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Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning
Open accessAbstract
Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.
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“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 [131]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [131]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 Storer et al., 2013
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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 Storer et al., 2013
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“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 Storer et al., 2013
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In the citing paper
“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 [131]
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In the citing paper
“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 [10]
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“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 [10]
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In the citing paper
“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 [40]
The cited source says what the claim attributes to it.
In the citing paper
“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 [21]
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In the citing paper
“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 Storer et al. 2013
The cited source says what the claim attributes to it.
In the citing paper
“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 Storer et al. 2013
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In the citing paper
“Interestingly, while developmental senescence also exhibits up-regulation of some SASP components, major DDR targets (see below) like IL6 and IL8 do not appear to be up-regulated (Storer et al. 2013).”
From Cellular senescence and its effector programs (2014) · cites this paper as Storer et al. 2013
In the citing paper
“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 Storer et al., 2013
In the citing paper
“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 Storer et al., 2013
In the citing paper
“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 Storer et al., 2013
In the citing paper
“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 [92]
In the citing paper
“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 [62]
In the citing paper
“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 [947]
In the citing paper
“However, these studies focused on the function of senescence in acute organ injury, not in chronic processes such as atherosclerosis.”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [208]
In the citing paper
“Experimental evidence shows that cellular senescence has roles in limiting myocardial206 and liver207 fibrosis, promoting skin healing,82 as well as in embryonal development,208 which have to be considered.”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [208]
In the citing paper
“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 [150]
In the citing paper
“using a mouse model in which senescent cells can be detected in living animals, SASP was also recently shown to promote wound healing and optimize the formation of certain embryonic structures.”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [21]
In the citing paper
“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 [28]
In the citing paper
“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 [28]
In the citing paper
“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 [28]
In the citing paper
“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 [22]
In the citing paper
“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 [10]
In the citing paper
“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 [21]
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Chan, A. S. L., & Narita, M. (2019) · Genes & Development · doi:10.1101/gad.320937.118 · Cited by 80
Non-cell autonomous effects of the senescence-associated secretory phenotype in cancer therapy.
Saleh, T., Tyutynuk-Massey, L., Cudjoe, E. K., Idowu, M. O., Landry, J. W., & Gewirtz, D. A. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00164 · Cited by 85
Ageing as developmental decay: insights from p16INK4a.
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ATF3 drives senescence by reconstructing accessible chromatin profiles
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“Senescent cells play intricate roles in many biological processes including tumor suppression, embryogenesis, tissue repair, host immunity, aging and age-related disorders(Chou & Effros, 2013; He & Sharpless, 2017; Jun & Lau, 2010; Munoz-Espin et al., 2013; Reddel, 2009; Storer et al., 2013).”
BackgroundMitochondria and cellular senescence: Implications for musculoskeletal ageing
Habiballa, L., Salmonowicz, H., & Passos, J. F. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.10.417 · Cited by 82
Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review
Amaya-Montoya, M., Pérez-Londoño, A., Guatibonza-García, V., Vargas-Villanueva, A., & Mendivil, C. O. (2020) · Advances in Therapy · doi:10.1007/s12325-020-01287-0 · Cited by 82
Efficacy and limitations of senolysis in atherosclerosis
Garrido, A. M., Kaistha, A., Uryga, A. K., Oc, S., Foote, K., Shah, A., Finigan, A., Figg, N., Dobnikar, L., Jørgensen, H., et al. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvab208 · Cited by 83
“Our data are therefore consistent with studies that show that deleting p16þ cells can have neutral or detrimental effects in development, wound healing and a variety of disease states.(10,11,19,44,45) While cycles of ABT-263 do reduce atherosclerosis, ABT-263 had no effect on tissue markers of cell senescence, and als…”
ResultNumb is required to prevent p53-dependent senescence following skeletal muscle injury
Le Roux, I., Konge, J., Le Cam, L., Flamant, P., & Tajbakhsh, S. (2015) · Nature Communications · doi:10.1038/ncomms9528 · Cited by 81
MicroRNA controls of cellular senescence
Suh, N. (2018) · BMB Reports · doi:10.5483/bmbrep.2018.51.10.209 · Cited by 78
Aquino‐Martinez, R., Eckhardt, B. A., Rowsey, J. L., Fraser, D. G., Khosla, S., Farr, J. N., & Monroe, D. G. (2021) · Journal of Periodontology · doi:10.1002/jper.20-0529 · Cited by 78
Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells
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Early SRC activation skews cell fate from apoptosis to senescence
Anerillas, C., Herman, A. B., Rossi, M., Munk, R., Lehrmann, E., Martindale, J. L., Cui, C.-Y., Abdelmohsen, K., De, S., & Gorospe, M. (2022) · Science Advances · doi:10.1126/sciadv.abm0756 · Cited by 71
Basisty, N., Kale, A., Patel, S., Campisi, J., & Schilling, B. (2020) · Expert Review of Proteomics · doi:10.1080/14789450.2020.1766976 · Cited by 69
Embryonic senescent cells re-enter cell cycle and contribute to tissues after birth
Li, Y., Zhao, H., Huang, X., Tang, J., Zhang, S., Li, Y., Liu, X., He, L., Ju, Z., Lui, K. O., et al. (2018) · Cell Research · doi:10.1038/s41422-018-0050-6 · Cited by 71
Therapeutic Potential of Senolytics in Cardiovascular Disease
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Mária, J., & Ingrid, Ž. (2017) · Food & Function · doi:10.1039/c7fo00161d · Cited by 71
Cherry, C., Andorko, J. I., Krishnan, K., Mejías, J. C., Nguyen, H. H., Stivers, K. B., Gray-Gaillard, E. F., Ruta, A., Han, J., Hamada, N., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00785-7 · Cited by 66
Induction of DNA double-strand breaks and cellular senescence by human respiratory syncytial virus
Martínez, I., García-Carpizo, V., Guijarro, T., García-Gomez, A., Navarro, D., Aranda, A., & Zambrano, A. (2016) · Virulence · doi:10.1080/21505594.2016.1144001 · Cited by 68
Geroconversion of aged muscle stem cells under regenerative pressure
Sousa-Victor, P., Perdiguero, E., & Muñoz-Cánoves, P. (2014) · Cell Cycle · doi:10.4161/15384101.2014.965072 · Cited by 68
Lung cellular senescence is independent of aging in a mouse model of COPD/emphysema
Rashid, K., Sundar, I. K., Gerloff, J., Li, D., & Rahman, I. (2018) · Scientific Reports · doi:10.1038/s41598-018-27209-3 · Cited by 58
Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase
Sasaki, T., Lian, S., Khan, A., Llop, J. R., Samuelson, A. V., Chen, W., Klionsky, D. J., & Kishi, S. (2017) · Autophagy · doi:10.1080/15548627.2016.1256934 · Cited by 60
Roadmap for alleviating the manifestations of ageing in the cardiovascular system
Liberale, L., Tual-Chalot, S., Sedej, S., Ministrini, S., Georgiopoulos, G., Grunewald, M., Bäck, M., Bochaton-Piallat, M.-L., Boon, R. A., Ramos, G. C., et al. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01130-5 · Cited by 59
Martini, H., Iacovoni, J. S., Maggiorani, D., Dutaur, M., Marsal, D. J., Roncalli, J., Itier, R., Dambrin, C., Pizzinat, N., Mialet‐Perez, J., et al. (2019) · Aging Cell · doi:10.1111/acel.13015 · Cited by 51
Old cells, new tricks: chromatin structure in senescence
Parry, A. J., & Narita, M. (2016) · Mammalian Genome · doi:10.1007/s00335-016-9628-9 · Cited by 53
Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain
Santoro, A., Spinelli, C. C., Martucciello, S., Nori, S. L., Capunzo, M., Puca, A. A., & Ciaglia, E. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.3mr0118-003r · Cited by 50
Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration
Yu, Q., Walters, H. E., Pasquini, G., Pal Singh, S., Lachnit, M., Oliveira, C. R., León-Periñán, D., Petzold, A., Kesavan, P., Subiran Adrados, C., et al. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.09.009 · Cited by 52
MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Redox Control of Cell Senescence
Lettieri-Barbato, D., Aquilano, K., Punziano, C., Minopoli, G., & Faraonio, R. (2022) · Antioxidants · doi:10.3390/antiox11030480 · Cited by 51
Timing and cell specificity of senescence drives postnatal lung development and injury
Yao, H., Wallace, J., Peterson, A. L., Scaffa, A., Rizal, S., Hegarty, K., Maeda, H., Chang, J. L., Oulhen, N., Kreiling, J. A., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-35985-4 · Cited by 48
United we stand not dividing: The syncytiotrophoblast and cell senescence
Goldman-Wohl, D., & Yagel, S. (2014) · Placenta · doi:10.1016/j.placenta.2014.03.012 · Cited by 44
The development of cell senescence.
Da Silva-Álvarez, S., Picallos-Rabina, P., Antelo-Iglesias, L., Triana-Martínez, F., Barreiro-Iglesias, A., Sánchez, L., & Collado, M. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110742 · Cited by 42
Senescent cells enhance newt limb regeneration by promoting muscle dedifferentiation
Walters, H. E., Troyanovskiy, K. E., Graf, A. M., & Yun, M. H. (2023) · Aging Cell · doi:10.1111/acel.13826 · Cited by 39
A BDNF-TrkB autocrine loop enhances senescent cell viability
Anerillas, C., Herman, A. B., Munk, R., Garrido, A., Lam, K.-W. G., Payea, M. J., Rossi, M., Tsitsipatis, D., Martindale, J. L., Piao, Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33709-8 · Cited by 35
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Regulation of cellular senescence by microRNAs
Ma, X., Zheng, Q., Zhao, G., Yuan, W., & Liu, W. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111264 · Cited by 30
Control of Mesenchymal Stromal Cell Senescence by Tryptophan Metabolites
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Out with the old, in with the new: senescence in development
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Senolytic effect of high intensity interval exercise on human skeletal muscle
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Stress-induced cellular senescence contributes to chronic inflammation and cancer progression.
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p21 facilitates chronic lung inflammation via epithelial and endothelial cells
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Self-citationMAPKs in the early steps of senescence implemEMTation
Anerillas, C., Altés, G., & Gorospe, M. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1083401 · Cited by 13
Human dermal fibroblast senescence in response to single and recurring oxidative stress
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Establishing the relationship between brain cellular senescence and brain structure
Lund, A. N., Kopell, B. H., Golestani, N., Vornholt, E., Thompson, R. C., Liharska, L. E., Luo, Y., Cheng, E., Park, Y. J., Fennessy, B., et al. (2026) · Cell · doi:10.1016/j.cell.2025.10.014 · Cited by 6
Overview of molecular signatures of senescence and associated resources: pros and cons
Ntintas, O. A., Vagena, S., Pantelis, P., Theocharous, G., Petty, R., Evangelou, K., & Gorgoulis, V. G. (2026) · FEBS Open Bio · doi:10.1002/2211-5463.70134 · Cited by 6
Metadata
- Authors
- Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., & Keyes, W. M.
- Affiliations
- Centre for Genomic Regulation (ES)
- Weizmann Institute of Science (IL)
- Corresponding author
- Keyes, William M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 155
- Issue
- 5
- Pages
- 1119-1130
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1976635482
- Cited by
- 1,186
- References
- 67
- Citations by year
- 2026: 72 · 2025: 83 · 2024: 107 · 2023: 113 · 2022: 113 · 2021: 119 · 2020: 130 · 2019: 95 · 2018: 90 · 2017: 74 · 2016: 82 · 2015: 51 · 2014: 49 · 2013: 7
- FWCI
- 43.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
- HAL (submittedVersion)
- Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, embryonic development, apical ectodermal ridge, embryonic patterning, oncogene-induced senescence, p21, p15, senescence-associated secretory phenotype, apoptosis, macrophage clearance, mesenchymal cells, signaling centers
- MeSH terms
- Animals, Chick Embryo, Embryo, Mammalian, Extremities, Fibroblasts, Humans, Cellular Senescence, Apoptosis, Paracrine Communication, Embryonic Development, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p15, Mice
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