Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

In the paper

“However, excessive accumulation of senescent cells causally shortens the healthy lifespan [11] and drives organ ageing [12], age-related organ deterioration/disorders [13,14], tissue dysfunction and chronic diseases, including cardiovascular diseases (CVDs) [15,16], cancer [2], neurodegenerative diseases [17,18] and osteoarthritis [19].”

What the sources say

• Not checked yetcites [11] Baker, 2016, Naturally occurring p16(ink4a)-positive cells shorten healthy lifespan, Nature source
• Not checked yetcites [12] Childs, 2015, Cellular senescence in aging and age-related disease: From mechanisms to therapy, Nat. Med. source
• Not checked yetcites [13] Baker, 2011, Clearance of p16ink4a-positive senescent cells delays ageing-associated disorders, Nature source
• Not checked yetcites [14] Childs, 2017, Senescent cells: An emerging target for diseases of ageing, Nat. Rev. Drug Discov. source

In the paper

“Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.”

In the paper

“Cellular senescence is a cell state in which the cell-cycle is generally irreversibly stopped [1], with cell-cycle reentry being a plausible scenario under specific circumstances, particularly in tumor cells [2].”

What the sources say

• Not checked yetcites [1] Gorgoulis, 2019, Cellular senescence: Defining a path forward, Cell source
• Not checked yetcites [2] Milanovic, 2018, Senescence-associated reprogramming promotes cancer stemness, Nature source

In the paper

“p16Ink4a (encoded by the INK4a/ARF locus, also known as CDKN2a, hereafter referred to as p16)-induced senescence of mouse and human pancreatic beta cells also promotes insulin secretion [10].”

What the sources say

• Not checked yetcites [10] Helman, 2016, P16(ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion, Nat. Med. source

In the paper

“Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors.”

What the sources say

• Not checked yetcites [1] Gorgoulis, 2019, Cellular senescence: Defining a path forward, Cell source

In the paper

“Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing.”

• Also stated in: § 1. Introduction · plain

  “However, excessive accumulation of senescent cells causally shortens the healthy lifespan [11] and drives organ ageing [12], age-related organ deterioration/disorders [13,14], tissue dysfunction and chronic diseases, including cardiovascular diseases (CVDs) [15,16], cancer [2], neurodegenerative diseases [17,18] and osteoarthritis [19].”

What the sources say

• Not checked yetcites [11] Baker, 2016, Naturally occurring p16(ink4a)-positive cells shorten healthy lifespan, Nature source
• Not checked yetcites [12] Childs, 2015, Cellular senescence in aging and age-related disease: From mechanisms to therapy, Nat. Med. source
• Not checked yetcites [13] Baker, 2011, Clearance of p16ink4a-positive senescent cells delays ageing-associated disorders, Nature source
• Not checked yetcites [14] Childs, 2017, Senescent cells: An emerging target for diseases of ageing, Nat. Rev. Drug Discov. source

In the paper

“There are two major types of cellular senescence: stress-induced premature cellular senescence [3] and replicative senescence due to a repeated cell cycle, which is usually mediated by telomere shortening [4].”

What the sources say

• Not checked yetcites [3] Liu, 2015, Impact of er stress-regulated atf4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy, Am. J. Physiol. Cell Physiol. source
• Not checked yetcites [4] Mao, 2012, Replicatively senescent cells are arrested in g1 and g2 phases, Aging source

In the paper

“Recently, cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase (cGAS) was shown to recognize cytosolic DNA in senescent cells to produce cGAMP, which triggers the generation of SASP factors via stimulator of interferon genes (STING) and promotes paracrine senescence [35].”

What the sources say

• Not checked yetcites [35] Gluck, 2017, Innate immune sensing of cytosolic chromatin fragments through cgas promotes senescence, Nat. Cell Biol. source

In the paper

“The first-in-human open-label pilot study indicates that D + Q directly eliminates senescent cells in human adipose tissue and skin [120] and significantly improves the physical function of participants with idiopathic pulmonary fibrosis [45].”

What the sources say

• Not checked yetcites [120] Hickson, 2019, Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease, EBioMedicine source
• 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

“Senescent cells generally demonstrate an enlarged and flattened cell morphology [27] and expanded nucleoli [28,29], enhanced senescence-associated beta-galactosidase (SA-β-gal) activity [30], telomere shortening, elevation of the cyclin-dependent kinase inhibitor p16 [11,31] or p21 [32], macromolecular damage and metabolism dysfunction [1].”

What the sources say

• Not checked yetcites [27] Mammoto, 2019, Effects of age-dependent changes in cell size on endothelial cell proliferation and senescence through yap1, Aging source
• Not checked yetcites [28] Buchwalter, 2017, Nucleolar expansion and elevated protein translation in premature aging, Nat. Commun. source
• Not checked yetcites [29] Tiku, 2017, Small nucleoli are a cellular hallmark of longevity, Nat. Commun. source
• Not checked yetcites [30] Matthews, 2006, Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: Effects of telomerase and oxidative stress, Circ. Res. source

In the paper

“Lipofuscin is an emerging and more sensitive biomarker than SA-β-gal activity for cellular senescence in vitro and in vivo.”

What the sources say

• Not checked yetcites [37] Evangelou, 2017, Robust, universal biomarker assay to detect senescent cells in biological specimens, Aging Cell. source

In the paper

“Bussian et al. reported that clearance of p16+ senescent astrocytes and microglia using INKATTAC transgene restrains gliosis, super-phosphorylation of both soluble and insoluble tau resulting in neurofibrillary tangle deposition and degeneration of cortical and hippocampal neurons, thus restoring cognitive function.”

What the sources say

• Not checked yetcites [18] Bussian, 2018, Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline, Nature source

In the paper

“Cellular senescence accumulation usually arises from increased stresses-induced cellular senescence and reduction of senescent cell removal due to apoptosis evasion and/or immune system dysfunction.”

In the paper

“DRP1-deficient macrophages present impaired efferocytosis in vivo and subsequently increased plaque necrosis in advanced atherosclerotic lesions of Western diet-fed LDLR knockout mice [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

“Both macrophage and apoptotic or senescent cells control macrophage efferocytosis ability.”

In the paper

“These senescent tumor cells recruit innate immune cells, such as macrophages, leading to the eradication of senescent tumor cells and subsequent tumor regression [145].”

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

“Antibodies blocking CD47 reactivate efferocytosis of diseased vascular tissue without altering cellular apoptosis, as well as alleviate atherosclerosis in both the aortic sinus and en face of the aorta in multiple mouse models [148].”

What the sources say

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

In the paper

“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

“F4/80+ macrophages are also key players in the removal of senescent uterine cells after parturition to keep postpartum uterine functionality in wild-type mice and maintain the success rate of a second pregnancy in a preterm birth mouse model [135].”

What the sources say

• Not checked yetcites [135] Egashira, 2017, F4/80+ macrophages contribute to clearance of senescent cells in the mouse postpartum uterus, Endocrinology source

In the paper

“Kang et al. demonstrated that CD4+ T cells require monocytes/macrophages but not NK cells, to remove pre-malignant senescent hepatocytes, subsequently blocking liver tumor development [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

“The impaired ability of macrophage efferocytosis would enhance atherogenesis [139,140,141] and atherosclerotic plaque instability [142,143,144].”

What the sources say

• Not checked yetcites [139] Proto, 2018, Regulatory t cells promote macrophage efferocytosis during inflammation resolution, Immunity source
• Not checked yetcites [140] Schrijvers, 2005, Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis, Arterioscler. Thromb. Vasc. Biol. source
• Not checked yetcites [141] Kojima, 2017, The role of efferocytosis in atherosclerosis, Circulation source
• Not checked yetcites [142] Seneviratne, 2017, Interferon regulatory factor 5 controls necrotic core formation in atherosclerotic lesions by impairing efferocytosis, Circulation source
• Not checked yetcites [143] Thorp, 2008, Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice, Arterioscler. Thromb. Vasc. Biol. source
• Not checked yetcites [144] Yurdagul, 2017, Mechanisms and consequences of defective efferocytosis in atherosclerosis, Front. Cardiovasc Med. source

In the paper

“Excessive and persistent accumulation of different senescent cells drives unique ageing and chronic disease development.”

In the paper

“p53-expressing senescent liver tumor cells recruit NK cells by inducing the chemokine CCL2 but not CCL3, CCL4 or CCL5, in senescent tumor cells without affecting the ligand expression of RAE-1 proteins in the tumor cells [153].”

What the sources say

• Not checked yetcites [153] Iannello, 2013, P53-dependent chemokine production by senescent tumor cells supports nkg2d-dependent tumor elimination by natural killer cells, J. Exp. Med. source

In the paper

“Thus, apoptotic cells without CDKN2B impair macrophages efferocytosis and result in the development of advanced atherosclerotic plaques with large necrotic cores.”

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

“the adoptive constitution of engineered specific CAR-CD8+ T cells selectively targeting FAP notably alleviates cardiac fibrosis and reverses both systolic and diastolic cardiac function in angiotensin II and phenylephrine-treated mice [134].”

What the sources say

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

In the paper

“mice with defects in granule exocytosis accumulate senescent stellate cells and display stronger liver fibrosis in response to a fibrogenic agent [131].”

What the sources say

• Not checked yetcites [131] Sagiv, 2013, Granule exocytosis mediates immune surveillance of senescent cells, Oncogene source

In the paper

“Notably, ligands or antigens to activate the receptors NKG2D and DNAM-1 or ligands HLA-E for the inhibitory receptor NKG2A, have demonstrated expression in senescent cells.”

In the paper

“NK cell activation by polyinosinic-polycytidylic acid [152] decreases the senescent cell number in the liver in vivo, leading to reduced liver fibrosis [20].”

What the sources say

• Not checked yetcites [152] Radaeva, 2006, Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in nkg2d-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners, Gastroenterology source
• Not checked yetcites [20] Krizhanovsky, 2008, Senescence of activated stellate cells limits liver fibrosis, Cell source