Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

In the paper

“Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases.”

In the paper

“Cellular senescence plays beneficial critical roles in numerous biological processes [5], such as tumor suppression [6,7], embryonic tissue remodeling [8] and wound healing after injury [9].”

What the sources say

• Not checked yetcites [5] Burton, 2014, Physiological and pathological consequences of cellular senescence, Cell Mol. Life Sci. source
• Not checked yetcites [6] Lin, 2010, Skp2 targeting suppresses tumorigenesis by arf-p53-independent cellular senescence, Nature source
• Not checked yetcites [7] Braig, 2005, Oncogene-induced senescence as an initial barrier in lymphoma development, Nature source
• Not checked yetcites [8] Canamero, 2013, Programmed cell senescence during mammalian embryonic development, Cell source

In the paper

“Immune cells can remove senescent cells.”

• Also stated in: § 3. Immunosurveillance of Senescent Cells · plain

  “Generally, senescent cells can be removed by apoptosis and the immune system [121,122].”

What the sources say

• Not checked yetcites [121] Ovadya, 2018, Strategies targeting cellular senescence, J. Clin. Investig. source
• Not checked yetcites [122] Prata, 2018, Senescent cell clearance by the immune system: Emerging therapeutic opportunities, Semin. Immunol. source

In the paper

“Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells.”

• Also stated in: § 3. Immunosurveillance of Senescent Cells · plain

  “Senescent cells recruit and make immune cells senescent and dysfunctional via SASP, leading to persistent and excessive accumulation of senescent cells [122].”

What the sources say

• Not checked yetcites [122] Prata, 2018, Senescent cell clearance by the immune system: Emerging therapeutic opportunities, Semin. Immunol. source

In the paper

“Senescent cells in patients with idiopathic pulmonary fibrosis (IPF) drive physical dysfunction [45].”

What the sources say

• Not checked yetcites [45] Justice, 2019, Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study, EBioMedicine source

In the paper

“Zhang et al. employed a senolytic cocktail of dasatinib plus quercetin (D + Q) to validate that senescent OLIG2- and NG2-expressing oligodendrocyte progenitor cells (OPCs) contribute to cognitive impairment in an AD mouse model [56].”

What the sources say

• Not checked yetcites [56] Zhang, 2019, Senolytic therapy alleviates aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an alzheimer’s disease model, Nat. Neurosci. source

In the paper

“Senescence of the central nervous system (CNS) drives many neurodegenerative diseases [55], including Alzheimer’s disease (AD), Parkinson’s disease (PD) and other types of dementia (Table 1).”

What the sources say

• Not checked yetcites [55] Kritsilis, M., V Rizou, R., Koutsoudaki, P.N., Evangelou, K., Gorgoulis, V.G., and Papadopoulos, D. (2018). Ageing, cellular senescence and neurodegenerative disease. Int. J. Mol. Sci., 19. source

In the paper

“Cellular senescence traditionally impairs stem-cell function (also termed as stemness) [58].”

What the sources say

• Not checked yetcites [58] Golomb, 2015, Age-associated inflammation connects ras-induced senescence to stem cell dysfunction and epidermal malignancy, Cell Death Differ. source

In the paper

“Mounting evidence from human samples and preclinical animal models shows that the excessive presence of senescent cells is a contributing cause of ageing, which is featured by a functional decline in multiple physiological systems [39,40].”

What the sources say

• Not checked yetcites [39] 2014, The role of senescent cells in ageing, Nature source
• Not checked yetcites [40] Ovadya, 2018, Impaired immune surveillance accelerates accumulation of senescent cells and aging, Nat. Commun. source

In the paper

“However, the senescence of specific cancer cells develops cancer stemness.”

What the sources say

• Not checked yetcites [2] Milanovic, 2018, Senescence-associated reprogramming promotes cancer stemness, Nature source

In the paper

“Excessive senescent cells have been demonstrated to play a causal role in driving ageing [26] and chronic diseases [18] using genetic and pharmacologic approaches.”

What the sources say

• Not checked yetcites [26] Campisi, 2019, From discoveries in ageing research to therapeutics for healthy ageing, Nature source
• Not checked yetcites [18] Bussian, 2018, Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline, Nature source

In the paper

“Another crucial feature of senescent cells is apoptotic resistance, which is, in part, attributable to the transcriptional and cap-independent translational elevation of anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins (BCL-2, BCL-XL and BCL-W) [36].”

What the sources say

• Not checked yetcites [36] Yosef, 2016, Directed elimination of senescent cells by inhibition of bcl-w and bcl-xl, Nat. Commun. source

In the paper

“These results suggest that senescent glial cells drive tau-dependent disease.”

In the paper

“Additionally, macrophage senescence instigates features of plaque instability, such as elastic fiber defects and fibrous cap thinning in the brachiocephalic artery and descending aorta [47].”

What the sources say

• Not checked yetcites [47] Childs, 2016, Senescent intimal foam cells are deleterious at all stages of atherosclerosis, Science source

In the paper

“Accumulation of senescent endothelial cells leads to cardiovascular thrombotic complications, including arterial (acute myocardial infarction, stroke) and venous (deep vein thrombosis, pulmonary embolism) thrombotic events [52].”

What the sources say

• Not checked yetcites [52] Bochenek, 2016, Endothelial cell senescence and thrombosis: Ageing clots, Thromb. Res. source

In the paper

“Senescence of vascular smooth muscle cells (VSMCs) generally drives the vulnerability of atherosclerotic plaques resulting in myocardial infarction and stroke [54].”

What the sources say

• Not checked yetcites [54] Wang, 2015, Vascular smooth muscle cell senescence promotes atherosclerosis and features of plaque vulnerability, Circulation source

In the paper

“Additionally, senescent astrocytes mediate dopaminergic neurodegeneration related to PD [57].”

What the sources say

• Not checked yetcites [57] Chinta, 2018, Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to parkinson’s disease, Cell Rep. source

In the paper

“It was reported that premature endothelium senescence reversibly triggers vascular ageing and the age-associated decrease in exercise endurance in old mice [42].”

What the sources say

• Not checked yetcites [42] Das, 2018, Impairment of an endothelial nad(+)-h2s signaling network is a reversible cause of vascular aging, Cell source

In the paper

“Senescent cardiovascular cells specifically contributes to chronic CVD, including atherosclerosis [47], abdominal aortic aneurysm (AAA) [48], thoracic aortic aneurysm (TAA) [49], artery stiffness [50] and heart failure [51].”

What the sources say

• Not checked yetcites [47] Childs, 2016, Senescent intimal foam cells are deleterious at all stages of atherosclerosis, Science source
• Not checked yetcites [48] Chen, 2016, Age-associated sirtuin 1 reduction in vascular smooth muscle links vascular senescence and inflammation to abdominal aortic aneurysm, Circ. Res. source
• Not checked yetcites [49] Watson, 2017, Nicotinamide phosphoribosyltransferase in smooth muscle cells maintains genome integrity, resists aortic medial degeneration, and is suppressed in human thoracic aortic aneurysm disease, Circ. Res. source

In the paper

“Different senescent cells with unique features have distinct functions in tissue ageing and various chronic diseases.”

• Also stated in: § 2.1. Features of Cellular Senescence · hedged

  “It is noteworthy that different senescent cells have unique features, which may lead to distinct types of ageing patterns in different individuals [38].”

What the sources say

• Not checked yetcites [38] Ahadi, 2020, Personal aging markers and ageotypes revealed by deep longitudinal profiling, Nat. Med. source

In the paper

“T-cell senescence is profoundly associated with physical frailty [46].”

What the sources say

• Not checked yetcites [46] Ng, 2015, Markers of t-cell senescence and physical frailty: Insights from singapore longitudinal ageing studies, NPJ Aging Mechan. Dis. source

In the paper

“Macrophage transcription factors Kruppel-like factors 2 (KLF2) and 4 (KLF4) are crucial controllers inducing gene expression necessary to silently eradicate apoptotic cells [138].”

What the sources say

• Not checked yetcites [138] Roberts, 2017, Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells, Immunity source

In the paper

“interferon regulatory factor 5 (IRF5) transcription factor enhances vulnerable plaque formation in hyperlipidemic apolipoprotein E-deficient (ApoE−/−) mice through the induction of pro-inflammatory CD11c+ macrophages within atherosclerotic lesions and increasing the expansion of the necrotic core by inhibiting macrophage efferocytosis [142].”

What the sources say

• Not checked yetcites [142] Seneviratne, 2017, Interferon regulatory factor 5 controls necrotic core formation in atherosclerotic lesions by impairing efferocytosis, Circulation source

In the paper

“activated Treg cells secrete IL-13 to stimulate IL-10 production in macrophages via binding to the IL-13 receptor.”

What the sources say

• Not checked yetcites [139] Proto, 2018, Regulatory t cells promote macrophage efferocytosis during inflammation resolution, Immunity source

In the paper

“Senescence immunotherapy strategy is also a promising alternative to senolytics to remove senescent cells in the prevention and cure of ageing and chronic diseases (Table 2).”

In the paper

“Although senescent cells can be induced to undergo apoptosis by senolytics and further removed by macrophages, macrophages also directly engulf senescent cells in cancer (Figure 1).”

In the paper

“cyclin-dependent kinase inhibitor 2B (CDKN2B)-deficient apoptotic cells show decreased expression of calreticulin [149]”

What the sources say

• Not checked yetcites [149] Kojima, 2014, Cyclin-dependent kinase inhibitor 2b regulates efferocytosis and atherosclerosis, J. Clin. Investig. source

In the paper

“Because apoptosis evasion features most senescent cells, the immune system, including adaptive and innate immune cells, plays a critical role in the eradication of senescent cells at a young stage or under physiological conditions.”

In the paper

“Generally, senescent cells can be removed by apoptosis and the immune system [121,122].”

What the sources say

• Not checked yetcites [121] Ovadya, 2018, Strategies targeting cellular senescence, J. Clin. Investig. source
• Not checked yetcites [122] Prata, 2018, Senescent cell clearance by the immune system: Emerging therapeutic opportunities, Semin. Immunol. source

In the paper

“p53 reconstitution induces liver tumor cell senescence with increased p16 and SA β-gal activity but not apoptosis, in mice in vivo.”

What the sources say

• Not checked yetcites [145] Xue, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature source

In the paper

“apoptotic or senescent cells have increased expression of cell-surface protein CD47, one of the “don’t eat me” signals, which impairs efferocytosis via binding to the inhibitory receptor signal regulatory protein alpha (SIRPα) on the macrophage.”

What the sources say

• Not checked yetcites [148] Kojima, 2016, Cd47-blocking antibodies restore phagocytosis and prevent atherosclerosis, Nature source

In the paper

“For example, senescence-activated hepatic stellate cells upregulate cell-surface MICA and ULBP2, ligands of activating receptor NKG2D on NK cells [20].”

What the sources say

• Not checked yetcites [20] Krizhanovsky, 2008, Senescence of activated stellate cells limits liver fibrosis, Cell source

In the paper

“The elevated IL-10 signaling upregulates macrophage STAT3-mediated VAV1 (a guanine nucleotide exchange factor), which activates GTPase Rac1 to enhance apoptotic cell engulfment by macrophages [139].”

What the sources say

• Not checked yetcites [139] Proto, 2018, Regulatory t cells promote macrophage efferocytosis during inflammation resolution, Immunity source

In the paper

“Specific populations of innate immune effector macrophages take up apoptotic cells in particular tissues, known as efferocytosis, which prevents apoptotic cells from being necrotic or pro-inflammatory [138].”

What the sources say

• Not checked yetcites [138] Roberts, 2017, Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells, Immunity source

In the paper

“which is a principal ligand required for engulfment activation via binding and activating LDL-receptor-related protein (LRP) on macrophages [150].”

What the sources say

• Not checked yetcites [150] Gardai, 2005, Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of lrp on the phagocyte, Cell source

In the paper

“It is noteworthy that the sustainable clearance of multiple apoptotic cells by macrophages requires dynamin-related protein 1 (DRP1)-mediated macrophage mitochondrial fission, allowing calcium release from mitochondria into the cytoplasm, triggered by the initial uptake of apoptotic cells [147].”

What the sources say

• Not checked yetcites [147] Wang, 2017, Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages, Cell source

In the paper

“Mounting evidence demonstrates that immune surveillance of senescent cells is executed by different immune cells such as macrophages, natural killer (NK) cells and cytotoxic T cells in cancer [5,130] and chronic liver cirrhosis [20].”

What the sources say

• Not checked yetcites [5] Burton, 2014, Physiological and pathological consequences of cellular senescence, Cell Mol. Life Sci. source
• Not checked yetcites [130] Kang, 2011, Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, Nature source
• Not checked yetcites [20] Krizhanovsky, 2008, Senescence of activated stellate cells limits liver fibrosis, Cell source

In the paper

“Different immune cells have a distinct capability to identify and eliminate the unique senescent cells.”

In the paper

“Yang et al. reported that the C-type lectin receptor LSECtin (Clec4g) on colon macrophages is required for macrophage engulfment and clearance of apoptotic cells, contributing to intestinal repair in dextran sulphate sodium-induced colitis [146].”

What the sources say

• Not checked yetcites [146] Yang, 2018, C-type lectin receptor lsectin-mediated apoptotic cell clearance by macrophages directs intestinal repair in experimental colitis, Proc. Natl. Acad. Sci. USA source

In the paper

“This selectivity is due to selective upregulation of NKG2D ligands MICA and ULBP2 in senescent IMR-90 cells but not growing or quiescent cells [151].”

What the sources say

• Not checked yetcites [151] Sagiv, 2016, Nkg2d ligands mediate immunosurveillance of senescent cells, Aging source

In the paper

“HLA-E expression is also increased in the senescent fibroblasts of human skin during ageing.”

What the sources say

• Not checked yetcites [124] Pereira, 2019, Senescent cells evade immune clearance via hla-e-mediated nk and cd8(+) t cell inhibition, Nat. Commun. source

In the paper

“Moreover, supplementation with exogenous calreticulin restores the clearance of CDKN2B-deficient apoptotic cells by macrophages [149].”

What the sources say

• Not checked yetcites [149] Kojima, 2014, Cyclin-dependent kinase inhibitor 2b regulates efferocytosis and atherosclerosis, J. Clin. Investig. source

In the paper

“CD4+ cytotoxic T cells can directly kill senescent tumor cells by recognizing MHC II molecules, which are usually absent in healthy cells but present in a subset of tumor or senescent cells [130].”

What the sources say

• Not checked yetcites [130] Kang, 2011, Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, Nature source

In the paper

“NKG2D receptor deletion instigates the accumulation of senescent stellate cells, resulting in increased liver fibrosis in mice in vivo [151].”

What the sources say

• Not checked yetcites [151] Sagiv, 2016, Nkg2d ligands mediate immunosurveillance of senescent cells, Aging source

In the paper

“CD11b+ DCs with dysfunctional autophagy due to Atg16l1 deficiency expand aortic CD4+ Treg cells and inhibit atherogenesis in Ldlr−/− mice [162].”

What the sources say

• Not checked yetcites [162] Clement, 2019, Impaired autophagy in cd11b(+) dendritic cells expands cd4(+) regulatory t cells and limits atherosclerosis in mice, Circ. Res. source

In the paper

“senescent cells generate specific cell-surface antigen, such as band 3 [158]”

What the sources say

• Not checked yetcites [158] Kay, 1993, Generation of senescent cell antigen on old cells initiates igg binding to a neoantigen, Cell Mol. Biol.

In the paper

“CD24+ DCs generally exert their removal function via T-cell regulation.”

What the sources say

• Not checked yetcites [161] Cummings, 2016, Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs, Nature source

In the paper

“high expression of fibroblast activation protein (FAP) in active cardiac fibroblasts but not cardiomyocytes, drives abundant cardiac fibrosis and consequent myocardial disease [134].”

What the sources say

• Not checked yetcites [134] Aghajanian, 2019, Targeting cardiac fibrosis with engineered t cells, Nature source

In the paper

“Reinstructing cytotoxic T cells to identify specific antigens on cancer cells using either a modified T-cell receptor or a chimeric antigen receptor (CAR) has been successfully used for specific cancer therapies [156].”

What the sources say

• Not checked yetcites [156] June, 2018, Car t cell immunotherapy for human cancer, Science source

In the paper

“CD103+ DCs selectively carry apoptotic intestinal epithelial cells to mesenteric lymph nodes, which function as critical determinants to induce tolerogenic CD4+ regulatory T-cell differentiation in mice [161].”

What the sources say

• Not checked yetcites [161] Cummings, 2016, Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs, Nature source

In the paper

“Indoleamine 2,3-dioxygenase 1 (IDO1)-expressing and chemokine (C-C motif) receptor 9 (CCR9)-positive plasmacytoid dendritic cells (pDCs) in the aorta locally induce aortic Treg cells, which produce IL-10 and subsequently prevent atherogenesis in mice [163].”

What the sources say

• Not checked yetcites [163] Yun, 2016, Indoleamine 2,3-dioxygenase-expressing aortic plasmacytoid dendritic cells protect against atherosclerosis by induction of regulatory t cells, Cell Metab. source

In the paper

“Dendritic cells (DCs), a professional phagocytic cell type, can also identify and eradicate apoptotic cells [160].”

What the sources say

• Not checked yetcites [160] Albert, 1998, Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and cd36, and cross-present antigens to cytotoxic t lymphocytes, J. Exp. Med. source

In the paper

“CD8+ cytotoxic T cells directly eradicate target cells using cytotoxic molecules via recognizing MHC I molecules within nearly all cells [127].”

What the sources say

• Not checked yetcites [127] Hashimoto, 2019, Single-cell transcriptomics reveals expansion of cytotoxic cd4 t cells in supercentenarians, Proc. Natl. Acad. Sci. USA source

In the paper

“These ligands enhance NK cell susceptibility [137].”

What the sources say

• Not checked yetcites [137] Soriani, 2009, Atm-atr-dependent up-regulation of dnam-1 and nkg2d ligands on multiple myeloma cells by therapeutic agents results in enhanced nk-cell susceptibility and is associated with a senescent phenotype, Blood source

In the paper

“Because senescent cells are also beneficial in the short term, the homeostasis of senescent cells is critical for healthy ageing.”

In the paper

“Chemotherapeutic drugs, including doxorubicin, melphalan and bortezomib, upregulate both the DNAX accessory molecule-1 (DNAM-1; CD226) ligand PVR (poliovirus receptor; CD155) and NKG2D ligands (MICA and MICB) on multiple myeloma cells presenting a senescent phenotype.”

What the sources say

• Not checked yetcites [137] Soriani, 2009, Atm-atr-dependent up-regulation of dnam-1 and nkg2d ligands on multiple myeloma cells by therapeutic agents results in enhanced nk-cell susceptibility and is associated with a senescent phenotype, Blood source

In the paper

“the YT human NK cell line preferentially destroys senescent IMR-90 fibroblasts [20].”

What the sources say

• Not checked yetcites [20] Krizhanovsky, 2008, Senescence of activated stellate cells limits liver fibrosis, Cell source

In the paper

“HLA-E then inhibits immune cytotoxicity targeting senescent cells by interacting with the inhibitory receptor NKG2A expressed on NK cells [124].”

What the sources say

• Not checked yetcites [124] Pereira, 2019, Senescent cells evade immune clearance via hla-e-mediated nk and cd8(+) t cell inhibition, Nat. Commun. source

In the paper

“NK cells are involved in the elimination of senescent cells through interaction between the activating NKG2D receptor and its ligands expressed on senescent cells.”

What the sources say

• Not checked yetcites [20] Krizhanovsky, 2008, Senescence of activated stellate cells limits liver fibrosis, Cell source

In the paper

“perforin- and granzyme-containing granule exocytosis but not death-receptor-mediated apoptosis, is required for NK cell-mediated killing of senescent cells [40].”

What the sources say

• Not checked yetcites [40] Ovadya, 2018, Impaired immune surveillance accelerates accumulation of senescent cells and aging, Nat. Commun. source

In the paper

“Pereira et al. recently reported that senescent human primary dermal fibroblasts and endothelial cells express higher levels of the atypical major histocompatibility complex (MHC) Ib molecule HLA-E via the p38 signaling pathway than non-senescent cells.”

What the sources say

• Not checked yetcites [124] Pereira, 2019, Senescent cells evade immune clearance via hla-e-mediated nk and cd8(+) t cell inhibition, Nat. Commun. source

In the paper

“c-Jun overexpression protects CAR-T cells from dysfunction by inducing T-cell exhaustion resistance [157].”

What the sources say

• Not checked yetcites [157] Lynn, 2019, C-jun overexpression in car t cells induces exhaustion resistance, Nature source