Table 1.
Summary of the different types of senescence and readouts.
| Senescence | SASPs | Known Pathways Involved |
|---|---|---|
| Replicative senescence | * Angiogenin, * bFGF, * CCL2, CCL3, CCL8, CCL16, * CCL20, * CCL26, * COX2, * CXCL1, CXCL2, CXCL3, * CXCR2, Fas, * FGF-7, * Fibronectin, * GM-CSF, * HGF, * ICAM-1, IFN-1, * IGFBP1, IGFBP2, IGFBP3, * IGFBP4, IGFBP5, IGFBP6, * IL1A, * IL1B, * IL6, IL7, * IL8, * IL11, * IL13, * IL15, * Leptin, * MIF, * MMP1, * MMP2, * MMP3, * MMP10, * Osteoprotegerin, * PAI-1, PAI-2, * PGE2, * PIGF, * SCF, * sgp130, sTNFRI, sTNFRII, * TGFβ, * TIMP2, * tPA, * TRAIL-R3, * uPA, * uPAR, and * WNT2 |
• DNA damage responses (due to telomere length) • * Telomere activity regulated by telomere length, capping and inhibition [16] • Derepression of the CDKN2A locus • DNA methylation pathways • * p53 pathway [24,25,26] • * p16 pathway [27] • * p21 pathway [16,28,29,30] • * SIRT1 [31,32] and * SIRT6 [31,33] signaling • * Klotho signaling [34] • * IGF1/Akt signaling [27] • * SA-βgal activity [24,26,35,36,37,38] • * ROS signaling [26,39,40] • Increased methylation of promoter of rDNA and reduced expression of 18S, 5.8S and 28S rRNA [41] • * S100A9 and TLR4 pathway [42] |
| Oncogene-induced Senescence (OIS) | * Angiogenin, * AREG, * A-SAA, * bFGF, * CCL1, * CCL2, CCL3, * CCL7, CCL8, * CCL13, CCL16, * CCL20, * CCL26, * COX2, * CXCL1, CXCL2, CXCL3, * CXCL5, * CXCL6, * CXCL7, * CXCL11, * CXCL12, * CXCL13, * CXCR2, * G-CSF, * GITR, * GMCSF, * HGF, * ICAM-1, IFN-1, * IFNγ, * IGFBP4, IGFBP6, * IGFBP7, * IL1A, * IL1B, * IL6, * IL6R, IL7, * IL8, * IL13, * LIF, * MIF, * MMP1, * MMP3, * MMP10, * Oncostatin M, * Osteoprotegerin, * PAI-1, * PGE-2, * PIGF, * sgp130, sTNFRI, * TNFRSF18, * t-PA, * TIMP1, * TIMP2, * uPAR, and * VEGF |
• * p53/p21WAF1/CIP1 pathway [24,25,26] • * DNA damage responses (not due to telomere length) [28] • * ADAM17 signaling [43] mTOR signaling [44] • * Autophagy [45] • * Phosphorylated H2AX [29] • Nicotinamide phosphoribosyltransferase (NAMPT) activity • * ROS signaling [26,39,40] • * SA-βgal activity [24,26,35,36,37,38] |
| DNA-damage induced senescence | * Acrp30, * Amphiregulin, * Angiogenin, * bFGF, * BTC, * CCL1, * CCL2, CCL3, * CCL5, CCL8, * CCL13, CCL16, * CCL20, * CCL26, * CCL27, * CXCL1, CXCL2, CXCL3, * CXCL5, * CXCL6, * CXCL11, * EGFR, Fas, * FGF-7, * GDNF, * GM-CSF, * HGF, * ICAM-1, * IGFBP1, IGFBP2, IGFBP3, * IGFBP4, IGFBP5, IGFBP6, * IL1A, * IL1B, * IL6, * IL6R, IL7, * IL8, * IL11, * IL13, * IL15, * IL1R1, IL2Rα, * Leptin, * MIF, * MMP1, * MMP2, * MMP3, * MMP10, * MMP12, * MMP13, * MMP14, * MSP-a, * Oncostatin M, * Osteoprotegerin, * PDGF-BB, * PIGF, * SCF, * SDF-1, * sgp130, sTNFRI, sTNFRII, * TNFRSF18, * Thrombopoietin, * TIMP1, * TIMP2, * tPA, * TRAIL-R3, * uPA, * uPAR, and * VEGF |
• * p16 pathway [27] • * p38 MAPK signaling [46] • NAD+/poly-ADP ribose polymerases mediated DNA damage repair • * p53 pathway [24,25,26] • DNA damage responses • Degradation of the transcription factor Sp1 • * ROS signaling [26,39,40] • * NFκB signaling [47] • * p21 pathway [16,28,29,30] • * Endoplasmic reticulum (ER) stress [48] • * SA-βgal activity [24,26,35,36,37,38] |
| Therapy-induced senescence | * AREG, * CXCL8, * IL1A, * IL-1B, * IL-6, * IL8 * MMP2, * MMP3, * PAI-1, * SPINK1, * t-PA, and WNT16B |
• * p53 pathway [24,25,26] • JAK/STAT signaling • RAS/PI3K/AKT/mTOR signaling • * p16 pathway [27] • * p21 pathway [16,28,29,30] • * SA-βgal activity [24,26,35,36,37,38] |
| Mitochondrial dysfunctional-associated senescence | Lacks IL-1-dependent factors (* IL-1A, * IL-1B, * IL-6 and * IL8 are all reduced at the mRNA level), but includes * IL10, * CCL27, and * TNFα |
• * ROS signaling [26,39,40] • * Telomere dysfunction [16] • * Mitochondrial DNA damage [49] • * Altered tricarboxylic acid (TCA) cycle [50] • * Reduced Parkin translocation [51] • * Cytoplasmic p53 accumulation [26] • Low NAD+/NADH ratios [52] • * Mitochondrial DAMPs [53] • Malic enzymes 1 and 2 • * Phosphorylated H2AX [29] • * SA-βgal activity [24,26,35,36,37,38] |
| Embryonic senescence | * AREG, * CCL2, * GM-CSF, * IL1A, * IL1B, * IL6, IL6R, * IL8, * ICAM1, * MIF, and * VEGF | • Shares many features to OIS • * p21 pathway [16,28,29,30] • * p15 pathway [24,25,26] • * TGFβ/SMAD and PI3K/FOXO pathways [54] • * Phosphorylated H2AX [29] • * SA-βgal activity [24,26,35,36,37,38] |
* Denotes a link to playing a role in early emphysema. SASPs data based on [20,55,56,57,58,59,60]. Abbreviations: Acrp, catenin alpha like; AREG, amphiregulin; A-SAA, acute-phase serum amyloids; BTC, betacellulin; bFGF, basic fibroblast growth factor; CCL, chemokine (CC-motif) ligand; COX, cyclooxygenase; CXCL, chemokine (C-X-C motif) ligand; CXCR, C-X-C chemokine receptor; EGFR, epidermal growth factor receptor; FGF, fibroblast growth factors; G-CSF, granulocyte-colony stimulating factor; GDNF, glial cell-line derived neurotrophic factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HGF, hepatocyte growth factor; ICAM, intercellular adhesion molecule; IFN, interferon; IGFBP, insulin-like growth factor binding protein; IL, interleukin; LIF, leukemia inhibitory factor; MIF, macrophage migration inhibitory factor; MMP, matrix metalloproteinase; MSP, macrophage stimulating protein; PAI, plasminogen activator inhibitor; PDGF-BB, platelet-derived growth factor; PGE, prostaglandin; PIGF, placental growth factor; S100A9, S100 calcium-binding protein A9; SCF, stem cell factor; SDF, stromal cell-derived factor; sgp130, soluble glycoprotein 130; sTNFR, soluble tumor necrosis factor receptors; TGFβ, transforming growth factor beta; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; TNFRSF18, tumor necrosis factor receptor superfamily member 18; tPA, tissue plasminogen activator; TRAIL-R, tumor necrosis factor-related apoptosis-inducing ligand receptor; uPA, urokinase plasminogen activator; uPAR, urokinase plasminogen activator receptor; VEGF, vascular endothelial growth factor; WNT, Wingless and Int-1.