The Communication of Senescence-Associated Secretory Phenotype: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Hugo Paulus.

Cellular senescence is a complex cell state that can occur during physiological ageing or after exposure to stress signals, regardless of age. It is a dynamic process that continuously evolves in a context-dependent manner. Senescent cells interact with their microenvironment by producing a heterogenous and plastic secretome referred to as the senescence-associated secretory phenotype (SASP). Hence, understanding the cross-talk between SASP and the microenvironment can be challenging due to the complexity of signal exchanges.

  • ageing
  • senescence
  • intercellular communication
  • senescence-associated secretory phenotype (SASP)
  • microenvironment

1. Introduction

Cellular senescence was first described as a stable and irreversible cellular state, in which cells permanently stop proliferating while remaining metabolically active. Since then, our understanding and definition of cellular senescence and its various roles have constantly evolved. Currently, senescence is presented as a complex and partially heterogeneous phenotype that can occur in response to the exhaustion of the proliferative capacity of the cell, and/or as a result of exposure to intrinsic and extrinsic stressors [1,2,3,4,5][1][2][3][4][5].
Since there is no universal marker for senescence, a combination of specific biochemical markers and phenotypic features is necessary to identify senescent cells. However, there is no consensus on the number and type of markers required to identify senescent cells, as one senescent cell is not equivalent to another [6]. Despite this, multiple pieces of evidence in the literature suggest that senescent cells share several characteristics, including a strong or prolonged growth arrest, an altered metabolism [3[3][4],4], and a specific senescence-associated secretory phenotype (SASP) [7,8,9,10][7][8][9][10]. Although SASP is a hallmark shared by various types of senescence, it is heterogeneous and can evolve in conjunction with changes in gene and protein expression, impacting biochemical features, trafficking, and intercellular signaling [3]. The diversity and the dynamic nature of SASP make it a complex process to understand, which is well demonstrated by its close association with both beneficial and detrimental effects depending on the physiological context [1,11,12,13,14,15][1][11][12][13][14][15].
These diverse effects are commonly linked with key SASP proteins whose secretion is increased in different senescence models. However, the variable component of SASP, which is modulated according to context, is often neglected in current knowledge, despite its importance.

2. Characteristics of SASP

During its lifespan, a cell can release a range of molecules into its surrounding extracellular environment. The secretory profile is constantly influenced by intrinsic characteristics, which depend on the cell type and its differentiation stage, as well as extrinsic factors such as the change in the cellular environment. Indeed, a clear remodeling of the secretory profile can be observed in cells undergoing senescence [58][16]. Examining the secretome of senescent cells reveals modifications in the levels of soluble, insoluble, and extracellular vesicle (EV)-related components. Senescence establishment can cause these components to be either exacerbated or partially depleted, and can also lead to the secretion of new components when compared to proliferative cells [59][17].

2.1. Reported SASP Factors

Senescent cells exhibit a distinct and dynamic secretome different from their exponentially growing counterparts [60][18]. This SASP is complex and is composed of hundreds of different proteins and non-protein signaling molecules [60,61][18][19]. Despite the diversity of the factors secreted, a core protein secretome can be distinguished from the soluble part of SASP (sSASP). In human primary fibroblasts subjected to various senescence inducers (IR, RAS, atazanavir (ATV)), this core protein sSASP includes, among others, STC1 (stanniocalcin 1), chemokines such as CXCL1 (C-X-C motif ligand 1), and proteases such as MMP-1 (matrix metalloproteinase 1) [60][18]. Hemostasis-related factors, another class of bioactive compounds, show a marked increase in secretion into the extracellular medium by senescent human primary fibroblasts when exposed to different inducers (IR, doxorubicin (DOX), and MiDAS) [61][19]. Non-protein signaling molecules, including various bioactive oxidized lipid metabolites, prostaglandins, and nitric oxide can also be found enriched in the sSASP of senescent cells [62,63,64,65][20][21][22][23]. While empirical research has focused on soluble factors secreted by senescent cells, new studies show evidence that EVs are also a substantial and effective part of SASP [66][24]. EVs are lipid membrane vesicles containing cytosol from the secreting cells and are released by multiple cell types. According to their origin, biological function, and secretion, EVs can be classified into two main subtypes: exosomes and microvesicles (MVs) [67][25]. In this context, it has been evidenced in multiple cell types that EV secretion increases after exposure to different senescence inducers, with changes in cargo composition including proteins and genomic content such as microRNAs (miRNAs) and lipids [63,68,69][21][26][27]. The core secretome is a concept based on a limited number of established cellular models used to study senescence, such as human primary fibroblasts, and represents only a portion of the complete picture. Hence, the application of a core SASP should be considered as a tool to evaluate the acquisition of the senescent phenotype in a standardized manner, rather than a way to generalize the effects of SASP on the cellular microenvironment. Indeed, the bioactive effects of SASP may be more closely linked to specific and possibly subtle variations in the secretome that result from the combination of a specific cell type and a particular senescence inducer, rather than the shared components.

2.2. SASP Heterogeneity and Plasticity

Coppé and colleagues demonstrated initially that only a subset of SASP proteins was shared between fibroblasts and prostate epithelial cells upon irradiation-induced senescence (IRIS) [9]. A subsequent large-scale proteomic analysis of SASP then revealed only 58 shared SASP factors between fibroblasts and renal epithelial cells in IRIS [60][18]. When considering other proteomic studies on various cell types and senescence inducers, such as UVA-induced senescent keratinocytes and IRIS mesenchymal stem cells [71[28][29],72], the number of shared SASP factors drops to 19, suggesting that only a handful of proteins are commonly secreted across all types of senescent cells. Given the differences in experimental parameters such as EV isolation methods, detection techniques, and time points assessed after senescence induction, comparing these studies remains challenging. Secondly, some SASP factors are secreted at different times depending on the cell type. For instance, in IRIS, the IL-1β gene is overexpressed on days 10 and 20 in fibroblasts, but only on day 10 in keratinocytes, and on day 20 in melanocytes [73][30]. This point emphasized SASP plasticity over time. Moreover, it showed an increased secretion of IL-6 and IL-8 in UVB-induced senescent keratinocytes on day 3 that disappeared on day 7 following senescence induction [70][31]. Thirdly, SASP composition is also influenced by the senescence inducers. Senescent IMR-90 fibroblasts present a different secretome profile depending on whether the senescence was induced by X-rays, ATZ, or RAS overexpression [60][18]. Similar results were observed on mesenchymal stem cells in senescence induced by oxidative stress, doxorubicin treatment, X-ray irradiation, or replicative exhaustion [72][29]. Finally, the matrix and cellular microenvironment of senescent cells can impact their secretome composition. The substrate stiffness impacts the NF-κB phosphorylation status in UV-induced senescence in fibroblasts [75][32], suggesting that the ECM composition could have an impact on SASP composition.

3. Regulation of SASP

The regulation of SASP involves transcriptional, post-transcriptional, epigenetic, and translational mechanisms. In addition, the secretion of SASP components is regulated through intracellular trafficking, and many compartments of secretion are altered during senescence. These alterations could potentially affect the dynamic and heterogeneous composition of SASP.

3.1. Transcriptional Regulation

Multiple signaling pathways have been identified to activate transcription factors that play a crucial role in regulating the expression of inflammatory cytokines. First, there is a clear link between the expression of SASP and the DNA Damage Response (DDR) pathway, as several DDR proteins (ATM, Chk2, and NBS1) are necessary for the initiation and maintenance of the cytokine response in IRIS fibroblasts [29][33]. It has recently been described that in the absence of DNA damage, such as after sodium butyrate treatment, the SASP of fibroblasts still relies on the non-canonical activation of DDR and the accumulation of ATM, MRE11, and NF-kB on chromatin [77][34]. Then, the NF-κB and C/EBPβ transcription factors were identified to be involved in the regulation of CXCR2 ligands expression, including IL8 in fibroblasts in OIS [79][35]. The activation of NF-κB in fibroblasts has been demonstrated to depend on GATA4, whose regulation by p62 is suppressed during senescence but mediated by DDR-related ATM and ATR [80][36]. NOTCH1 plays a dual role in the regulation of SASP. It is positively associated with early SASP expression in OIS in fibroblasts but then represses late SASP expression by suppressing C/EBPβ expression [81][37].  Finally, the cGAS/STING pathway has been highlighted to be involved in the regulation of inflammatory SASP factors, notably, IL-6 and CXCL10 secretion, via NF-κB activation in vitro and in vivo [84][38], following the detection of cytoplasmic chromatin fragments (CCFs) [85][39] associated with a loss of nuclear integrity following Lamin B1 (LMNB1) downregulation [86][40]. It has recently been demonstrated that COX2 plays an important role in regulating the expression of several inflammatory SASP components in OIS through an autocrine feedback loop involving prostaglandin E2 (PGE2) binding to EP4, but the downstream pathways of PGE2 and EP4 remain unknown.

3.2. Post-Transcriptional Regulation

While early SASP is mainly regulated at the transcriptional level, its long-term SASP expression is mainly driven by post-transcriptional mechanisms. This has been demonstrated by the lack of impact of actinomycin D treatment, an inhibitor of transcription, on the expression of several SASP factors [88][41]. P38MAPK appears to be an important factor in the temporal regulation of SASP. If it is first activated after the induction of senescence, it enables the expression of SASP factors, such as IL-6 and IL-8, through NF-κB activation in IRIS fibroblasts [89][42]. It is also involved in the subsequent post-transcriptional regulation of SASP by restricting the binding of AUF1 to the 3′-UTRs of several SASP mRNAs, including IL-6 and IL-8, thereby preventing their destabilization, as demonstrated in bleomycin-induced senescent fibroblasts [88][41]. The mTOR pathway is also involved in the post-transcriptional regulation of SASP. Specifically, mTOR activates the translation of MK2 (or MAPKAPK2), which can phosphorylate and inhibit the RNA-binding protein ZFP36L1, also involved in the destabilization of several SASP mRNAs [90][43]. The mTORC1 kinase has also been shown to modulate senescence-induced inflammation and SASP [91][44].

3.3. Epigenetic Regulation

The physical clustering of SASP genes, such as MMPs (MMP-1, -3, -10, and -12) or chemokines (CXCLs and CCLs), suggests that the regulation of their expression may depend, at least in part, on broader changes in chromatin conformation [94][45]. Indeed, several histone variants can influence the expression of SASP genes. For example, the relocation of the macroH2A1 histone variant away from SASP genes following ER stress response-mediated activation of ATM in fibroblasts in OIS is involved in the maintenance of SASP gene expression [56][46]. Moreover, the increased expression of histone variant H2A.J in fibroblasts undergoing etoposide-induced senescence enhances the expression of multiple genes associated with inflammation and immune response. This effect is likely attributed to the interaction of H2A.J with other factors [95][47].

3.4. Secretory Control: Compartments of Secretion and Vesicular Trafficking

Even though most organelles are morphologically or functionally affected during senescence, their proportion increases in senescent cells due to various signaling defects. In addition to nuclear and mitochondrial dysfunction, the endoplasmic reticulum, Golgi apparatus, and lysosomal compartments are strongly involved in the generation, processing, and release of SASP factors [91][44]. The ER is the site of membrane biosynthesis used in secretory and excretory pathways. It is responsible for folding and maturating secreted proteins, making it the first compartment of secretion. Recently, it has been proposed that ER stress and the subsequent activation of the unfolded protein response upon senescence could contribute to the modified secretome of senescent cells [98][48]. While there are multiple connections between the UPR and inflammation [99[49][50],100], the UPR and normal or tumoral secretome [101[51][52][53],102,103], as well as the UPR and direct control of MMPs [104][54], the data directly linking ER stress with SASP are scarce. The Golgi structure is also altered in senescent cells [105][55]. These alterations can not only be mediated by the translocation of a G protein γ subunit from the plasma membrane to the Golgi [106][56] but also by the impaired expression of the vacuolar ATPase ATP6V0A2, which acidifies organelles such as Golgi, endosomes, or lysosomes [107][57].  Lysosomes are at the crossroads of endocytic and exocytic pathways, and their increased abundance in senescent cells may be associated with the exacerbation or deregulation of these pathways. Besides their partnership with the Golgi apparatus and the endosomal compartments, lysosomes are also important for the clearance of cytoplasmic chromatin fragments (CCFs). CCFs may leak from the nucleus in the cytoplasm of senescent cells and induce an SASP; both CCFs and SASP inductions would be related to a retrograde mitochondrial–nucleus signaling pathway associated with the mitochondrial increase in ROS species [91][44]. Small EV and exosome secretions are now part of the specific secretory phenotype. The release of senescence-associated exosomes is linked to RAB27A expression, as silencing of RAB27A leads to decreased exosome secretion in fibroblasts undergoing RS or OIS [110][58]. Rab27 GTPases are associated with the connection of multivesicular endosomes and the secretion of exosomes [111][59]. The enhanced biogenesis of EVs and their release by senescent cells have been demonstrated to be associated with the extent of DNA damage generated by the senescence inducer, as well as the activation of the ceramide synthetic pathway [112][60]. EVs and exosomes also contribute to SASP and its paracrine impact. 

4. Senescence and SASP In Vivo

Senescent cells accumulate in tissues with age. A meta-analysis showed that even if the proportion of senescent cells in 14 different human tissues is correlated with chronological age, it varies depending on the tissue type and the senescence marker used [114][61]. Moreover, the accumulation of senescent cells is also detected at pathological sites due to various stress signals regardless of age [115][62]. As a result, there is a wide diversity of senescent cells throughout the body. Furthermore, several studies have indicated that the elimination of senescent cells using transgenic mice, such as the INK-ATTAC and p16-3MR mouse models that both specifically target the elimination of p16-positive cells [15[15][63],116], or through the use of small pharmacological molecules called senolytics (which kill senescent cells) or senomorphics (which suppress some or all of their phenotype/properties) has shown improvements in healthspan, alleviated several age-associated conditions, delayed tumor formation, and mitigated the side effects of chemotherapy [117,118,119,120][64][65][66][67]. Another study showed that doxorubicin-induced senescence enriched the SERPINE1/PAI-1 SASP factor in plasma in vivo [61][19]. However, these markers can also serve as biomarkers for several diseases such as cardiovascular, metabolic, neurodegenerative, and malignant diseases, regardless of age. This makes them indicators of a “state of ageing” rather than a chronological accumulation of senescent cells. Surprisingly, the production of SASP factor IL-6 is increased in in vitro senescent models, but the circulating levels of IL-6 are not significantly different between young and elderly subjects [121,122][68][69]. 

5. Pleiotropic Roles of SASP

5.1. Extracellular Matrix Remodeling

Collagen alterations in the dermal ECM have been associated with the decline in human skin structure and function during ageing. This emphasizes the overexpression of cysteine-rich protein 61 (CCN1) and MMP-1 expression in the SASP of senescent fibroblasts [127][70]. Changes in ECM composition and ECM-degrading molecules produced by SASP also disrupt elastin and collagen fiber networks and basement membranes in ageing tissue [128][71]. In the context of tissue injury, senescent cells can play a role in regeneration by accelerating wound healing or limiting fibrosis. For instance, the transient secretion of PDGF-AA (Platelet-derived growth factor AA) from senescent fibroblasts is necessary for effective healing following skin injury [15]. Strikingly, the short-term presence of miR-23a-3p in EVs derived from senescent fibroblasts allows a faster wound closure of epidermal keratinocytes [129][72]. However, to date, few studies have investigated the link between senescent cells and ECM since the matricellular protein CCN1 has been shown to induce ROS-induced senescence in fibroblasts during wound healing [130][73]. 

5.2. Tumor Suppression and Promotion

While cellular senescence is widely recognized as an anti-tumor barrier, there is growing evidence to suggest that senescence may also have a tumor-promoting role. Senescent cells have been observed at sites of benign tumors, such as prostatic hyperplasia and melanocytic naevi [136,137][74][75]. The factors secreted by these cells influence the tissue microenvironment and impact cellular differentiation and proliferation, notably in cancer cells [136,138][74][76]. Moreover, the first studies pointing out the role of the cellular microenvironment in the promotion of cancer progression highlighted the role of Carcinoma-Associated Fibroblasts (CAFs) in prostate cancer progression [139][77]. It has been subsequently reported that senescent fibroblasts share many features with CAFs, and can have a similar impact on the differentiation of epithelial cells initiated by cancer, and on tumor growth both in vitro and in vivo [13,140][13][78]. Another point is that the alteration in the secretion of ECM components and regulators by senescent prostate cells generates a favorable environment for tumor development [148][79]. UVB-induced senescent fibroblasts were shown to produce an ECM that promotes proliferative signaling pathways of preneoplastic HaCaT epidermal keratinocytes [149][80]. Enhanced collagen deposition has been described along breast cancer progression, with dysregulated architecture and increased reticulation via abnormal expression of lysyl oxidase and MMP-resistant collagen isoforms, contributing to carcinoma progression [150][81]. 

5.3. Senescence Induction and Reinforcement

In addition, SASP primarily influences the induction and reinforcement of senescence. It is now clear that senescent cells maintain their phenotype through an autocrine positive feedback loop in which the main factors identified are cytokines such as IL-6 and IL-8 [79,153][35][82]. Similarly, the same SASP factors and many others such as TGF-β family ligands, VEGF, and chemokines such as CCL2 and CCL20 also play an important role in inducing paracrine senescence in neighboring cells [154][83]. The intensity of SASP can impact local homeostasis paracrine through signals that propagate the senescent state, exacerbating local stress, and inducing ROS-mediated damage in neighboring cells. This is the so-called SMS effect of SASP. Hence, conditioned media (CM) of cells exposed to UV radiations (UVA, B, and C) initiate bystander DNA damage in non-exposed neighboring cells [155][84].

5.4. Other Functions of SASP

SASP can modulate the fate of neighboring cells in several ways and can even impact the differentiation of surrounding cells. For example, Wiley et al. [21][85] have shown that CM harvested from fibroblasts whose mtDNA has been depleted (rho0) can block adipogenesis in preadipocytes but promote keratinocyte differentiation. A recent study also showed that TGF-β secreted by senescent cells can influence the differentiation of T helper cells during the response to influenza infection in mice [158][86]. A proteomic analysis of CM of fibroblasts in IRIS identified a role for SASP in hemostasis, platelet activation, and degranulation [61][19]. Moreover, transient exposure of primary mouse keratinocytes to SASP of OIS keratinocytes led to enhanced plasticity via the increased expression of stemness markers and better regenerative capacities in vivo, while long-term exposure promoted senescence, reducing regenerative stimuli [159][87]. Therefore, SASP may induce cellular plasticity and tissue regeneration capacities according to its intensity and duration, and may promote cellular reprogramming in neighboring cells [160][88].

6. Developing Strategies to Block SASP or Its Specific Effects

Given the importance of senescence in physiological processes, it is reasonable to think that there is a threshold beyond which the accumulation of senescent cells induces a microenvironment conducive to the development of pathologies via SASP. The accumulation of senescent cells can also occur when the immune system ages, altering the ability of immune cells to clear senescent cells. Elimination of senescent cells by senolytics demonstrated a contributive role of senescent cells in ageing and age-related diseases [165][89] and paved the way for the development of senotherapeutic approaches. Therefore, over the past 5 years, senotherapeutic research has emerged to slow down the ageing phenotypes. Current senotherapeutic strategies targeting senescent cells are mainly based on drugs that specifically kill senescent cells (senolytics) and components that suppress the detrimental effects of SASP without inducing senescent cell death (senomorphics, also known as senostatics) [166,167,168,169,170,171,172][90][91][92][93][94][95][96]. Other senotherapeutic strategies include prodrugs, protein degraders, nanocarriers, and immunotherapies [173][97]. It is worth noting that a recent study showed that eliminating senescent cells by using chimeric antigen receptor (CAR) T cells that specifically target senescence-specific surface antigens such as uPAR improved the survival of mice with lung adenocarcinoma and restored tissue homeostasis in a chemical-induced liver fibrosis mouse model [41][98]. Emerging preclinical evidence has highlighted the significant potential of these approaches [27,28,124][99][100][101]. A first strategy would consist in using neutralizing antibodies, recognizing and blocking specific surface proteins upregulated at senescence. Secretion of IL-6 has been decreased in senescent HUVECs and fibroblasts treated with anti-TNFα or anti-ephrin B2 antibodies, respectively [178,179][102][103]. A second strategy would be to use pharmacological and natural compounds. Many senomorphics are polyphenols (including flavonoids, phenolic acids, lignans, and stilbenesenes) that possess antioxidant activities, but their modes of action have not been thoroughly studied. Other senomorphics are plant extracts consisting of a mixture of terpenes, alkaloids, and polyphenols. The biological effects of these compounds are multiple, ranging from the activation of antioxidant enzymes to the reduction in interleukin or MMP expression, and the inhibition of MAPKs.

 

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