accumulate with age in several organs and tissues, such as the skin, heart, lung, spleen, kidney, and liver (Wang et al., 2009; Yang and Fogo, 2010). Aging entails a progressive loss of tissue functions that eventually leads to several chronic and age-related diseases (Campisi, 2013). So, a causal link between cellular senescence and aging seems quite plausible. In fact, senescence has been associated to a wide range of human age-associated pathologies, including cancer, fibrosis, cardiovascular diseases, type 2 diabetes, obesity, sarcopenia, osteoarthritis, osteoporosis, and neurological disorders (Calcinotto et al., 2019; van Deursen, 2014). Remarkably, the use of progeroid mouse models has provided evidence that ablation of p16^INK4a+ cells improves many of these disease symptoms, reinforcing a detrimental role of SCs in aged tissues (Baker et al., 2011; Rhinn et al., 2019).

Some studies have also suggested that, with aging, senescence plays a role in the decline of regenerative capacity, namely by functionally depleting stem cell progenitor pools (Braun et al., 2012; Janzen et al., 2006). This was recently proposed during skeletal muscle regeneration in aged mice (Sousa-Victor et al., 2014). Through aging, geriatric muscle stem cells (MuSCs) suffer a quiescence-senescence switch triggered by an age-associated increase in p38MAPK activation and p16^INK4a expression, becoming unable to activate and expand upon injury. Importantly, inhibition of p38MAPK or p16^INK4a restored quiescence and regenerative functions in MuSCs (Cosgrove et al., 2014; Sousa-Victor et al., 2014). In the aging heart, cardiac progenitor cells (CPCs) progressively lose their regenerative capacity, as senescent CPCs render other healthy CPCs to senesce (Lewis-McDougall et al., 2019). It is still unclear if differentiated muscle cells develop senescent phenotypes, as they age, and consequently induce senescence in stem cell progenitor pools in a paracrine manner.

Similar to a ‘chicken or the egg’ paradox, one might wonder whether it is the accumulation of SCs that leads to aging or the opposite. The mechanisms behind SC accumulation with age and their influence on disease progression are still unclear. Some hypothesize that SCs develop ways to escape from immunosurveillance. In support of this, authors have shown that senescent dermal fibroblasts express atypical levels of MHC molecule HLA-E, induced by SASP-associated cytokines and regulated by p38MAPK (Pereira et al., 2019). HLA-E interacts with the inhibitory receptor NKG2A expressed by natural killer (NK) and highly differentiated CD8⁺ T cells, allowing senescent fibroblasts to evade immune clearance. Others theorize that, with age, the immune system becomes progressively compromised (immunosenescence) and cannot efficiently clear SCs as it should or that the generation rate of SCs is just too big to cope with (Furman et al., 2019). In any case, there is a very important notion to take from the relationship between senescence and aging: a persistent accumulation of SCs without a controlled clearance is detrimental for tissue function.

Cancer

Cellular senescence is a powerful barrier to tumourigenesis (Collado and Serrano, 2010). The first experimental evidence of OIS came from the overexpression of oncogenic Ras in human fibroblasts, resulting in upregulation of p53, p16^INK4a, pRB, and permanent cell cycle arrest (Serrano et al., 1997). This can be bypassed by inactivation of p53 and p16^INK4a or co-expression of other oncogenes like c-MYC, E1A, or DRIL1 (Serrano et al., 1997). BRAF is another oncogene that promotes OIS by inducing p16^INK4a expression, in a process that requires the co-expression of IGFBP7 (Wajapeyee et al., 2008). The loss or inactivation of tumour suppressor genes, such as PTEN, also induces a senescence response (Chen et al., 2005). Loss of PTEN induces p53 through activation of mTOR and ARF-mediated inhibition of MDM2, but also p16^INK4a through upregulation of the transcription factor Ets2 (Ohtani et al., 2001). Contrarily to OIS, PTEN loss-induced senescence occurs in the absence of DNA damage response (DDR) but can also be bypassed by p53 inactivation (Ohtani et al., 2001).

The SASP of senescent tumour cells modulates the tumour microenvironment, which is also composed of non-senescent proliferating tumour cells, stromal cells, and infiltrating immune cells (Calcinotto et al., 2019). Thus, the SASP can act as another blocker of tumour growth by reinforcing autocrine senescence or inducing paracrine senescence in neighbouring tumour cells. For example, release of IL-1α by SCs spreads senescence to normal and tumour cells (Di Mitri and Alimonti, 2016). On the other hand, inhibition of IL-1α and IL-6 promotes OIS evasion (Di Mitri and Alimonti, 2016; Kuilman et al., 2008). Importantly, some SASP factors of tumour cells, such as TGF-β, VEGF, CCL2, and CCL20, also induce senescence in normal cells (Acosta et al., 2013). Highly relevant for tumour regression is the efficient removal of senescent tumour cells by immune cells that are recruited by the SASP itself (Vicente et al., 2016). Likewise, the immune response can then limit tumourigenesis by releasing factors, such as IFN-γ, TNF-α (tumour necrosis factor alpha), and TGF-β, in the tumour microenvironment and inducing senescence in tumour cells, generating a positive feedback loop (Braumüller et al., 2013; Calcinotto et al., 2019; Reimann et al., 2010). Yet, the SASP can also have immunosuppressive properties, attracting a high number of infiltrating myeloid-derived suppressor cells (MDSCs) that block the effect of other immune effector populations and inhibit the senescence response by releasing IL-1 receptor antagonist in the tumour microenvironment (Di Mitri et al., 2014).

Strikingly, the SASP of senescent tumour cells can also promote tumour progression, driving tumour vascularization and invasiveness through secretion of VEGF and a number of different matrix metalloproteinases (MMPs) (Coppé et al., 2006; Coppé et al., 2010). Several other SASP factors, such as Gro-α, basic fibroblast growth factor, and PAI-1, have been shown to stimulate malignant cell growth and cancer invasion. Secretion of IL-6 and IL-8 has been shown to promote both tumourigenesis and tumour suppression in different contexts (Rodier and Campisi, 2011). The SASP stands, therefore, as a double-edged sword, eliciting both antitumourigenic and tumour-promoting effects. SASP effects on cancer progression/suppression seem to rely not only on the context but also on the persistence of SCs through time. In line with this, a recent study has shown that telomerase-deficient zebrafish, who exhibit an accumulation of senescence similar to human aging, display increased systemic chronic inflammation through time, which potentiates cancer incidence and invasiveness (Lex et al., 2020). In fact, pre-cancer lesions developed into cancer at twice the rate if neighbouring tissues were senescent.

Chemotherapy drugs or ionizing radiation are used to induce senescence in cancer cells, in what is called therapy-induced senescence (TIS) (Calcinotto et al., 2019). The mechanisms underlying TIS are usually connected to the DDR. Presently, several TIS drugs are used for human cancer treatment, including Palbociclib, Doxorubicin, Bleomycin, Docetaxel, Cyclophosphamide, Etoposide, Vincristine, and Cisplatin (Ewald et al., 2010). Among all of them, the CDK4/6 inhibitor Palbociclib is currently considered the most relevant prosenescent compound in the clinic. However, in spite of its efficiency in blocking tumour cell proliferation, TIS must be used and monitored with attentive care. By also affecting normal cells, the senescence response might be so intense that the immune system fails to efficiently clear SCs from the tumour microenvironment. Indeed, the accumulation of SCs after TIS has been shown to promote tumour relapse with increased malignancy and premature aging features in human adults and children after chemotherapy (Marcoux et al., 2013; Ness et al., 2015). Furthermore, a recent study has demonstrated that, after TIS, some senescent tumour cells are able to escape from cell cycle blockade and acquire stemness properties with highly aggressive growth potential, which contradicts the terminal proliferative phenotype and has profound implications for the treatment outcome (Milanovic et al., 2018). This has been suggested as a form of tumour cell evasion from therapy, allowing their survival in a transient dormant state with potential to recover self-renewal capacity and lead to disease recurrence, normally with increased malignancy (Saleh et al., 2019). This led to a reassessment of treatment strategies, in view of taking advantage of the beneficial effects of senescence in blocking cancer cell proliferation but controlling subsequent detrimental outcomes due to its accumulation. As a result, current therapeutic strategies generally encompass a double approach, involving an initial pro-senescent step followed by an anti-senescent phase (Calcinotto et al., 2019). In summary, chemo/radiotherapy or senescence-inducing drugs can be combined with senolytic drugs that eliminate excess senescent tumour cells that are not efficiently cleared by the immune system. Additionally, modulation of the SASP or MDSC function (e.g. with antagonists of CXCR2, a receptor for several SASP cytokines) may be used to enhance the efficacy of pro-senescence therapies and promote senescence immune surveillance (Calcinotto et al., 2019; Toso et al., 2014).

The role of senescence in cancer rightfully epitomizes the good, the bad, and the ugly sides of this cellular phenomenon, by suppressing tumour growth in early stages, contributing to tumour development in later stage and eliciting tumour relapse and increased malignancy after arrest escape or chemotherapy. Importantly, with aging, this scenario becomes even more grim as SCs accumulate and supply pro-tumourigenic chronic inflammatory environments.

Development

The discovery of SCs throughout embryonic development was very exciting and brought relevant insights to better understand the physiological roles of senescence. So far, SCs have been found during development of mouse and human embryos (Chuprin et al., 2013; Muñoz-Espín et al., 2013; Storer et al., 2013), but also in naked mole rats (Zhao et al., 2018), birds (Gibaja et al., 2019; Nacher et al., 2006; Storer et al., 2013), amphibians (Davaapil et al., 2017; Villiard et al., 2017), and fish (Da Silva-Álvarez et al., 2020; Villiard et al., 2017) embryos and/or larvae. SCs in developing embryonic structures exhibit SA-β-gal activity and upregulation of p21^CIP1, while expression of other senescence markers, like p53, p16^INK4a, and DDR, is absent (Muñoz-Espín et al., 2013). This suggests a different senescence phenotype from that observed later in life and pinpoints the relevance of p21^CIP1 in developmental senescence. Indeed, genetic disruption of p21^CIP1 or senolytic treatment results in loss of senescence and patterning abnormalities in various structures (Davaapil et al., 2017; Gibaja et al., 2019; Muñoz-Espín et al., 2013; Storer et al., 2013). Interestingly, patterning defects are only observed transiently and are eventually compensated by other mechanisms, namely apoptosis (Muñoz-Espín et al., 2013; Storer et al., 2013). This suggests that SCs are intrinsic to development but not essential.

Overall, existing studies suggest that developmental senescence is not a damage-triggered event but rather a highly organized and programmed process with precise patterns in time and space, which may be orchestrated by other cues such as biophysical forces during morphogenesis. During development, SCs seem to contribute to tissue remodelling by controlling the balance of cell populations, fine-tuning of cell fate specification, morphogenetic signalling, and structural degeneration (the latter mediated by macrophage-dependent elimination).

Wound healing and tissue repair

A role of senescence in wound healing and tissue repair has been described in several organs, such as the liver (Krizhanovsky et al., 2008), the skin (Demaria et al., 2014; Jun and Lau, 2010), the heart (Meyer et al., 2016; Zhu et al., 2013), and the lung (Schafer et al., 2017; Table 1). In all cases, SCs seem to be closely associated with the levels of fibrotic tissue generated upon wound resolution, which in turn affect the outcome of the repair process (Baker et al., 2016; Yun, 2018). The deposition of ECM is critical for the maintenance of tissue integrity during wound healing but, if left unchecked, may lead to fibrosis and scarring. In the skin, CCN1, a matricellular protein expressed upon wound healing, elicits a senescence response in fibroblasts by triggering p53 and p16^INK4a via ERK and p38MAPK pathways (Jun and Lau, 2010). This response controls the proliferation of fibroblasts and ECM deposition, limiting the fibrotic scar and contributing to the healing process. Importantly, defects in CCN1 lead to fibrosis exacerbation (Jun and Lau, 2010). Also in the skin, in a more recent study using the p16-3MR transgenic model, Demaria and colleagues demonstrated that a transient accumulation of senescent fibroblasts and endothelial cells at the wound site induces myofibroblast differentiation through secretion of platelet growth factor AA (PDGF-AA) (Demaria et al., 2014). Elimination of p16⁺ cells resulted in delayed wound healing and increased fibrosis. Notably, topical administration of PDGF-AA reverted the delay in wound closure while maintaining the levels of fibrotic tissue, suggesting more SASP factors (likely MMPs) are involved in the healing process. In a mouse model of chronic liver damage, the administration of CCl₄ induces fibrotic scarring and senescence in hepatic stellate cells (HSCs) also via a CCN1/p53/p16^INK4a pathway (Krizhanovsky et al., 2008). Senescent HSCs facilitate fibrotic resolution through secretion of MMPs. Finally, the cycle is completed by recruitment of NK cells to promote their own elimination. Moreover, p53;INK4A/ARF null mice displayed decreased numbers of senescent HSCs and extensive cirrhosis upon CCl₄ treatment (Krizhanovsky et al., 2008). A time-controlled SASP-mediated clearance of SCs seems to be, in fact, a fundamental step for the outcome of the repair process. In a recent study using both human and mouse models of ischemic retinopathy, the SASP of senescent endothelial cells stimulated neutrophil recruitment and the extrusion of neutrophil extracellular traps, which both removed dysfunctional endothelial SCs and facilitated vascular pruning and repair (Binet et al., 2020).

Table 1

Species	Model (tissue/type of injury)	Role (beneficial vs. detrimental)	Profile (transient vs. persistent)	Main findings	Biomarkers	SASP factors (identified)	Reference
Mouse	Cutaneous wound healing	BeneficialAnti-fibrotic.	N/E	- CCN1 → DNA damage/p53 activation + ROS-dependent p16INK4a/pRB activation → fibroblast senescence → ↑ expression of antifibrotic genes- CCN1 mutant mice → ↓ senescence → exacerbated fibrosis	SA-β-Gal, p16INK4a, p53	IL-6, IL-8, IL-11, MMP1, MMP3	Jun and Lau, 2010
Mouse	Cutaneous wound healing	BeneficialAnti-fibrotic.Promote differentiation.	Transient	- Fibroblast and endothelial cell senescence at the wound site → PDGF-AA secretion → myofibroblast differentiation- Elimination of p16INK4a+ cells → delayed wound healing + ↑ fibrosis	SA-β-Gal, p16INK4a, p21CIP1,↓ laminB1	PDGF-AA, VEGF, PAI-1, CCL5, and CCL2	Demaria et al., 2014
Mouse	Chronic liver damage	BeneficialAnti-fibrotic.Recruitment of immune system.	N/E	- CCl4 administration → activation of CCN1/p53/p16INK4a pathway → hepatic stellate cell senescence → secretion of MMPs → fibrotic resolution → recruitment of NK cells to promote their own clearance- p53;INK4A/ARF null mice → ↓ senescence upon CCl4 treatment → ↑ cirrhosis	SA-β-Gal, p21CIP1, p53, HMGA1	MICA, IL-8, ULBP2, CD58,MMP1, MMP3	Krizhanovsky et al., 2008
Mouse	Heart infarction	BeneficialAnti-fibrotic.	Transient	- CCN1-dependent cardiac myofibroblast senescence → ↓ fibrosis → improved heart function- p53 deficiency → ↑ collagen deposition	SA-β-Gal, p16INK4a, p21CIP1, p53, p19ARF	MMP2, MMP9, IL-6, IL-11, CXCL1	Zhu et al., 2013
Mouse	Cardiac hypertrophy	BeneficialAnti-fibrotic.	N/E	- CCN1-dependent cardiac myofibroblast senescence → ↓ fibrosis → improved heart function- SC genetic ablation → ↑ fibrosis	SA-β-Gal, p16INK4a, p21CIP1,	N/E	Meyer et al., 2016;
Mouse	Cardiac ischaemia-reperfusion injury	Detrimental.Pro-fibrotic.Pro-inflammatory.	Persistent	- Oxidative stress → Cardiomyocyte and interstitial cell senescence → ↑ fibrosis and inflammation → impaired heart function- SC clearance → ↓ scar size and inflammation + ↑ myocardial vascularization → improved heart function	SA-β-Gal, p16INK4a, p21CIP1,	IP-10, TGF-β3, IL-6, IL-11, IL-16, CCL22, MIP-3β, CX3CL1	Dookun et al., 2020
Human/mouse	Ischemic retinopathy	BeneficialRecruitment of immune system.Pro-regenerative.	Transient	- Rapid proliferation of vascular cells → ↑ endothelial cell senescence → cytokine secretion+ neutrophil recruitment → formation of neutrophil extracellular traps (NETs) → removal of SCs → regression of pathological angiogenesis + regeneration of functional vessels- Inhibition of NETosis / neutrophil inactivation → impaired SC clearance → no regression of pathological angiogenesis	SA-β-Gal, PML	CXCL1, IL-1β	Binet et al., 2020
Mouse	Idiopathic pulmonary fibrosis (IPF)	Detrimental.Promote differentiation.Pro-fibrotic (indirectly).	Persistent	- Accumulation of senescent epithelial cells and fibroblasts → myofibroblast differentiation → ↑ fibrosis- SC elimination (genetic ablation and pharmacological) → improved pulmonary function and physical health	P16INK4a, p53, γH2AX	PAPPA, IGFBP2, IGFBP4, COL1A1, MMP10, MMP12, VCAM1, MCP1, PAI1, TNF-α	Schafer et al., 2017
Salamander	Limb amputation	N/E	Transient	- Turnover of SCs (unidentified) at injury site during regeneration	SA-β-Gal(in vivo)	N/E(in vivo)	Yun et al., 2015
Zebrafish/mouse (P1)	Heart injury	N/E	Transient	- Turnover of senescent cardiac fibroblasts during regeneration	SA-β-Gal, p53	N/E	Sarig et al., 2019
Zebrafish	Caudal fin amputation	Beneficial.	Transient	- Turnover of SCs (unidentified) at injury site during regeneration.SC removal → impaired regeneration	SA-β-Gal, p21CIP1	N/E	Da Silva‐Álvarez et al., 2019
Mouse	Acute muscle injury	Beneficial.Anti-inflammatory.Pro-regenerative.	Transient	- Senescence of fibro-adipogenic progenitors (FAPs) → cytokine secretion → anti-inflammatory environment → muscle regeneration	SA-β-Gal, γH2AX, p16INK4a, p53	TSG-6IL-33	Saito et al., 2020
Mouse	Biliary injury	Detrimental.Pro-fibrotic.Pro-inflammatory.Paracrine senescence.	Persistent	- Senescent cholangiocytes → TGF-β secretion → paracrine senescence of cholangiocytes and hepatocytes → ↑ fibrosis and inflammation → impaired liver regeneration- Inhibition of TGF-β-signaling → disruption of paracrine senescence → restoration of liver function	p16INK4a, p21CIP1, DCR2,γH2AX, p27, p53	TGF-β, IL1α	Ferreira-Gonzalez et al., 2018
Zebrafish	Spinal cord injury	N/E	Transient	- Turnover of senescent neurons at lesion periphery during regeneration	SA-β-Gal, p21CIP1,No BrdU	N/E	Paramos-de-Carvalho et al., 2021
Mouse	Spinal cord injury	Detrimental.Pro-inflammatory.Pro-fibrotic.	Persistent	- Continuous accumulation of senescent neurons at lesion periphery.- SC pharmacological depletion → ↑ myelin and axonal sparing + ↓ fibrosis and inflammation → improved motor and sensory functions	SA-β-Gal, p16INK4a,γH2AX	Amphiregulin, PDGF-BB, IGFBP-3, Serpin E1, IL-15, TNF- α, M-CSF, I-TAC, CCL11, ICAM-1, CCL20	Paramos-de-Carvalho et al., 2021

1. N/E - not explored.

The contrasting effects of transient vs. persistent senescence responses are further substantiated upon cardiac injury. In mouse models of cardiac hypertrophy and heart infarction, cardiac myofibroblasts enter senescence through a CCN1-dependent manner, reducing fibrosis in the short-term and improving heart function (Meyer et al., 2016; Zhu et al., 2013). However, after cardiac ischaemia-reperfusion injury, a long-term oxidative stress-induced senescence response in cardiomyocytes and interstitial cells promotes fibrosis and mediates a pro-inflammatory SASP, impairing heart function (Dookun et al., 2020). Similarly, in a mouse model of idiopathic pulmonary fibrosis (IPF), a chronic lung disease characterized by decreased lung function due to persistent scarring, senescent epithelial cells and fibroblasts accumulate continuously over time, inducing myofibroblast differentiation and exacerbating the fibrotic response (Schafer et al., 2017). In this case, the elimination of SCs improves the disease condition.

Together, these results suggest that timely and coordinated activation of SCs controls the early fibrotic response and is beneficial for wound repair. Yet, in the absence of proper clearance, persistent SCs accumulate and have a negative impact in tissue repair (Figure 2).

Regeneration

Though still a very understudied topic, recent findings suggest that SCs have indeed a part to play in regenerative processes (Table 1). In 2015, the team of Jeremy Brockes (UCL, London) reported a recurrent turnover of senescence during limb regeneration in the salamander (Yun et al., 2015). SCs were transiently induced near the amputation plane throughout regeneration and subsequently cleared by a macrophage-dependent immunosurveillance mechanism. This finding led to the obvious question of whether these transient SCs could be contributing to the regenerative response. Considering that salamanders regenerate limbs through dedifferentiation (Tanaka et al., 2016), this model constitutes a good system to study the impact of senescence on this particular process of cellular plasticity. However, due to the scarcity of tools to manipulate SCs in this model and assess their function, it is still unclear how senescence contributes to limb regeneration. One hypothesis is that SCs might stimulate dedifferentiation and/or create a more pro-regenerative microenvironment through the SASP (e.g., ECM remodelling, vascularization). Recruited immune cells, namely macrophages and NK cells, can also execute pro-regenerative functions (Godwin et al., 2013; Lucas et al., 2010; Rajagopalan and Long, 2012). Another possibility is that SCs work as a population balancing mechanism, controlling the proliferation of certain cell types during tissue re-growth and patterning, much like during development. Yet, it is possible that SCs are just a consequence of the local tissue damage cues from the injury and need to be removed, which then still raises the question of why not follow the apoptosis route instead. Whatever the case, current understanding of the functions of cell senescence tells us that these cells are likely modulating the surrounding microenvironment.

So far, very few studies have associated cellular senescence to regeneration, with most being accounted for during the past 5 years. In 2019, a transient burst of SA-β-gal⁺ cardiac fibroblasts was reported in zebrafish and neonatal mouse hearts after an injury (Sarig et al., 2019). Even though the effects of senescence on cardiac regeneration are yet to be determined, a study from 2015 demonstrated that telomerase-deficient zebrafish display an aberrant accumulation of SCs and fail to regenerate their hearts (Bednarek et al., 2015). Also in 2019, another study showed evidence of a transient accumulation of SCs after zebrafish caudal fin amputation (Da Silva‐Álvarez et al., 2019). In this case, tissue regeneration was impaired by removal of SCs with a senolytic drug, a type of drug that acts by inducing apoptosis in SCs (Zhu et al., 2015).

Yet, the association of senescence with regeneration phenomena goes beyond organisms with outstanding regenerative capabilities. In a mouse model of chronic inflammatory myopathy, senescence of fibro-adipogenic progenitors (FAPs) in response to exercise-induced muscle damage is necessary to promote functional recovery and muscle regeneration (Saito et al., 2020). In addition, the expression of p53 was found to be upregulated in the rat soleus muscle after a spinal cord injury (Graham et al., 2020). This upregulation disappears 3 months after injury, accompanied by a reduction in the expression of p16^INK4a. Even though this study lacks the identification of some key senescence biomarkers, such as SA-β-gal and p21^CIP1, it does seem to point to another transient turnover of SCs in tissues with regenerative capacity.

In a mouse model of biliary injury, TGF-β secretion-mediated paracrine senescence of cholangiocytes and hepatocytes was shown to have deleterious repercussions in the surrounding microenvironment and impair liver regeneration (Ferreira-Gonzalez et al., 2018). The inhibition of TGF-β signalling disrupted the continuous propagation of senescence, reduced collagen deposition, and restored liver function. This work attests the detrimental impact of a persistent SASP exposure in regenerative paradigms.

In our lab, we have recently provided evidence that there are distinct senescence responses induced after a spinal cord injury between two animal models with different regenerative capabilities (Paramos-de-Carvalho et al., 2021). In this study, the regenerating zebrafish exhibits a transient accumulation of SCs at the lesion periphery, which are then cleared out. In contrast, in the injured mice SCs persistently accumulate over time and are not eliminated. Targeting of SCs in the mouse spinal cord in order to prevent their accumulation after injury resulted in improved motor, sensory, and bladder functions, supported by beneficial effects on myelin preservation, axonal growth, fibrotic resolution, and inflammation. These effects were accompanied by a reduced secretion of pro-fibrotic and pro-inflammatory factors in the injury microenvironment (Table 1). This work highlights the role of SCs in modulating the spinal cord injury microenvironment, which is permissive for regeneration in the zebrafish but is inhibitory in mammals.

Transversal to all these reports is the timely elimination of SCs, which suggests that their persistence could eventually turn detrimental for the regenerative response. Current knowledge seems to support this hypothesis, given the outcome of transient vs. persistent SASP exposure in pathological conditions or aging.

Reprogramming

Recent studies have uncovered another unexpected facet of senescence: a role in cellular reprogramming. This facet became even more interesting when it was discovered that senescence has opposite effects in vitro and in vivo reprogramming. In vitro, the expression of the four Yamanaka factors (OCT3/4, SOX2, KLF4 and c-MYC, OSKM) activates senescence markers in targeting cells, such as SA-β-gal, p16^INK4a, p21^CIP1, and SAHF (Banito et al., 2009). This seemingly intrinsic barrier to reprogramming probably explains why the iPS cell generation efficiency is so low (≈0.02%) (Takahashi et al., 2007; Takahashi and Yamanaka, 2006). In fact, silencing of senescence-associated genes like p53, CIP1, and INK4a has been shown to increase iPS cell generation rate from mouse and human fibroblasts (Banito et al., 2009; Hong et al., 2009; Li et al., 2009). Strikingly, cellular senescence exerts a contrary effect on in vivo reprogramming. Such has been demonstrated in mice engineered to transiently express the four OSKM factors in an inducible fashion (i4F). i4F wild-type mice exhibited co-expression of SA-β-gal and NANOG, a pluripotency marker (Mosteiro et al., 2016). Without INK4a/ARF, this co-expression was lost. Remarkably, in mouse models of lung and muscle damage in which senescence is induced at the lesion sites, the efficiency of reprogramming of i4F mice was increased (Chiche et al., 2017; Mosteiro et al., 2016). This efficiency was also enhanced in conditions that elicit senescence activation, including Palbociclib treatment, irradiation, and even aging. On the other hand, reprogramming was decreased after p16^INK4a deletion or treatment with the senolytic drug ABT-263 (Chiche et al., 2017; Mosteiro et al., 2016). This senescence-induced favourable environment for reprogramming was found to be mediated by secretion of the SASP factor IL-6 that activates the JAK/STAT target PIM1 to promote cellular plasticity, which can be reverted by treatment with IL-6 antibodies (Chiche et al., 2017; Mosteiro et al., 2016). In another study, Ras-mediated OIS in the skin and liver was shown to induce the expression of stemness markers, such as CD34, Lgr6, and Nestin, in senescent keratinocytes (Ritschka et al., 2017). This was also demonstrated to be SASP-dependent, as it was abolished with nuclear factor kappa B (NF-κB) inhibition. However, the expression of stemness markers was overcome by senescence features upon a longer (6 days) exposure to the OIS-driven SASP, which was proposed as a cell-intrinsic anti-tumourigenic response to counteract stemness. It is interesting to speculate that there is a risk that a short exposure to an oncogenic trigger can initiate a premature senescent response entailing a stemness profile with aberrant plasticity and high tumour-initiating capability. In any case, the relationship between senescence and reprogramming seems to be defined by the time of exposure to the SASP.

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Author details

1. Diogo Paramos-de-Carvalho

   1. Instituto de Medicina Molecular – João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
   2. CEDOC, NOVA Medical School, Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisbon, Portugal

   Contribution

   Conceptualization, Figures design., Writing - original draft, Writing - review and editing

   For correspondence

   diogo.paramos@gmail.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2274-7167

2. Antonio Jacinto

   CEDOC, NOVA Medical School, Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisbon, Portugal

   Contribution

   Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4193-6089

3. Leonor Saúde

   Instituto de Medicina Molecular – João Lobo Antunes e Instituto de Histologia e Biologia do Desenvolvimento, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

   Contribution

   Conceptualization, Writing - review and editing

   For correspondence

   msaude@fm.ul.pt

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5933-8872

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