Classical and Nonclassical Intercellular Communication in Senescence and Ageing
2020; Elsevier BV; Volume: 30; Issue: 8 Linguagem: Inglês
10.1016/j.tcb.2020.05.003
ISSN1879-3088
AutoresJuan Fafián‐Labora, Ana O’Loghlen,
Tópico(s)Circadian rhythm and melatonin
ResumoIntercellular communication is a key feature in physiological and pathological conditions. We hypothesize that several means of intercellular communication occur either simultaneously or in succession.The most studied means of intercellular communication are soluble factors. However, important alternative means are emerging.Senescent cells are highly proactive and communicate with neighboring cells via various means of intercellular communication including but not limited to the senescence-associated secretory phenotype (SASP).Most studies of pharmacological drugs preventing the release of soluble factors oversee the influence of these drugs on other means of communication. Intercellular communication refers to the different ways through which cells communicate with each other and transfer a variety of messages. These communication methods involve a number of different processes that occur individually or simultaneously, which change depending on the physiological or pathological context. The best characterized means of intercellular communication is the release of soluble factors that affect the function of neighboring cells. However, there are many other ways by which cells can communicate with each other. Here, we review the different means of intercellular communication including soluble factors in the context of senescence, ageing, and age-related diseases. Intercellular communication refers to the different ways through which cells communicate with each other and transfer a variety of messages. These communication methods involve a number of different processes that occur individually or simultaneously, which change depending on the physiological or pathological context. The best characterized means of intercellular communication is the release of soluble factors that affect the function of neighboring cells. However, there are many other ways by which cells can communicate with each other. Here, we review the different means of intercellular communication including soluble factors in the context of senescence, ageing, and age-related diseases. The discovery of a cellular phenotype termed senescence (see Glossary) was first identified by Moorehead and Hayflick in the 1960s. When culturing in vitro primary fibroblasts isolated from human donors, they observed that these cells reached a point where they lost their proliferative capacity, and termed this phenotype cellular senescence. Cleverly, they hypothesized that this phenotype could mimic ageing and be exploited as 'ageing in a Petri dish' [1.Muñoz-Espin D. Serrano M. Cellular senescence: from physiology to pathology.Nat. Rev. Mol. 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However, it was not until 2011 that the van Deusen laboratory established a causative role between the activation of senescence and ageing [4.Baker D.J. et al.Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.Nature. 2011; 479: 232-236Crossref PubMed Scopus (1754) Google Scholar]. Here, the authors established that the accumulation of p16Ink4a in certain organs in a prematurely aged mouse model deficient for the mitotic checkpoint protein BubR1 triggers natural features common in premature ageing. Interestingly, they showed for the first time that genetic inactivation of p16Ink4a ameliorated these ageing phenotypes [4.Baker D.J. et al.Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.Nature. 2011; 479: 232-236Crossref PubMed Scopus (1754) Google Scholar]. It is now well established that the induction of cellular senescence is a hallmark of ageing [5.Lopez-Otin C. et al.The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (5680) Google Scholar]. Furthermore, senescence is a driver not only of ageing but also of certain age-related diseases such as cancer, osteoarthritis, atherosclerosis, Alzheimer's diseases, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) among others [6.Childs B.G. et al.Senescent intimal foam cells are deleterious at all stages of atherosclerosis.Science. 2016; 354: 472-477Crossref PubMed Scopus (427) Google Scholar, 7.Baker D.J. et al.Naturally occurring p16Ink4a-positive cells shorten healthy lifespan.Nature. 2016; 530: 184-189Crossref PubMed Scopus (1129) Google Scholar, 8.Jeon O.H. et al.Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment.Nat. 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The senescence-associated secretory phenotype (SASP) could be considered the 'soul' of senescence as it is highly proactive and it changes its composition with time. It has both beneficial and detrimental effects depending on the trigger and context where senescence is induced [12.Coppe J.P. et al.The senescence-associated secretory phenotype: the dark side of tumor suppression.Annu. Rev. Pathol. 2010; 5: 99-118Crossref PubMed Scopus (1960) Google Scholar,13.Lee S. Schmitt C.A. The dynamic nature of senescence in cancer.Nat. Cell Biol. 2019; 21: 94-101Crossref PubMed Scopus (151) Google Scholar]. However, the SASP is still not well characterized, as only a number of factors have been identified in very specific scenarios. It is important to note that senescence is a complex heterogeneous cellular phenotype that affects tissue homeostasis in many different contexts and caution should be taken when it is standardized to certain markers (Box 1). It is likely that there remain novel, unveiled characteristics of senescence that are context dependent [14.Faget D.V. et al.Unmasking senescence: context-dependent effects of SASP in cancer.Nat. Rev. Cancer. 2019; 19: 439-453Crossref PubMed Scopus (130) Google Scholar].Box 1Guidelines to Identify Senescent Cells In VitroCellular senescence can be induced by a variety of triggers, including telomere shortening, oncogenic stress, ROS, and DNA damage. The main response of primary cells entering senescence is to induce a stable cell cycle arrest by expressing the cell cycle inhibitors CDKN2A, CDKN2B, and/or CDKN1A (encoding p16INK4A, p15INK4B, and/or p21CIP proteins, respectively) and showing a lack of proliferation-related markers such as Ki67, BrdU, or EdU (Figure I) [13.Lee S. Schmitt C.A. The dynamic nature of senescence in cancer.Nat. Cell Biol. 2019; 21: 94-101Crossref PubMed Scopus (151) Google Scholar,14.Faget D.V. et al.Unmasking senescence: context-dependent effects of SASP in cancer.Nat. Rev. Cancer. 2019; 19: 439-453Crossref PubMed Scopus (130) Google Scholar]. However, as these markers are not exclusive to senescent cells but are also present in nondividing somatic cells, additional markers should be used to confirm a senescent phenotype [89.Sharpless N.E. Sherr C.J. Forging a signature of in vivo senescence.Nat. Rev. Cancer. 2015; 15: 397-408Crossref PubMed Scopus (419) Google Scholar]. The identification of more than three biomarkers is recommended to confirm the activation of senescence. Another marker used to identify senescence is senescence-associated beta galactosidase (SA-β-Gal) activity. An increase in SA-β-Gal is due to higher lysosomal activity in senescent cells, which could be due to an increase in the number of lysosomes in senescence [37.Borghesan M. et al.Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3.Cell Rep. 2019; 27: 3956-3971.e6Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar] or an increase in lysosomal activity and can be detected by a specific stain. Finally, additional markers such as DNA damage, the release of a particular secretome that has been termed the SASP [12.Coppe J.P. et al.The senescence-associated secretory phenotype: the dark side of tumor suppression.Annu. Rev. Pathol. 2010; 5: 99-118Crossref PubMed Scopus (1960) Google Scholar], or the activation of specific signalling pathways should also be verified. However, these last markers are slightly more challenging as some triggers, such as oncogene-induced senescence by H-RasG12V expression, induce all of them simultaneously. Instead, other triggers, such as developmental senescence or an increase in αvβ3, do not induce a DNA damage response, which was long believed to be a key biomarker of senescence [65.Rapisarda V. et al.Integrin beta 3 regulates cellular senescence by activating the TGF-β pathway.Cell Rep. 2017; 18: 2480-2493Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar,73.Muñoz-Espin D. et al.Programmed cell senescence during mammalian embryonic development.Cell. 2013; 155: 1104-1118Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar,74.Storer M. et al.Senescence is a developmental mechanism that contributes to embryonic growth and patterning.Cell. 2013; 155: 1119-1130Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar]. This confirms that not all biomarkers are expressed simultaneously when senescence is induced, adding intricacy to the identification of senescence.It is important to note that senescence is an extremely complex and heterogeneous cellular phenotype that affects tissue homeostasis in many different contexts, and the generalization of standardized markers might be disadvantageous as it is likely that there are as-yet-unveiled characteristics of senescence that are context dependent [14.Faget D.V. et al.Unmasking senescence: context-dependent effects of SASP in cancer.Nat. Rev. Cancer. 2019; 19: 439-453Crossref PubMed Scopus (130) Google Scholar]. Cellular senescence can be induced by a variety of triggers, including telomere shortening, oncogenic stress, ROS, and DNA damage. The main response of primary cells entering senescence is to induce a stable cell cycle arrest by expressing the cell cycle inhibitors CDKN2A, CDKN2B, and/or CDKN1A (encoding p16INK4A, p15INK4B, and/or p21CIP proteins, respectively) and showing a lack of proliferation-related markers such as Ki67, BrdU, or EdU (Figure I) [13.Lee S. Schmitt C.A. The dynamic nature of senescence in cancer.Nat. Cell Biol. 2019; 21: 94-101Crossref PubMed Scopus (151) Google Scholar,14.Faget D.V. et al.Unmasking senescence: context-dependent effects of SASP in cancer.Nat. Rev. Cancer. 2019; 19: 439-453Crossref PubMed Scopus (130) Google Scholar]. However, as these markers are not exclusive to senescent cells but are also present in nondividing somatic cells, additional markers should be used to confirm a senescent phenotype [89.Sharpless N.E. Sherr C.J. Forging a signature of in vivo senescence.Nat. Rev. Cancer. 2015; 15: 397-408Crossref PubMed Scopus (419) Google Scholar]. The identification of more than three biomarkers is recommended to confirm the activation of senescence. Another marker used to identify senescence is senescence-associated beta galactosidase (SA-β-Gal) activity. An increase in SA-β-Gal is due to higher lysosomal activity in senescent cells, which could be due to an increase in the number of lysosomes in senescence [37.Borghesan M. et al.Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3.Cell Rep. 2019; 27: 3956-3971.e6Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar] or an increase in lysosomal activity and can be detected by a specific stain. Finally, additional markers such as DNA damage, the release of a particular secretome that has been termed the SASP [12.Coppe J.P. et al.The senescence-associated secretory phenotype: the dark side of tumor suppression.Annu. Rev. Pathol. 2010; 5: 99-118Crossref PubMed Scopus (1960) Google Scholar], or the activation of specific signalling pathways should also be verified. However, these last markers are slightly more challenging as some triggers, such as oncogene-induced senescence by H-RasG12V expression, induce all of them simultaneously. Instead, other triggers, such as developmental senescence or an increase in αvβ3, do not induce a DNA damage response, which was long believed to be a key biomarker of senescence [65.Rapisarda V. et al.Integrin beta 3 regulates cellular senescence by activating the TGF-β pathway.Cell Rep. 2017; 18: 2480-2493Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar,73.Muñoz-Espin D. et al.Programmed cell senescence during mammalian embryonic development.Cell. 2013; 155: 1104-1118Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar,74.Storer M. et al.Senescence is a developmental mechanism that contributes to embryonic growth and patterning.Cell. 2013; 155: 1119-1130Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar]. This confirms that not all biomarkers are expressed simultaneously when senescence is induced, adding intricacy to the identification of senescence. It is important to note that senescence is an extremely complex and heterogeneous cellular phenotype that affects tissue homeostasis in many different contexts, and the generalization of standardized markers might be disadvantageous as it is likely that there are as-yet-unveiled characteristics of senescence that are context dependent [14.Faget D.V. et al.Unmasking senescence: context-dependent effects of SASP in cancer.Nat. Rev. Cancer. 2019; 19: 439-453Crossref PubMed Scopus (130) Google Scholar]. There are currently two main therapeutic strategies to deal with the presence of senescent cells in ageing and age-related diseases. One relates to the potential for selective killing of senescent cells (using pharmacological compounds termed senolytics). The second aims to neutralize the deleterious effects of intercellular communication, in particular the SASP, on senescent cells by using drugs denominated senomorphics. Here, we review the different means of intercellular communication for senescent cells and their relation to ageing and some age-related diseases, classifying them as classical, emerging, and nonclassical. We include soluble factors and extracellular matrix (ECM) remodeling proteins, but also describe additional ways by which cells communicate. We focus on how intercellular communication is regulated and its functionality in different biological and age-related pathological contexts. The SASP is a means of intercellular communication that specifically refers to senescent cells. The classical SASP is characterized by soluble factors, growth factors, and ECM remodeling enzymes [12.Coppe J.P. et al.The senescence-associated secretory phenotype: the dark side of tumor suppression.Annu. Rev. Pathol. 2010; 5: 99-118Crossref PubMed Scopus (1960) Google Scholar]. However, emerging SASP and other means of intercellular communication that we have denominated nonclassical have also been described during senescence and ageing. Here, we review the current knowledge on what we call classical, emerging, and nonclassical SASP. The sSASP can be both beneficial and detrimental for tissue homeostasis; therefore, the sSASP needs to be tightly regulated. One of the main drivers of the sSASP is a persistent DNA damage response [15.Rodier F. et al.Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.Nat. Cell Biol. 2009; 11: 973-979Crossref PubMed Scopus (1233) Google Scholar]. This converges in the activation of two major regulators of the SASP: NF-κB and C/EBPβ, where NF-κB is further regulated by the transcription factor GATA4 (Figure 1A ) [16.Kang C. et al.The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.Science. 2015; 349aaa5612Crossref PubMed Scopus (394) Google Scholar]. However, the sSASP can also be induced independent of a noncanonical DNA damage response by p38MAPK [17.Freund A. et al.p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.EMBO J. 2011; 30: 1536-1548Crossref PubMed Scopus (496) Google Scholar] and by the presence of cytoplasmic chromatin fragments (CCFs). These are DNA fragments that can be released from the nucleus during senescence and activate the antiviral cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway [18.Dou Z. et al.Cytoplasmic chromatin triggers inflammation in senescence and cancer.Nature. 2017; 550: 402-406Crossref PubMed Scopus (376) Google Scholar,19.Gluck S. et al.Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence.Nat. Cell Biol. 2017; 19: 1061-1070Crossref PubMed Scopus (339) Google Scholar]. Still, both p38MAPK and CCF activate the sSASP via NF-κB signaling. Curiously, activation of the inflammasome can also control the sSASP. This is mediated by interleukin (IL)-1 signaling and IL-1α expression and is mainly involved in paracrine senescence signaling [20.Acosta J.C. et al.A complex secretory program orchestrated by the inflammasome controls paracrine senescence.Nat. Cell Biol. 2013; 15: 978-990Crossref PubMed Scopus (839) Google Scholar]. Furthermore, IL-1A is regulated by mammalian target of rapamycin (mTOR) inhibition. mTOR selectively regulates a number sSASP factors post-transcriptionally via IL-1A, but also through MK2 [mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2)] by the protein synthesis factor 4EBP1 [21.Herranz N. et al.mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.Nat. Cell Biol. 2015; 17: 1205-1217Crossref PubMed Scopus (294) Google Scholar,22.Laberge R.M. et al.mTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation.Nat. Cell Biol. 2015; 17: 1049-1061Crossref PubMed Scopus (473) Google Scholar]. Alternatively, epigenetic alterations are also known to regulate the sSASP. A recent study found that derepression of the retrotransposable element line 1 (L1) increased during senescence and ageing. This in turn activated cGAS/STING and, consequently, the sSASP [23.De Cecco M. et al.L1 drives IFN in senescent cells and promotes age-associated inflammation.Nature. 2019; 566: 73-78Crossref PubMed Scopus (246) Google Scholar]. Furthermore, the sSASP is regulated by global chromatin remodeling and the recruitment of BRD4 to superenhancers near sSASP genes [24.Tasdemir N. et al.BRD4 connects enhancer remodeling to senescence immune surveillance.Cancer Discov. 2016; 6: 612-629Crossref PubMed Scopus (133) Google Scholar]. Overall, the sSASP is tightly regulated as dysfunctional expression and release can drive pathological conditions. This highlights the importance of understanding how the sSASP is regulated. It was long believed that the sSASP would change in composition throughout time. Thus, it was not until recently that a comprehensive study found the sSASP to comprise two distinctive functional waves [25.Hoare M. et al.NOTCH1 mediates a switch between two distinct secretomes during senescence.Nat. Cell Biol. 2016; 18: 979-992Crossref PubMed Scopus (168) Google Scholar]. The first wave is formed by an anti-inflammatory transforming growth factor (TGF)-β-enriched sSASP. This particular sSASP is regulated by membrane-bound NOTCH1, whose expression increases during the initial stages of the induction of senescence and mediates C/EBPβ repression. Second and through time, NOTCH1 expression decreases causing the activation of C/EBPβ, which in turn induces a proinflammatory sSASP [25.Hoare M. et al.NOTCH1 mediates a switch between two distinct secretomes during senescence.Nat. Cell Biol. 2016; 18: 979-992Crossref PubMed Scopus (168) Google Scholar]. Our advancement of knowledge of the sSASP has greatly increased, with many novel roles emerging in the past decades. On the one hand, the sSASP is important for reinforcing a stable cell cycle arrest in an autocrine manner through IL-8 and IL-6 and their corresponding receptors (Figure 1A) [26.Acosta J.C. et al.Chemokine signaling via the CXCR2 receptor reinforces senescence.Cell. 2008; 133: 1006-1018Abstract Full Text Full Text PDF PubMed Scopus (1013) Google Scholar,27.Kuilman T. et al.Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.Cell. 2008; 133: 1019-1031Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar]. On the other hand, it acts in a paracrine fashion influencing a variety of cell types. It can induce senescence in primary fibroblasts and epithelial cells [20.Acosta J.C. et al.A complex secretory program orchestrated by the inflammasome controls paracrine senescence.Nat. Cell Biol. 2013; 15: 978-990Crossref PubMed Scopus (839) Google Scholar], while promoting tumorigenesis in cancer cells [13.Lee S. Schmitt C.A. The dynamic nature of senescence in cancer.Nat. Cell Biol. 2019; 21: 94-101Crossref PubMed Scopus (151) Google Scholar,14.Faget D.V. et al.Unmasking senescence: context-dependent effects of SASP in cancer.Nat. Rev. Cancer. 2019; 19: 439-453Crossref PubMed Scopus (130) Google Scholar,28.Demaria M. et al.Cellular senescence promotes adverse effects of chemotherapy and cancer relapse.Cancer Discov. 2017; 7: 165-176Crossref PubMed Scopus (399) Google Scholar]. Importantly, the sSASP also acts in a paracrine fashion by mediating both an innate and an adaptive tissue response favoring the removal of senescent cells from the tissue, which is essential for the maintenance of tissue homeostasis [20.Acosta J.C. et al.A complex secretory program orchestrated by the inflammasome controls paracrine senescence.Nat. 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Although the SASP is classically defined as the secretome released from senescent cells, most of the current literature focuses on soluble factors, growth factors, and ECM remodeling enzymes. In this section, we aim to review emerging literature on novel SASP components such as extracellular vesicles (EVs) and noncellular metabolites and ions (Figure 1B). EVs are lipid membrane vesicles that are released by all cells and are therefore found in most biological fluids [35.van Niel G. et al.Shedding light on the cell biology of extracellular vesicles.Nat. Rev. Mol. Cell Biol. 2018; 19: 213-228Crossref PubMed Scopus (1898) Google Scholar]. Although initially thought of as a mechanism to release unwanted components from the cell, they are now recognized as a well-established mechanism for intercellular communication. Despite this, senescent cells remove toxic cytoplasmic DNA via EVs to maintain cellular homeostasis [36.Takahashi A. et al.Exosomes maintain cellular homeostasis by excreting harmful DNA from cells.Nat. Commun. 2017; 8: 15287Crossref PubMed Scopus (292) Google Scholar]. Indeed, senescent cells release more EVs (evSASP) than proliferating cells [36.Takahashi A. et al.Exosomes maintain cellular homeostasis by excreting harmful DNA from cells.Nat. Commun. 2017; 8: 15287Crossref PubMed Scopus (292) Google Scholar, 37.Borghesan M. et al.Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3.Cell Rep. 2019; 27: 3956-3971.e6Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 38.Takasugi M. et al.Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2.Nat. 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Interestingly, it has been shown that these EVs induce paracrine senescence in healthy cells, highlighting their importance as intercellular communication mediators (Figure 1B) [37.Borghesan M. et al.Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3.Cell Rep. 2019; 27: 3956-3971.e6Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,39.Jeon O.H. et al.Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers.JCI Insight. 2019; 4: 125019Crossref PubMed Scopus (40) Google Scholar]. While the mechanisms responsible for this are unknown, several miRNAs, interferon-related proteins, and antiapoptotic proteins were found enriched in senescent-derived EVs [37.Borghesan M. et al.Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3.Cell Rep. 2019; 27: 3956-3971.e6Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,39.Jeon O.H. et al.Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers.JCI Insight. 2019; 4: 125019Crossref PubMed Scopus (40) Google Scholar, 40.Terlecki-Zaniewicz L. et al.Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype.Aging (Albany NY). 2018; 10: 1103-1132Crossref PubMed Scopus (77) Google Scholar, 41.Zhang Y. et al.Hypothalamic stem cells control ageing speed partly through exosomal miRNAs.Nature. 2017; 548: 52-57Crossref PubMed Scopus (220) Google Scholar, 42.Basisty N. et al.A proteomic atlas of senescence-associated secretomes for aging biomarker development.PLoS Biol. 2020; 18e3000599Crossref PubMed Scopus (150) Google Scholar]. By contrast, a protumorigenic role for EVs derived from senescent cells mediated by ephrin A2 (EphA2) has been suggested [38.Takasugi M. et al.Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2.Nat. Commun. 2017; 8: 15729Crossref PubMed Scopus (142) Google Scholar] adding an extra layer of complexity to the evSASP. Interestingly, several ephrin-related proteins are enriched in plasma derived from old healthy donors [43.Tanaka T. et al.Plasma proteomic signature of age in healthy humans.Aging Cell. 2018; 17e12799Crossref PubMed Scopus (114) Google Scholar,44.Lehallier B. et al.Undulating changes in human plasma proteome profiles across the lifespan.Nat. Med. 2019; 25: 1843-1850Crossref PubMed Scopus (130) Google Scholar], although whether they are free proteins or EV associated remains to be determined. Metabolites are small chemical byproduct molecules of metabolic activity in cells and tissues that provide functional evidence of biochemical activity [45.Patti G.J. et al.Innovation: metabolomics: the apogee of the omics trilogy.Nat. Rev. Mol. Cell Biol. 2012; 13: 263-269Crossref PubMed Scopus (1325) Google Scholar]. Thus, several metabolites are emerging as biomarkers of senescence, ageing, and related diseases. Interestingly, metabolite regulators have also been fo
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