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Senescence in Health and Disease
Open accessAbstract
Many cellular stresses activate senescence, a persistent hyporeplicative state characterized in part by expression of the p16 INK4a cell-cycle inhibitor. Senescent cell production occurs throughout life and plays beneficial roles in a variety of physiological and pathological processes including embryogenesis, wound healing, host immunity, and tumor suppression. Meanwhile, the steady accumulation of senescent cells with age also has adverse consequences. These non-proliferating cells occupy key cellular niches and elaborate pro-inflammatory cytokines, contributing to aging-related diseases and morbidity. This model suggests that the abundance of senescent cells in vivo predicts "molecular," as opposed to chronologic, age and that senescent cell clearance may mitigate aging-associated pathology.
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In the citing paper
“Quiescence is a temporary arrest state with proliferation re-instated by appropriate stimuli; terminal differentiation is the acquisition of specific cellular functions accompanied by a durable cell-cycle arrest mediated by pathways distinct from those of cellular senescence (Figure 2).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as He and Sharpless, 2017
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
“The role of senescence in human disease is clear from cellular studies, while in vivo evidence is only now catching up”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as He and Sharpless, 2017
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
“Evidence linking senescence to other common age-associated human diseases has recently emerged. These diseases include neurodegenerative disorders, glaucoma, cataract, atherosclerosis and cardiovascular disease, diabetes, osteoarthritis, pulmonary, and renal and liver fibrosis”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as He and Sharpless, 2017
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
“In most studies, senescence is assessed in ex vivo cultures or fresh samples by SAb -gal staining or indirect markers in formalin-fixed tissues”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as He and Sharpless, 2017
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
“In contrast to the beneficial effects of SASP in the living body, long‐term survival of senescent cells also drives age‐related diseases, such as atherosclerosis, neuropsychiatric disorders, chronic nephritis and cancer.42”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [42]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The drug causes massive apoptosis of senescent cells, which may lead to tissue atrophy [114].”
From Modulation of fracture healing by senescence-associated secretory phenotype (SASP): a narrative review of the current literature (2024) · cites this paper as [114]
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
“This inflammatory signature of potentially senescent-like microglia has been identified in most tissues of all ages in human and mice, but their number increases with age”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as He and Sharpless, 2017
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“This initiates and maintains cellular senescence, a key contributor to organismal ageing and multiple age-related diseases6,7.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [6]
The cited source says what the claim attributes to it.
In the citing paper
“In humans, mice and some other species, cellular senescence has been shown to contribute to various physiological and pathological processes1.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [1]
The cited source says what the claim attributes to it.
In the citing paper
“This cell-cycle withdrawal differs from quiescence and terminal differentiation (He and Sharpless, 2017).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as He and Sharpless, 2017
The cited source says what the claim attributes to it.
In the citing paper
“Quiescence is a temporary arrest state with proliferation re-instated by appropriate stimuli; terminal differentiation is the acquisition of specific cellular functions accompanied by a durable cell-cycle arrest mediated by pathways distinct from those of cellular senescence (Figure 2).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as He and Sharpless, 2017
The cited source says what the claim attributes to it.
In the citing paper
“Accumulation of senescent cells is causally linked to functional decline in aging tissues.”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [25]
The cited source says what the claim attributes to it.
In the citing paper
“Senescent cells accumulate inside the body during aging4,8”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [8]
In the citing paper
“However, expression of p21WAF1/CIP1 does not persist in senescent cells as it is mainly required for induction of senescence (Stein et al., 1999; Sharpless and Sherr, 2015; He and Sharpless, 2017; Song et al., 2020).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as He and Sharpless, 2017
In the citing paper
“At the biochemical level, cellular senescence is often characterized by: (1) increased lysosomal galactosidase beta 1 (GLB1) activity; (2) inhibition of multiple cyclin-dependent kinases (CDKs) and consequent dephosphorylation of various members of the retinoblastoma (RB) protein family—including RB transcriptional corepressor 1 (RB1), RB transcriptional corepressor like 1 (RB1L; best known as p”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [941]
In the citing paper
“Mounting evidence, however, indicates that senescent cells accumulate during organismal aging due to their increased generation coupled to inefficient clearance [935, 941, 960, 961].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [941]
In the citing paper
“Although such a senescence-associated secretory phenotype (SASP) appears to be involved in the immunological clearance of senescent cells, it also affects the biology of neighboring cells with an intact proliferative potential (and this has major implications for senescence-inducing anticancer agents) [941–945].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [941]
In the citing paper
“Senescent cells secrete a variety of immunomodulatory and mitogenic cytokines, chemokines, growth, and MMPs [941–943].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [941]
In the citing paper
“Senescent cells exhibit a senescence-associated secretory phenotype (SASP) characterized by an overproduction of proinflammatory molecules such as IL6, TGFβ, IL8, MCP-1, extracellular matrix remodeling enzymes (MMPs), serine/cysteine proteinase inhibitors (serpins), and tissue inhibitors of metalloproteinases (61).”
From Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19 (2021) · cites this paper as [61]
In the citing paper
“Ageing is arguably primarily characterised by the accumulation of cells which have undergone the process of permanent cell cycle arrest, termed senescence (9).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [9]
In the citing paper
“Cellular senescence, which was initially described by Leonard Hayflick and colleagues in 1961,1 plays crucial roles in a variety of physiological and pathological processes, including embryonic development, cancer, aging, and multiple other diseases.2,3,4,5,6,7”
From Identifying specific functional roles for senescence across cell types (2024) · cites this paper as [3]
In the citing paper
“Not only is this condition in common for regenerating tissues in the early phase, but it also somehow mimics the senescence-associated secretory phenotype (SASP) of presenescent and senescent cells. It appears to be beneficial if intermittent, but it causes pathology if chronically active.”
From Interactions between Muscle and Bone—Where Physics Meets Biology (2020) · cites this paper as [126]
In the citing paper
“These studies demonstrated that senescence is one of the major drivers of aging and that clearing senescent cells is a promising approach to treat age-related diseases and improve physical function.6,10”
From Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice (2020) · cites this paper as [10]
In the citing paper
“Senescence was traditionally considered an innate anti-cancer mechanism as it can serve to eliminate damaged cells,3,5 whereby activation of the senescence programme in cells harbouring oncogenic mutations serves as a tumour suppressor mechanism, preventing the expansion of these mutated cells and progression into malignancies.3,5”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [3]
In the citing paper
“Cells undergoing damage-induced senescence are often cleared by the immune system, as several SASP factors are cytokines and chemokines that can modulate the local immune environment.2,3,5,70,71”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [3]
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Citations
Cites
The serial cultivation of human diploid cell strains
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A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
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Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours
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Genome-wide methylation profiles reveal quantitative views of human aging rates
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Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
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Aging, Cellular Senescence, and Cancer
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Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
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Items 101–121 of 121
The Interaction of Viruses with the Cellular Senescence Response
Seoane, R., Vidal, S., Bouzaher, Y. H., El Motiam, A., & Rivas, C. (2020) · Biology · doi:10.3390/biology9120455 · Cited by 49
The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24−/− Progeria Mouse Model
Hambright, W. S., Mu, X., Gao, X., Guo, P., Kawakami, Y., Mitchell, J., Mullen, M., Nelson, A.-L., Bahney, C., Nishimura, H., et al. (2023) · Journal of Osteoporosis · doi:10.1155/2023/5572754 · 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
Wang, Y., Chen, D., Liu, Y., Shi, D., Duan, C., Li, J., Shi, X., Zhang, Y., Yu, Z., Sun, N., et al. (2023) · Cell Death & Disease · doi:10.1038/s41419-023-05992-w · Cited by 39
Senopathies-Diseases Associated with Cellular Senescence
Lushchak, O., Schosserer, M., & Grillari, J. (2023) · Biomolecules · doi:10.3390/biom13060966 · Cited by 35
Zhao, S., Qiao, Z., Pfeifer, R., Pape, H.-C., Mao, K., Tang, H., Meng, B., Chen, S., & Liu, H. (2024) · European Journal of Medical Research · doi:10.1186/s40001-023-01604-7 · Cited by 35
“The drug causes massive apoptosis of senescent cells, which may lead to tissue atrophy [114].”
BackgroundRegulation 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
Cellular Senescence in Chronic Obstructive Pulmonary Disease: Multifaceted and Multifunctional
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Out with the old, in with the new: senescence in development
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Unlocking Longevity with GLP-1: A Key to Turn Back the Clock?
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Senolytic effect of high intensity interval exercise on human skeletal muscle
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Metadata
- Authors
- He, S., & Sharpless, N. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Sharpless, Norman E.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-06
- Volume
- 169
- Issue
- 6
- Pages
- 1000-1011
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5643029
- OpenAlex
- W2620914886
- Cited by
- 1,766
- References
- 107
- Citations by year
- 2026: 173 · 2025: 232 · 2024: 240 · 2023: 266 · 2022: 228 · 2021: 225 · 2020: 157 · 2019: 128 · 2018: 102 · 2017: 14
- FWCI
- 13.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Glenn Foundation
- Breast Cancer Research Foundation
- Burroughs Wellcome Foundation
- NIH (CA203023, AG024379)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, senolytics, senescent cell clearance, aging, age-related diseases, inflammatory cytokines, tumor suppression, wound healing, embryonic development, host immunity, cell cycle inhibitors
- MeSH terms
- Aging, Animals, Cell Cycle, Humans, Neoplasms, Wound Healing, Cellular Senescence
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