Programmed cell senescence during mammalian embryonic development
Open accessAbstract
Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Recent reports showed a beneficial role for the SASP during embryonic development and in limiting fibrosis after tissue injury.
“recent reports showed a beneficial role for the SASP during embryonic development (Muñoz-Espín et al., 2013; Storer et al., 2013) and a role in limiting fibrosis after tissue injury (Jun and Lau, 2010; Krizhanovsky et al., 2008).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Muñoz-Espín et al., 2013
The Clearance of Senescent Cells and Compensatory Mechanisms section (page unavailable) reports that developmental senescence triggers macrophage-mediated elimination of embryonic mesonephric tubules. The Introduction describes how the SASP can promote tissue remodeling, but the paper does not establish that the SASP specifically causes the beneficial developmental effects. The fibrosis clause is cited to other papers in the citing sentence, not to Muñoz-Espín et al. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSenescence can occur in a programmed way and contribute to mammalian embryonic development and tissue patterning, mainly through p21, p15 and SASP mediators rather than overt DDR signalling.
“it was reported that senescence occurs in a programmed manner and contributes to mammalian embryonic development and tissue patterning, although mainly via induction of p21, p15 and mediators of the SASP rather than through overt DDR signalling131,132.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [132]
The Essential Role of p21 section reports programmed senescence during embryonic development, tissue remodeling, dependence on p21, and no detectable DNA-damage signaling. But the Developmentally Programmed Senescence Requires p21 Independently of p53 section explicitly excludes a relevant role for p15; the cited passages do not establish SASP mediators as a main mechanism. (LLM, conf=0.90)
Experimental — accuracy not yet measuredA distinct form of cellular senescence occurs in the mammalian developing embryo and placenta to control growth and patterning.
“A distinct form of cellular senescence occurs in the mammalian developing embryo and in the placenta to control growth and patterning131,132,142,143.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [132]
The Abstract and Introduction report a distinct, developmentally programmed form of senescence in mammalian embryos. The Abstract links it to tissue remodeling and developmental abnormalities, supporting a role in embryonic development. The passages do not establish senescence in the placenta or a placental role in growth and patterning. (LLM, conf=0.87)
Experimental — accuracy not yet measuredNK cells, T cells and macrophages can physically interact with senescent cells in both pathological and physiological conditions.
“Among these cell types, NK cells, T cells and macrophages can physically interact with senescent cells in pathological and physiological conditions131,132,145,150,153–156.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [132]
The “Clearance of Senescent Cells and Compensatory Mechanisms” section reports that macrophages surround senescent embryonic tubules and describes macrophage clearance of senescent tumor cells. It does not establish the claimed physical interactions involving NK cells or T cells. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCellular senescence has beneficial roles in tissue remodelling during embryogenesis and wound healing.
“Cellular senescence, a stress-induced irreversible growth arrest often characterized by p16 Ink4a expression and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing.”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [9]
The Abstract concludes that developmentally programmed senescence promotes tissue remodeling during embryogenesis. The Additional information section proposes that senescence was later adapted to aid tissue regeneration and healing after damage in adults, but does not establish a beneficial role in wound healing. Page numbers are not provided for these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Senescent cells have beneficial effects in injury repair and tissue remodelling.
“Furthermore, recent studies showing that senescent cells have beneficial effects in injury repair and tissue remodelling 6 - 10 have called into question the simplistic view of senescence as only a driver of age-dependent pathologies, raising the specter that senescent cell clearance might remove useful cells in addition to detrimental ones.”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [9]
The Abstract reports that programmed senescence promotes tissue remodeling during embryonic development, and the Introduction links senescence-associated inflammation to damage resolution. But the paper presents a role in healing after injury in adults as a possibility, not as a demonstrated beneficial effect. Page numbers are not provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSASP factors mediate developmental senescence.
“SASP factors mediate developmental senescence (Mun ˜ oz-Espı ´n et al., 2013; Storer et al., 2013), wound healing (Demaria et al., 2014), and tissue plasticity (Mosteiro et al., 2016) and also contribute to persistent chronic inflammation (known as inflammaging) (Franceschi and Campisi, 2014).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Munoz-Espin et al., 2013
The Introduction (page unavailable) identifies TGF-β as a secreted senescence-associated factor. The section on signaling pathways regulating developmentally programmed senescence reports that inhibiting TGF-β signaling reduced embryonic senescence markers, but it does not establish that SASP factors as a group mediate developmental senescence. (LLM, conf=0.78)
Experimental — accuracy not yet measuredSenescent cells play crucial roles in development, tumor suppression, and tissue repair.
“Senescent cells play crucial roles in development, tumor suppression, and tissue repair (Demaria et al, 2014; Muñoz-Espín et al, 2013; Serrano et al, 1997).”
From Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues (2025) · cites this paper as Muñoz-Espín et al, 2013
The Abstract reports that senescence promotes tissue remodeling during embryonic development, supporting the developmental role. The Introduction links senescence to tumors and damage resolution, but does not directly establish a tumor-suppressive role; the Additional information section proposes adult tissue regeneration and healing as a possibility rather than a demonstrated role. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSASP factors are involved in embryonic development of the apical ectodermal ridge and neural roof plate.
“In addition to tissue repair, SASP factors are involved in embryonic development of the apical ectodermal ridge and neural roof plate.40, 41”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [41]
In “Developmentally Programmed Senescence in Whole-Mount Embryos” (page unavailable), the paper reports senescence-marker staining in the apical ectodermal ridge and near the closing neural tube. Its Introduction describes SASP factors generally, but the copy does not show that those factors are involved in development of the ridge or neural roof plate specifically. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSenescent cells have shown beneficial effects as tumour suppressors, during embryo development, and in liver and skin repair or reprogramming.
“By contrast, senescent cells have shown beneficial effects as tumour suppressors, during embryo development, and in liver and skin repair18–21 or reprogramming22–24.”
From Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration (2023) · cites this paper as [20]
The paper’s Additional information section states that cellular senescence contributes to embryonic development and tissue remodeling. It proposes a possible role in adult regeneration and healing, but does not establish liver or skin repair specifically; the cited passages also do not address reprogramming. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDefective senescence programmes or removal of senescent cells during various developmental stages results in patterning abnormalities.
“defective senescence programmes or removal of senescent cells during various developmental stages results in patterning abnormalities 1 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [1]
The Abstract and “Developmental Defects Associated with Impaired Programmed Senescence” report developmental abnormalities when p21-dependent senescence is absent, including vaginal septa. The paper describes clearance of senescent cells as part of normal tissue remodeling; it does not show that removing those cells causes patterning abnormalities. Its detailed defect findings concern specific structures, rather than various developmental stages generally (page numbers unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measuredSenescent cells were recently detected during embryogenesis, where they appear to play a nonessential role in optimizing the development of certain embryonic structures.
“Of possible relevance to this puzzle, senescent cells were recently detected during embryogenesis, where they appear to play a nonessential role in optimizing the development of certain embryonic structures (Muñoz-Espín et al., 2013; Storer et al., 2013).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Muñoz-Espín et al., 2013
Senescence contributes to embryonic patterning, much like apoptosis.
“Senescence, much like apoptosis, contributes to embryonic patterning (Muñoz-Espín et al. 2013; Storer et al. 2013).”
From Cellular senescence and its effector programs (2014) · cites this paper as Muñoz-Espín et al. 2013
Programmed cellular senescence contributes to tissue remodeling during mammalian embryonic development at multiple regions.
“In addition, two recent studies have identified “programmed” cellular senescence, which contributes to tissue remodeling during mammalian embryonic development at multiple regions (Muñoz-Espín et al. 2013; Storer et al. 2013).”
From Cellular senescence and its effector programs (2014) · cites this paper as Muñoz-Espín et al. 2013
Senescence plays key physiological roles in normal development, maintaining tissue homeostasis, tissue remodeling and repair, wound healing, secretion of insulin by pancreatic beta cells, and limiting tumor progression.
“Senescence plays key physiological roles in normal development (Muñoz-Espín et al., 2013; Storer et al., 2013), maintaining tissue homeostasis, tissue remodeling and repair (Yun et al., 2015), wound healing (Ramakrishna et al., 2012; Demaria et al., 2014), secretion of insulin by pancreatic beta cells (Helman et al., 2016), and limits tumor progression by ensuring that potentially dysfunctional,”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Muñoz-Espín et al., 2013
Upregulation of p21 plays a key role in developmental senescence, as mice lacking it show defects in embryonic senescence, apical ectodermal ridge maintenance and patterning, and other developmental defects.
“Upregulation of p21WAF1/CIP1 plays a key role in developmental senescence as mice lacking it show defects in embryonic senescence, apical ectodermal ridge maintenance and patterning as well as other developmental defects.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Muñoz-Espín et al., 2013
Developmental senescence is a transient programmed cellular senescence that occurs during mammalian embryonic development.
“Developmental senescence is a transient programmed cellular senescence that occurs during mammalian embryonic development (Muñoz-Espín et al., 2013; Storer et al., 2013).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Muñoz-Espín et al., 2013
DDR markers have limited potential for identifying senescent cells in vivo since DDR independent mechanisms are also capable of inducing senescence via p53/p21WAF1/CIP1 pathway.
“However, despite this, DDR markers have a limited potential for identifying senescent cells in vivo since DDR independent mechanisms are also capable of inducing senescence via p53/p21WAF1/CIP1 pathway (Alimonti et al., 2010; Freund et al., 2011; Muñoz-Espín et al., 2013; Storer et al., 2013; Salama et al., 2014).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Muñoz-Espín et al., 2013
Developmentally programmed and transiently-regulated senescence is vital in promoting tissue remodeling, embryogenesis and patterning.
“developmentally programmed and transiently-regulated senescence is established to be vital in promoting tissue remodeling, embryogenesis and patterning”
From Redox control of senescence and age-related disease. (2017) · cites this paper as [91]
This pathway can positively contribute to normal development and wound healing.
“This pathway can positively contribute to normal development and wound healing (15, 17, 61, 62).”
From The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. (2015) · cites this paper as [61]
Waves of cellular senescence followed by RCD contribute to developmental embryogenesis (dispensable) and to adult tissue repair/regeneration, immunity, stem cell preservation, and oncosuppression.
“Waves of cellular senescence (followed by RCD) appear to contribute to developmental embryogenesis (although in a dispensable manner) [6, 946, 947] as well as to multiple pathophysiological processes in the adult, including tissue repair and regeneration, immunity, preservation of the stem cell compartment, and oncosuppression [948–957].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [946]
Senescent cells play beneficial roles during embryonic development, tumor suppression, wound healing, and tissue repair.
“Recent data indicates that senescent cells play a variety of beneficial roles during processes such as embryonic development, tumor suppression, wound healing and tissue repair (Krizhanovsky et al., 2008, Muñoz-Espín et al., 2013, Demaria et al., 2014, Ritschka et al., 2017).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Muñoz-Espín et al., 2013
Senescent cells detected during development are not associated with activation of a DNA damage response.
“senescent cells detected during development, which are present transiently in tissues (Muñoz-Espín et al., 2013) are not associated with the activation of a DNA damage response”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Muñoz-Espín et al., 2013
TGF-β regulates senescence.
“previous reports have shown that TGF-β regulates senescence”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Muñoz-Espín et al., 2013
TGF-β ligands are part of the SASP and play an important role in senescence through p21CIP regulation.
“a number of studies have found that TGF-β ligands are part of the SASP and play an important role in senescence through p21CIP regulation, in agreement with our data (Acosta et al., 2013, Hoare et al., 2016, Muñoz-Espín et al., 2013, Storer et al., 2013).”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Muñoz-Espín et al., 2013
Embryonic cell senescence is p21-dependent but not p53-dependent, is accompanied by the SASP, and these cells are eliminated by macrophages.
“Embryonic cell senescence is p21, but not p53, dependent, is accompanied by the SASP, and these cells are eliminated by macrophages 149,150”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [149]
Unlike chronic senescence, the acute induction of cellular senescence represents a transient physiological response during embryonic development and adult tissue homeostasis.
“Indeed, unlike chronic senescence (i.e., accumulation of deleterious senescent cells with aging), the acute induction of cellular senescence represents a transient physiological response during embryonic development [27,28] and adult tissue homeostasis (e.g., to facilitate tissue repair after liver damage, in skin fibrosis, and wound healing) [29,30,31].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
Senescence can occur in mouse and human embryos.
“Senescence is classically viewed as a stress response but can also occur in mouse and human embryos [27,28].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
In senescent embryonic cells, p21, but not p16, enforces cell cycle arrest, together with p15.
“In senescent embryonic cells, p21, but not p16, enforces cell cycle arrest, together with p15 that is a p16-related CDK inhibitor.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
Other mechanisms, such as apoptosis, may partially compensate for the loss of developmental senescence in embryos lacking p21.
“Other mechanisms, such as apoptosis, may partially compensate for the loss of developmental senescence in such embryos [27,28].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
In senescent embryonic cells, p21 is not induced by p53 or DNA damage but is regulated by the TGF-beta/SMAD and PI3K/FOXO signaling pathways.
“Moreover, p21 is not induced by p53 or DNA damage but is regulated by the transforming growth factor (TGF)-β/SMAD and PI3K/Forkhead box O (FOXO) signaling pathways [27].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
Senescent cells can be cleared by the immune system rather than directly through apoptosis.
“Senescent cells can be cleared by the immune system [27,263,264] rather than directly through apoptosis.”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [27]
Senescence contributes to tissue remodeling during embryonic development.
“Finally, recent work has shown that senescence contributes also to tissue remodeling during embryonic development, 21,22”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [21]
Cellular senescence plays beneficial critical roles in numerous biological processes, such as tumor suppression, embryonic tissue remodeling and wound healing after injury.
“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].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [8]
Developmental senescent cells express p21WAF1/Cip1 but not p16INK4a, while the reverse is observed in melanocytic nevi.
“For example, developmental senescent cells express p21WAF1/Cip1 but not p16INK4a9,10, while the reverse is observed in melanocytic nevi36,37.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [9]
The SASP is involved in valuable physiological processes such as promoting tissue repair, fine-tuning development of embryonic structures, and stimulating immune surveillance.
“Furthermore, the SASP is involved in valuable physiological processes such as promoting tissue repair,18–20 fine-tuning the development of embryonic structures,21–23 and stimulating immune surveillance.24,25”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [22]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · see citing works
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477 · see citing works
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441 · see citing works
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941 · see citing works
Blinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163 · see citing works
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473 · see citing works
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · cited 1× · see citing works
“To further document senescence in the mesonephric tubules andendolymphatic sac,weusedmarkers of senescence-associated heterochromatin (Narita et al., 2003) and observed that epithelial cells from both structures at E14.”
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · cited 4× · see citing works
“We focused on the TGF-b pathway because of its previous involvement in senescence (Acosta et al., 2013; Kuilman and Peeper, 2009) and its well-established capacity to activate the transcription of the p21 gene through SMAD complexes (Datto et al.”
InfluentialOncogene-Induced Senescence Relayed by an Interleukin-Dependent Inflammatory Network
Kuilman, T., Michaloglou, C., Vredeveld, L. C. W., Douma, S., van Doorn, R., Desmet, C. J., Aarden, L. A., Mooi, W. J., & Peeper, D. S. (2008) · Cell · doi:10.1016/j.cell.2008.03.039 · Cited by 2,086 · cited 1× · see citing works
“…induced by the infliction of DNA damage (Lafferty-Whyte et al., 2010), replicative senescence (Kim et al., 2013; Shelton et al., 1999), oncogene-induced senescence (Collado et al., 2005; Kuilman et al., 2008), or activation of tumor suppressors (Abad et al., 2007; Rovillain et al., 2011).”
Tumor spectrum analysis in p53-mutant mice
Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., & Weinberg, R. A. (1994) · Current Biology · doi:10.1016/s0960-9822(00)00002-6 · Cited by 2,051 · see citing works
Programmed Cell Death in Animal Development and Disease
Fuchs, Y., & Steller, H. (2011) · Cell · doi:10.1016/j.cell.2011.10.033 · Cited by 1,915 · see citing works
An Oncogene-Induced DNA Damage Model for Cancer Development
Halazonetis, T. D., Gorgoulis, V. G., & Bartek, J. (2008) · Science · doi:10.1126/science.1140735 · Cited by 1,851 · see citing works
Cellular senescence in cancer and aging.
Collado, M., Blasco, M. A., & Serrano, M. (2007) · Cell · doi:10.1016/j.cell.2007.07.003 · Cited by 1,708 · see citing works
Self-citationSenescence surveillance of pre-malignant hepatocytes limits liver cancer development
Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011) · Nature · doi:10.1038/nature10599 · Cited by 1,621 · see citing works
Role of the INK4a Locus in Tumor Suppression and Cell Mortality
Serrano, M., Lee, H.-W., Chin, L., Cordon-Cardo, C., Beach, D., & DePinho, R. A. (1996) · Cell · doi:10.1016/s0092-8674(00)81079-x · Cited by 1,585 · see citing works
Self-citationLindsten, T., Ross, A. J., King, A., Zong, W.-X., Rathmell, J. C., Shiels, H. A., Ulrich, E., Waymire, K. G., Mahar, P., Frauwirth, K., et al. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00136-2 · Cited by 1,489 · see citing works
Senescence in premalignant tumours
Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A. J., Barradas, M., Benguría, A., Zaballos, A., Flores, J. M., Barbacid, M., et al. (2005) · Nature · doi:10.1038/436642a · Cited by 1,482 · see citing works
Self-citationFero, M. L., Rivkin, M. J., Tasch, M., Porter, P. L., Carow, C. E., Firpo, E. J., Polyák, K., Tsai, L., Broudy, V. C., Perlmutter, R. M., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81239-8 · Cited by 1,459 · see citing works
Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia
Barlow, C., Hirotsune, S., Paylor, R. E., Liyanage, M., Eckhaus, M., Collins, F. S., Shiloh, Y., Crawley, J. N., Ried, T., Tagle, D. A., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)80086-0 · Cited by 1,450 · see citing works
Use of within-array replicate spots for assessing differential expression in microarray experiments
Smyth, G. K., Michaud, J., & Scott, H. S. (2005) · Computer applications in the biosciences · doi:10.1093/bioinformatics/bti270 · Cited by 1,406 · see citing works
Inflammatory networks during cellular senescence: causes and consequences.
Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.03.003 · Cited by 1,354 · see citing works
FOXO transcription factors at the interface between longevity and tumor suppression
Greer, E. L., & Brunet, A. (2005) · Oncogene · doi:10.1038/sj.onc.1209086 · Cited by 1,306 · see citing works
Radiation-induced cell cycle arrest compromised by p21 deficiency
Brugarolas, J., Chandrasekaran, C., Gordon, J. I., Beach, D., Jacks, T., & Hannon, G. J. (1995) · Nature · doi:10.1038/377552a0 · Cited by 1,242 · see citing works
Senescence is a developmental mechanism that contributes to embryonic growth and patterning
Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.041 · Cited by 1,186 · see citing works
Senescence in tumours: evidence from mice and humans
Collado, M., & Serrano, M. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2772 · Cited by 1,124 · cited 1× · see citing works
“For instance, cyclin-dependent kinase inhibitors p21 and p27 also contribute to senescent phenotypes (Collado and Serrano, 2010).”
Self-citationSeoane, J., Le, H.-V., Shen, L., Anderson, S. A., & Massagué, J. (2004) · Cell · doi:10.1016/s0092-8674(04)00298-3 · Cited by 1,029 · see citing works
Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta.
Reynisdóttir, I., Polyak, K., Iavarone, A., & Massagué, J. (1995) · Genes & Development · doi:10.1101/gad.9.15.1831 · Cited by 962 · see citing works
Datto, M., Li, Y., Panus, J. F., Howe, D. J., Xiong, Y., & Wang, X. F. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5545 · Cited by 945 · see citing works
The polarization of immune cells in the tumour environment by TGFβ
Flavell, R. A., Sanjabi, S., Wrzesinski, S. H., & Licona-Limón, P. (2010) · Nature Reviews Immunology · doi:10.1038/nri2808 · Cited by 940 · see citing works
Senescence-messaging secretome: SMS-ing cellular stress
Kuilman, T., & Peeper, D. S. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2560 · Cited by 909 · see citing works
Kurz, D. J., Decary, S., Hong, Y., & Erusalimsky, J. D. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.20.3613 · Cited by 899 · see citing works
Microarray analysis of replicative senescence
Shelton, D. N., Chang, E., Whittier, P. S., Choi, D., & Funk, W. D. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80420-5 · Cited by 764 · see citing works
The Forkhead Transcription Factor Foxo1 Regulates Adipocyte Differentiation
Nakae, J., Kitamura, T., Kitamura, Y., Biggs, W., Arden, K. C., & Accili, D. (2003) · Developmental Cell · doi:10.1016/s1534-5807(02)00401-x · Cited by 727 · see citing works
'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally
García‐Cao, I., García‐Cao, M., Martín‐Caballero, J., Criado, L. M., Klatt, P., Flores, J. M., Weill, J., Blasco, M. A., & Serrano, M. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf595 · Cited by 529 · see citing works
Self-citationBID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death Program
Ren, D., Tu, H.-C., Kim, H., Wang, G. X., Bean, G. R., Takeuchi, O., Jeffers, J. R., Zambetti, G. P., Hsieh, J. J.-D., & Cheng, E. H. Y. (2010) · Science · doi:10.1126/science.1190217 · Cited by 472 · see citing works
The power and the promise of oncogene-induced senescence markers
Collado, M., & Serrano, M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1884 · Cited by 404 · see citing works
Self-citationPten positively regulates brown adipose function, energy expenditure, and longevity
Ortega-Molina, A., Efeyan, A., Lopez-Guadamillas, E., Muñoz-Martin, M., Gómez-López, G., Cañamero, M., Mulero, F., Pastor, J., Martinez, S., Romanos, E., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.02.001 · Cited by 356 · see citing works
Self-citationA mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging
Murga, M., Bunting, S. F., Montaña, M. F., Soria, R., Mulero, F., Cañamero, M., Lee, Y., McKinnon, P. J., Nussenzweig, A., & Fernández-Capetillo, Ó. (2009) · Nature Genetics · doi:10.1038/ng.420 · Cited by 351 · see citing works
Self-citationOncogene-induced senescence: the bright and dark side of the response
Gorgoulis, V. G., & Halazonetis, T. D. (2010) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2010.07.013 · Cited by 257 · see citing works
Hoenicke, L., & Zender, L. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs124 · Cited by 248 · cited 4× · see citing works
“…secretory phenotype (SASP) can also evoke a local inflammatory response with complex effects, including the elimination of senescent cells by phagocytosis, thus leading to tissue remodeling and damage resolution (Freund et al., 2010; Hoenicke and Zender, 2012; Krizhanovsky et al., 2008).”
InfluentialCellular mechanisms of Müllerian duct formation in the mouse
Orvis, G. D., & Behringer, R. R. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.03.027 · Cited by 222 · see citing works
Wide spectrum of tumors in knock‐in mice carrying a Cdk4 protein insensitive to INK4 inhibitors
Sotillo, R., Dubus, P., Martn, J., de la Cueva, E., Ortega, S., Malumbres, M., & Barbacid, M. (2001) · The EMBO Journal · doi:10.1093/emboj/20.23.6637 · Cited by 208 · see citing works
Activation of nuclear factor-kappa B signalling promotes cellular senescence
Rovillain, E. M. I., Mansfield, L., Caetano, C., Álvarez‐Fernández, M., Caballero, O. L., Medema, R. H., Hummerich, H., & Jat, P. (2011) · Oncogene · doi:10.1038/onc.2010.611 · Cited by 197 · see citing works
ATR signaling can drive cells into senescence in the absence of DNA breaks
Toledo, L. I., Murga, M., Gutierrez-Martinez, P., Soria, R., & Fernandez-Capetillo, O. (2008) · Genes & Development · doi:10.1101/gad.452308 · Cited by 183 · see citing works
Genetic Control of Programmed Cell Death During Animal Development
Conradt, B. (2009) · Annual Review of Genetics · doi:10.1146/annurev.genet.42.110807.091533 · Cited by 173 · see citing works
The kidney: from normal development to congenital disease
Grantham, J. J. (2003) · American Journal of Kidney Diseases · doi:10.1016/s0272-6386(03)00685-1 · Cited by 142 · see citing works
Krizhanovsky, V., Xue, W., Zender, L., Yon, M., Hernando, E., & Lowe, S. W. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.048 · Cited by 138 · see citing works
The Arf/p53 Pathway in Cancer and Aging
Matheu, A., Maraver, A., & Serrano, M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6851 · Cited by 129 · see citing works
Self-citationHirota, Y., Cha, J., Yoshie, M., Daikoku, T., & Dey, S. K. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1108180108 · Cited by 125 · see citing works
Implications of time-series gene expression profiles of replicative senescence.
Kim, Y., Byun, H., Jee, B. A., Cho, H., Seo, Y., Kim, Y., Park, M. H., Chung, H., Woo, H. G., & Yoon, G. (2013) · Aging Cell · doi:10.1111/acel.12087 · Cited by 106 · see citing works
Developmental origin of vaginal epithelium
Kurita, T. (2010) · Differentiation · doi:10.1016/j.diff.2010.06.007 · Cited by 93 · see citing works
The endolymphatic duct and sac.
Lo, W. W. M., Daniels, D. L., Chakeres, D. W., Linthicum, F. H., Ulmer, J. L., Mark, L. P., & Swartz, J. D. (1997) · PubMed Central · Cited by 82 · see citing works
Davidson, A. (2008) · StemBook · doi:10.3824/stembook.1.34.1 · Cited by 79 · see citing works
Kim, H., & Wangemann, P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017949 · Cited by 69 · see citing works
The quail mesonephros: a new model for renal senescence?
Nacher, V., Carretero, A., Navarro, M., Armengol, C., Llombart, C., Rodríguez, A., Herrero-Fresneda, I., Ayuso, E., & Ruberte, J. (2006) · Journal of Vascular Research · doi:10.1159/000096076 · Cited by 47 · see citing works
Self-citationThe role of macrophages in clearing programmed cell death in the developing kidney
Camp, V., & Martin, P. B. (1996) · Anatomy and Embryology · doi:10.1007/bf00198535 · Cited by 29 · see citing works
Lafferty‐Whyte, K., Bilsland, A. E., Cairney, C. J., Hanley, L., Jamieson, N. B., Zaffaroni, N., Oien, K. A., Burns, S., Roffey, J., Boyd, S. M., et al. (2010) · BMC Genomics · doi:10.1186/1471-2164-11-532 · Cited by 26 · see citing works
Ing1 Mediates p53 Accumulation and Chromatin Modification in Response to Oncogenic Stress
Abad, M., Menéndez, C., Füchtbauer, A. C., Serrano, M., Füchtbauer, E., & Palmero, I. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701639200 · Cited by 24 · see citing works
Self-citationNon-developmentally programmed cell death in Caenorhabditis elegans
Kourtis, N., & Tavernarakis, N. (2006) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2006.11.004 · Cited by 21 · see citing works
Development of the Mesonephric Kidney
Sainio, K. (2003) · Elsevier eBooks · doi:10.1016/b978-012722441-1/50008-7 · Cited by 20 · see citing works
Vaginal septa in mice: incidence, inheritance, and effect on reproductive, performance.
Cunliffe-Beamer, T. L., & Feldman, D. B. (1976) · PubMed · Cited by 20 · see citing works
3D Reconstruction of the Mouse's Mesonephros
Vazquez, M. D., Bouchet, P., Mallet, J. L., Foliguet, B., Gérard, H., & Leheup, B. (1998) · Anatomia Histologia Embryologia · doi:10.1111/j.1439-0264.1998.tb00194.x · Cited by 15 · see citing works
Lezmi, S., Thibault-Duprey, K., Bidaut, A., Hardy, P., Pino, M., Macary, G. S., Barbellion, S., Brunel, P., Dorchies, O. M., Clifford, C. B., et al. (2010) · Veterinary Pathology · doi:10.1177/0300985810391113 · Cited by 13 · see citing works
The Development of the Endolymphatic Duct and Sac: A Light Microscopical Study
Hultcrantz, M., Bagger‐Sjöbäck, D., & Rask‐Andersen, H. (1987) · Acta Oto-Laryngologica · doi:10.3109/00016488709128268 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Cellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225 · see citing works
Self-citationCellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
Self-citationNaturally occurring p16Ink4a-positive cells shorten healthy lifespan
Baker, D. J., Childs, B. G., Durik, M., Wijers, M. E., Sieben, C. J., Zhong, J., A. Saltness, R., Jeganathan, K. B., Verzosa, G. C., Pezeshki, A., et al. (2016) · Nature · doi:10.1038/nature16932 · Cited by 2,891 · see citing works
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623 · see citing works
Cellular senescence in aging and age-related disease: from mechanisms to therapy
Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M. (2015) · Nature Medicine · doi:10.1038/nm.4000 · Cited by 2,363 · see citing works
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277 · see citing works
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.11.012 · Cited by 2,045 · see citing works
“However, recent reports showed a beneficial role for the SASP during embryonic development (Muñoz-Espı́n et al., 2013; Storer et al., 2013) and a role in limiting fibrosis after tissue injury (Jun and Lau, 2010; Krizhanovsky et al.”
Senescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766 · see citing works
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
Origin and functions of tissue macrophages
Epelman, S., Lavine, K. J., & Randolph, G. J. (2014) · Immunity · doi:10.1016/j.immuni.2014.06.013 · Cited by 1,585 · see citing works
Facing up to the global challenges of ageing
Partridge, L., Deelen, J., & Slagboom, P. E. (2018) · Nature · doi:10.1038/s41586-018-0457-8 · Cited by 1,475 · see citing works
Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.031 · Cited by 1,454 · see citing works
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · see citing works
Senescent cells: an emerging target for diseases of ageing
Childs, B. G., Gluscevic, M., Baker, D. J., Laberge, R.-M., Marquess, D., Dananberg, J., & van Deursen, J. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.116 · Cited by 1,284 · see citing works
Senescence and aging: Causes, consequences, and therapeutic avenues
McHugh, D., & Gil, J. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201708092 · Cited by 1,233 · see citing works
Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines
Rea, I. M., Gibson, D. S., McGilligan, V., McNerlan, S. E., Alexander, H. D., & Ross, O. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00586 · Cited by 1,267 · see citing works
Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · see citing works
Senescence is a developmental mechanism that contributes to embryonic growth and patterning
Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.041 · Cited by 1,186 · see citing works
Senescence and the SASP: many therapeutic avenues
Birch, J., & Gil, J. (2020) · Genes & Development · doi:10.1101/gad.343129.120 · Cited by 1,177 · see citing works
“…Spring Harbor Laboratory Press; ISSN 0890-9369/20; www.genesdev.org 1565 Immune-mediated clearance of senescent cells suppresses tumor initiation (Kang et al. 2011), contributes to tumor regression (Xue et al. 2007), and is essential during development (Muñoz-Espín et al. 2013; Storer et al. 2013).”
BackgroundCellular senescence: the good, the bad and the unknown
Huang, W., Hickson, L. J., Eirin, A., Kirkland, J. L., & Lerman, L. O. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00601-z · Cited by 1,150 · see citing works
Forging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104 · see citing works
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL
Yosef, R., Pilpel, N., Tokarsky-Amiel, R., Biran, A., Ovadya, Y., Cohen, S., Vadai, E., Dassa, L., Shahar, E., Condiotti, R., et al. (2016) · Nature Communications · doi:10.1038/ncomms11190 · Cited by 1,032 · see citing works
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
Kang, C., Xu, Q., Martin, T. D., Li, M. Z., Demaria, M., Aron, L., Lu, T., Yankner, B. A., Campisi, J., & Elledge, S. J. (2015) · Science · doi:10.1126/science.aaa5612 · Cited by 982 · see citing works
Unmasking Transcriptional Heterogeneity in Senescent Cells
Hernandez-Segura, A., de Jong, T. V., Melov, S., Guryev, V., Campisi, J., & Demaria, M. (2017) · Current Biology · doi:10.1016/j.cub.2017.07.033 · Cited by 972 · see citing works
“Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5–8], and organismal aging [9].”
BackgroundSenescence and apoptosis: dueling or complementary cell fates?
Childs, B. G., Baker, D. J., Kirkland, J. L., Campisi, J., & van Deursen, J. M. (2014) · The EMBO Reports · doi:10.15252/embr.201439245 · Cited by 915 · see citing works
Unmasking senescence: context-dependent effects of SASP in cancer
Faget, D. V., Ren, Q., & Stewart, S. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0156-2 · Cited by 863 · see citing works
TGF-β signaling in health and disease
Massagué, J., & Sheppard, D. (2023) · Cell · doi:10.1016/j.cell.2023.07.036 · Cited by 890 · see citing works
How the ageing microenvironment influences tumour progression
Fane, M., & Weeraratna, A. T. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0222-9 · Cited by 849 · see citing works
The senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948 · see citing works
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · see citing works
TGF-β1 Signaling and Tissue Fibrosis
Kim, K. K., Sheppard, D., & Chapman, H. A. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022293 · Cited by 800 · see citing works
Senescence and cancer — role and therapeutic opportunities
Schmitt, C. A., Wang, B., & Demaria, M. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00668-4 · Cited by 794 · see citing works
Exosomes maintain cellular homeostasis by excreting harmful DNA from cells
Takahashi, A., Okada, R., Nagao, K., Kawamata, Y., Hanyu, A., Yoshimoto, S., Takasugi, M., Watanabe, S., Kanemaki, M. T., Obuse, C., et al. (2017) · Nature Communications · doi:10.1038/ncomms15287 · Cited by 761 · see citing works
The metabolic roots of senescence: mechanisms and opportunities for intervention
Wiley, C. D., & Campisi, J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00483-8 · Cited by 691 · see citing works
The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration.
Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., Sansom, O. J., Zender, L., & Keyes, W. M. (2017) · Genes & Development · doi:10.1101/gad.290635.116 · Cited by 650 · see citing works
A guide to assessing cellular senescence <i>in vitro</i> and <i>in vivo</i>
González‐Gualda, E., Baker, A. G., Fruk, L., & Muñoz‐Espín, D. (2021) · The FEBS Journal · doi:10.1111/febs.15570 · Cited by 645 · see citing works
Self-citationTGF-β Family Signaling in the Control of Cell Proliferation and Survival
Zhang, Y., Alexander, P. B., & Wang, X.-F. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a022145 · Cited by 626 · see citing works
Role of innate and adaptive immune mechanisms in cardiac injury and repair
Epelman, S., Liu, P. P., & Mann, D. L. (2015) · Nature reviews. Immunology · doi:10.1038/nri3800 · Cited by 631 · see citing works
Targeting cellular senescence with senotherapeutics: senolytics and senomorphics
Zhang, L. J., Pitcher, L. E., Prahalad, V., Niedernhofer, L. J., & Robbins, P. D. (2022) · FEBS Journal · doi:10.1111/febs.16350 · Cited by 648 · see citing works
Cellular senescence: a key therapeutic target in aging and diseases
Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158450 · Cited by 631 · see citing works
The dynamic nature of senescence in cancer
Lee, S., & Schmitt, C. A. (2019) · Nature Cell Biology · doi:10.1038/s41556-018-0249-2 · Cited by 588 · see citing works
The senescence-associated secretory phenotype and its regulation
Lopes-Paciencia, S., Saint-Germain, E., Rowell, M.-C., Ruiz, A. F., Kalegari, P., & Ferbeyre, G. (2019) · Cytokine · doi:10.1016/j.cyto.2019.01.013 · Cited by 601 · see citing works
The role of cellular senescence in ageing and endocrine disease
Khosla, S., Farr, J. N., Tchkonia, T., & Kirkland, J. L. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0335-y · Cited by 523 · see citing works
NOTCH1 mediates a switch between two distinct secretomes during senescence
Hoare, M., Ito, Y., Kang, T.-W., Weekes, M. P., Matheson, N. J., Patten, D. A., Shetty, S., Parry, A. J., Menon, S., Salama, R., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3397 · Cited by 522 · see citing works
Senescent cell clearance by the immune system: Emerging therapeutic opportunities
Prata, L. G. P. L., Ovsyannikova, I. G., Tchkonia, T., & Kirkland, J. L. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2019.04.003 · Cited by 497 · see citing works
Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis
Ruhland, M. K., Loza, A. J., Capietto, A.-H., Luo, X., Knolhoff, B. L., Flanagan, K. C., Belt, B. A., Alspach, E., Leahy, K., Luo, J., et al. (2016) · Nature Communications · doi:10.1038/ncomms11762 · Cited by 496 · see citing works
The quest to slow ageing through drug discovery
Partridge, L., Fuentealba, M., & Kennedy, B. K. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0067-7 · Cited by 468 · see citing works
Calder, P. C., Bosco, N., Bourdet‐Sicard, R., Capuron, L., Delzenne, N. M., Dore, J. M., Franceschi, C., Lehtinen, M. J., Recker, T., Salvioli, S., et al. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.09.001 · Cited by 498 · see citing works
Role of dietary polyphenols on gut microbiota, their metabolites and health benefits
Aravind, S. M., Wichienchot, S., Tsao, R., Ramakrishnan, S., & Chakkaravarthi, S. (2021) · Food Research International · doi:10.1016/j.foodres.2021.110189 · Cited by 502 · see citing works
Loo, T. M., Kamachi, F., Watanabe, Y., Yoshimoto, S., Kanda, H., Arai, Y., Nakajima-Takagi, Y., Iwama, A., Koga, T., Sugimoto, Y., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0932 · Cited by 478 · see citing works
Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan
Grosse, L., Wagner, N., Emelyanov, A., Molina, C., Lacas-Gervais, S., Wagner, K.-D., & Bulavin, D. V. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.002 · Cited by 460 · see citing works
Inside and out: the activities of senescence in cancer
Pérez-Mancera, P. A., Young, A. R. J., & Narita, M. (2014) · Nature Reviews Cancer · doi:10.1038/nrc3773 · Cited by 462 · see citing works
Dimitrova, N., Zamudio, J. R., Jong, R. M., Soukup, D., Resnick, R., Sarma, K., Ward, A. J., Raj, A., Lee, J. T., Sharp, P. A., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.025 · Cited by 445 · see citing works
Masaldan, S., Clatworthy, S. A. S., Gamell, C., Meggyesy, P. M., Rigopoulos, A.-T., Haupt, S., Haupt, Y., Denoyer, D., Adlard, P. A., Bush, A. I., et al. (2018) · Redox Biology · doi:10.1016/j.redox.2017.08.015 · Cited by 452 · see citing works
BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
Tasdemir, N., Banito, A., Roe, J.-S., Alonso-Curbelo, D., Camiolo, M., Tschaharganeh, D. F., Huang, C.-H., Aksoy, O., Bolden, J. E., Chen, C.-C., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0217 · Cited by 415 · see citing works
Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration
Moiseeva, V., Cisneros, A., Sica, V., Deryagin, O., Lai, Y., Jung, S., Andrés, E., An, J., Segalés, J., Ortet, L., et al. (2023) · Nature · doi:10.1038/s41586-022-05535-x · Cited by 423 · see citing works
Takasugi, M., Okada, R., Takahashi, A., Virya Chen, D., Watanabe, S., & Hara, E. (2017) · Nature Communications · doi:10.1038/ncomms15728 · Cited by 410 · see citing works
A multidimensional systems biology analysis of cellular senescence in aging and disease
Avelar, R. A., Ortega, J. G., Tacutu, R., Tyler, E. J., Bennett, D., Binetti, P., Budovsky, A., Chatsirisupachai, K., Johnson, E., Murray, A., et al. (2020) · Genome Biology · doi:10.1186/s13059-020-01990-9 · Cited by 399 · see citing works
Telomeres and cell senescence—size matters not
Victorelli, S., & Passos, J. F. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.03.027 · Cited by 413 · see citing works
Senescence-associated inflammatory responses: aging and cancer perspectives
Lasry, A., & Ben-Neriah, Y. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.009 · Cited by 408 · see citing works
Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity
Palmer, A. K., Tchkonia, T., LeBrasseur, N. K., Chini, E. N., Xu, M., & Kirkland, J. L. (2015) · Diabetes · doi:10.2337/db14-1820 · Cited by 423 · see citing works
Inflammation, ageing and chronic disease
Pawelec, G., Goldeck, D., & Derhovanessian, E. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.03.007 · Cited by 420 · see citing works
Lehmann, M., Korfei, M., Mutze, K., Klee, S., Skronska-Wasek, W., Alsafadi, H. N., Ota, C., Costa, R., Schiller, H. B., Lindner, M., et al. (2017) · European Respiratory Journal · doi:10.1183/13993003.02367-2016 · Cited by 403 · see citing works
Cai, Y., Song, W., Li, J., Jing, Y., Liang, C., Zhang, L., Zhang, X., Zhang, W., Liu, B., An, Y., et al. (2022) · Science China Life Sciences · doi:10.1007/s11427-022-2161-3 · Cited by 436 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
SenNet recommendations for detecting senescent cells in different tissues
Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., et al. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00738-8 · Cited by 408 · see citing works
Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers
Chera, S., Baronnier, D., Ghila, L., Cigliola, V., Jensen, J. N., Gu, G., Furuyama, K., Thorel, F., Gribble, F. M., Reimann, F., et al. (2014) · Nature · doi:10.1038/nature13633 · Cited by 410 · see citing works
Immune ageing at single-cell resolution
Mogilenko, D. A., Shchukina, I., & Artyomov, M. N. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00646-4 · Cited by 392 · see citing works
Recurrent turnover of senescent cells during regeneration of a complex structure
Yun, M. H., Davaapil, H., & Brockes, J. P. (2015) · eLife · doi:10.7554/elife.05505 · Cited by 385 · see citing works
Bao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 389 · see citing works
Global reorganization of the nuclear landscape in senescent cells
Chandra, T., Ewels, P. A., Schoenfelder, S., Furlan-Magaril, M., Wingett, S. W., Kirschner, K., Thuret, J.-Y., Andrews, S., Fraser, P., & Reik, W. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.055 · Cited by 348 · see citing works
p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion
Helman, A., Klochendler, A., Azazmeh, N., Gabai, Y., Horwitz, E., Anzi, S., Swisa, A., Condiotti, R., Granit, R. Z., Nevo, Y., et al. (2016) · Nature Medicine · doi:10.1038/nm.4054 · Cited by 351 · see citing works
Takahashi, A., Loo, T. M., Okada, R., Kamachi, F., Watanabe, Y., Wakita, M., Watanabe, S., Kawamoto, S., Miyata, K., Barber, G. N., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03555-8 · Cited by 350 · see citing works
Redox control of senescence and age-related disease.
Chandrasekaran, A., Idelchik, M. D. P. S., & Melendez, J. A. (2017) · Redox Biology · doi:10.1016/j.redox.2016.11.005 · Cited by 360 · see citing works
Höhn, A., Weber, D., Jung, T., Ott, C., Hugo, M., Kochlik, B., Kehm, R., König, J., Grune, T., & Castro, J. P. (2016) · Redox Biology · doi:10.1016/j.redox.2016.12.001 · Cited by 368 · see citing works
Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes
Thompson, P. J., Shah, A., Ntranos, V., Van Gool, F., Atkinson, M., & Bhushan, A. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.021 · Cited by 353 · see citing works
Senescent cells and osteoarthritis: a painful connection
Jeon, O. H., David, N. E., Campisi, J., & Elisseeff, J. H. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95147 · Cited by 354 · see citing works
Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity
Marín, I., Boix, O., García-Garijo, A., Sirois, I., Caballé, A., Zarzuela, E., Ruano, I., Attolini, C. S., Prats, N., Lopez-Dominguez, J. A., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0523 · Cited by 358 · see citing works
Self-citationRole of immune cells in the removal of deleterious senescent cells
Kale, A., Sharma, A., Stolzing, A., Desprez, P.-Y., & Campisi, J. (2020) · Immunity & Ageing · doi:10.1186/s12979-020-00187-9 · Cited by 351 · see citing works
Cellular senescence in renal ageing and disease
Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J., & van Deursen, J. M. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.183 · Cited by 345 · see citing works
Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span
Robbins, P. D., Jurk, D., Khosla, S., Kirkland, J. L., LeBrasseur, N. K., Miller, J. D., Passos, J. F., Pignolo, R. J., Tchkonia, T., & Niedernhofer, L. J. (2021) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-050120-105018 · Cited by 339 · see citing works
“For example, Sncs are critical during development, can suppress tumor growth, and assist with tissue repair (23, 32), but they also drive pathology, including cancer (9, 17).”
BackgroundA versatile drug delivery system targeting senescent cells
Muñoz‐Espín, D., Rovira, M., Galiana, I., Giménez, C., Lozano‐Torres, B., Paez‐Ribes, M., Llanos, S., Chaib, S., Muñoz‐Martín, M., Ucero, A. C., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201809355 · Cited by 339 · see citing works
Self-citationStress, cell senescence and organismal ageing
de Magalhães, J. P., & Passos, J. F. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.07.001 · Cited by 316 · see citing works
Mitochondrial dysfunction and cell senescence: deciphering a complex relationship
Chapman, J., Fielder, E., & Passos, J. F. (2019) · FEBS Letters · doi:10.1002/1873-3468.13498 · Cited by 325 · see citing works
Watanabe, S., Kawamoto, S., Ohtani, N., & Hara, E. (2017) · Cancer Science · doi:10.1111/cas.13184 · Cited by 321 · see citing works
Senescence from G2 arrest, revisited
Gire, V., & Dulić, V. (2015) · Cell Cycle · doi:10.1080/15384101.2014.1000134 · Cited by 300 · see citing works
Agustí, A. G. N., Melén, E., DeMeo, D. L., Breyer‐Kohansal, R., & Faner, R. (2022) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(21)00555-5 · Cited by 319 · see citing works
The role of cellular senescence in cardiac disease: basic biology and clinical relevance
Mehdizadeh, M., Aguilar, M., Thorin, É., Ferbeyre, G., & Nattel, S. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00624-2 · Cited by 316 · see citing works
Immune Modulation of Stem Cells and Regeneration
Aurora, A. B., & Olson, E. N. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.06.009 · Cited by 309 · see citing works
Neuroinflammation in Alzheimer’s Disease
Onyango, I. G., Jauregui, G. V., Čarná, M., Bennett, J. P., & Stokin, G. B. (2021) · Biomedicines · doi:10.3390/biomedicines9050524 · Cited by 330 · see citing works
Interconnections between Inflammageing and Immunosenescence during Ageing
Teissier, T., Boulanger, É., & Cox, L. S. (2022) · Cells · doi:10.3390/cells11030359 · Cited by 310 · see citing works
Cellular Senescence in the Kidney
Docherty, M.-H., O’Sullivan, E. D., Bonventre, J. V., & Ferenbach, D. A. (2019) · Journal of the American Society of Nephrology · doi:10.1681/asn.2018121251 · Cited by 291 · see citing works
Cellular senescence in development, regeneration and disease
Rhinn, M., Ritschka, B., & Keyes, W. M. (2019) · Development · doi:10.1242/dev.151837 · Cited by 296 · see citing works
Ohtani, N. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00197-8 · Cited by 306 · see citing works
Targeting senescent cells in translational medicine
Pàez‐Ribes, M., González‐Gualda, E., Doherty, G. J., & Muñoz‐Espín, D. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201810234 · Cited by 289 · see citing works
Self-citationInjury-Induced Senescence Enables In Vivo Reprogramming in Skeletal Muscle
Chiche, A., Le Roux, I., von Joest, M., Sakai, H., Aguín, S. B., Cazin, C., Salam, R., Fiette, L., Alegria, O., Flamant, P., et al. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2016.11.020 · Cited by 295 · see citing works
Cuollo, L., Antonangeli, F., Santoni, A., & Soriani, A. (2020) · Biology · doi:10.3390/biology9120485 · Cited by 291 · see citing works
p21 produces a bioactive secretome that places stressed cells under immunosurveillance
Sturmlechner, I., Zhang, C., Sine, C. C., van Deursen, E.-J., Jeganathan, K. B., Hamada, N., Grasic, J., Friedman, D., Stutchman, J. T., Can, I., et al. (2021) · Science · doi:10.1126/science.abb3420 · Cited by 295 · see citing works
“In mammals, cellular senescence has also been implicated in biological processes beyond cancer, including development (8, 9), tissue repair (10), aging, and age-related disorders (3, 11–15).”
BackgroundAging of the cells: Insight into cellular senescence and detection Methods.
Mohamad Kamal, N. S., Safuan, S., Shamsuddin, S., & Foroozandeh, P. (2020) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2020.151108 · Cited by 287 · see citing works
- Authors
- Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., Rodríguez-Baeza, A., Varela-Nieto, I., Ruberte, J., Collado, M., & Serrano, M.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Universidad Complutense de Madrid (ES)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Serrano, Manuel
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 155
- Issue
- 5
- Pages
- 1104-1118
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2090067193
- Cited by
- 1,428
- References
- 64
- Citations by year
- 2026: 92 · 2025: 117 · 2024: 121 · 2023: 134 · 2022: 143 · 2021: 140 · 2020: 160 · 2019: 98 · 2018: 119 · 2017: 90 · 2016: 94 · 2015: 57 · 2014: 55 · 2013: 6
- FWCI
- 49.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- RUNA. Repositorio Institucional del Sergas (Servicio Gallego de Salud (SERGAS)) (submittedVersion, other-oa)
- Funders
- European Commission
- Ministerio de Ciencia e Innovación (SAF2011-24391)
- Instituto de Salud Carlos III
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- embryonic development, p21, mesonephros, endolymphatic sac, TGF-β/Smad signaling, macrophage infiltration, apoptosis, human embryo
- MeSH terms
- Animals, Embryo, Mammalian, Endolymphatic Sac, Female, Humans, Kidney, Male, Mesonephros, Signal Transduction, Transforming Growth Factor beta, Cellular Senescence, Phosphatidylinositol 3-Kinases, Embryonic Development, Cyclin-Dependent Kinase Inhibitor p21, Mice, Smad Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
