Senescence-Associated Secretory Phenotype: History
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Subjects: Immunology

The Senescence-Associated Secretory Phenotype (SASP), also known as Senescence-Messaging Secretome (SMS), is one of the fundamental characteristics of the senescent cell, consisting in the abundant secretion of generally proinflammatory compounds in the tissue microenvironment.

  • senescence,SASP

The Senescence-Associated Secretory Phenotype (SASP), also known as Senescence-Messaging Secretome (SMS), is one of the fundamental characteristics of the senescent cell. Cellular senescence represents a central stress response triggered by molecular damage or dysregulated activation of oncogenes that leads to a stable arrest of proliferation, resistance to apoptosis and enhanced secretory capacity [1]. The SASP is thus a complex and temporally regulated metabolic program entailing the increased secretion of bioactive molecules, especially proteins, in the surrounding microenvironment. Exosomes and microvesicles are also abundantly secreted as part of the SASP [2]. The establishment of SASP, contrary to the proliferative arrest, requires days instead of hours to complete; moreover, the quality of the secretome can change dynamically over time [3,4].

Even though the secretome’s composition can be highly heterogeneous depending on cell type and senescence-inducing stimulus, SASP has a prominently inflammatory nature [5,6]. Numerous cytokines, chemokines, matrix-remodelling enzymes, growth factors and angiogenic factors and are typically secreted by senescent cells and act in a paracrine fashion, influencing the behaviour of cells nearby and recruiting immune cells in the proximity of the damaged tissue. The recruitment of immune cells results, in some cases, in the clearance of senescent cells and in the restoration of tissue homeostasis [7-10]. The SASP has also the potential to induce senescence in nearby cells, as observed in several experimental conditions [11,12].

Despite the heterogeneity among various SASPs, specific proteins are found almost invariably, namely IL-1, IL-6, IL-8, GROα/β, GM-CSF, MMP-1, MMP-3, MMP-10, ICAM-1, PAI-1, and IGFBPs [13].

The emergence and maintenance of SASP are controlled by multiple stress response pathways; however, many of these seem to converge on two central transcription factors, NF-κB and GATA-4, which therefore are considered the main regulators of SASP transcriptional control [14,15].

The biological function of SASP is a highly debated subject. SASP is thought to contribute to age-related organ dysfunction; indeed, senescent cells accumulate in various tissues during aging and the inflammatory milieu created by them contributes to the so-called “inflammaging”, a low-grade, sterile and chronic state of inflammation that characterizes the aged organism [16]. Accordingly, the seminal work of Baker and colleagues (2011) demonstrated how the selective elimination of senescent cells (or at least of p16 Ink4a -expressing cells) in progeroid mice results in delayed onset of age-related conditions [17]. Abrogation of SASP in senescent preadipocytes using JAK inhibitors similarly reduces systemic inflammation and frailty in aged mice [18].

Being senescence often considered a tumor-suppressing mechanism [19], the pro-tumorigenic activity of SASP, demonstrated in vivo and in vitro, is difficult to explain [20]. For instance, SASP largely promotes the proliferation of malignant epithelial cells, presumably through the secretion of growth factors and matrix metalloproteinases [21,22]. The degradation of the extracellular matrix mediated by the secreted enzymes fosters tumor migration and metastatization [23]. In specific contexts, SASP shows to promote tumor angiogenesis through the production of VEGF and other angiogenic factors [24]. Consistently to this evidence, ablation of the proinflammatory secretome of premalignant senescent cells leads to a lesser number of neoplastic lesions in a mouse model of pancreatic cancer [25].

In contrast, in an experimental model of liver carcinoma, the SASP is required for the effective tumor clearance mediated by innate immune cells, especially by Natural Killer cells [26]. The immune surveillance of senescent cells evoked by the SASP may represent an important mechanism to control the development of pre-malignant lesions in the liver [27].

From the point of view of evolution, the apparent contradiction between the tumor-suppressive role of senescence and the pro-tumorigenic activity of SASP has been partially addressed with the concept of “antagonistic pleiotropy” [28].

According to this concept, senescence as a tumor-suppressive mechanism underwent positive selection because of the benefit it confers at young ages. On the other hand, the detrimental effects of SASP on tumor development and age-related conditions are manifested only in aged organisms, on which negative selection does not act. It is clear that the accumulation of senescent cells is typical of old age and might be due to the decline of immune surveillance and induction of paracrine senescence. Therefore, the negative impact of SASP could be prevalent only in tissues highly populated by senescent cells and not in young tissues.

An alternative explanation can be found in functions unrelated to aging and cancer, like the positive role of senescence on tissue regeneration and remodeling during embryonic development [29-31].

Strategies aimed at abrogating or modulating the SASP are currently being investigated for translational purposes, although this area of research is still in its infancy [32,33].



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This entry is adapted from the peer-reviewed paper 10.3390/biology9120485

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