The DOI matches its Crossref record; 170 of the 170 references it cites were found in a registry or an index.
Cellular senescence in aging and age-related disease: from mechanisms to therapy
Open accessAbstract
Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy.
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In the citing paper
“These findings suggest that even in whole tissues where the number of senescent cells is small (most aged or diseased tissues contained 1%–3% senescent cells [33]), some of the genes of our core signature can be identified as differentially regulated.”
From Unmasking Transcriptional Heterogeneity in Senescent Cells (2017) · cites this paper as [33]
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 SASP composition and strength varies substantially, depending on the duration of senescence, origin of the pro-senescence stimulus, and cell type (Childs et al., 2015).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Childs et al., 2015
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 Childs et al., 2015
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 Childs et al., 2015
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Senescent cells contribute to aging and age-related pathologies21,22,23 through their senescence-associated secretory phenotype (SASP).24,25,26”
From Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex (2026) · cites this paper as [23]
In the citing paper
“Furthermore, senescent cell accumulation via aging-induced epigenetic, proteotoxic and genotoxic stresses usually exhibits a causal role in many age-related diseases, including glaucoma, cataracts, diabetes mellitus, osteoarthritis, among others (Childs et al. 2015).”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Childs et al. 2015
In the citing paper
“Cells can resume proliferation upon resolution of the stress (Childs et al., 2015).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Childs et al., 2015
In the citing paper
“The accumulation of senescent cells in ageing organisms contributes to many diseases, including cancer 46.”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [46]
In the citing paper
“In vivo, the best currently available models for senescent cell detection are reporter-harbouring transgenic mice (p16-LUC, p16 tdTom)199,200 and transgenic mouse strains used for selective senescent cell removal (INK-ATTAC, p16-3MR).201”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [201]
In the citing paper
“Ageing is a significant risk factor for T2DM36”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [36]
In the citing paper
“SCs accumulate with age and as a result of the exposure to a variety of stressors including radiation.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [1]
In the citing paper
“They play a causal role in many age-related diseases (such as neurodegenerative and cardiovascular diseases, osteoarthritis, and cancer) via expression of the senescence-associated secretory phenotype (SASP) to secret various inflammatory mediators and proteases1–7.”
From Using proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity (2020) · cites this paper as [1]
In the citing paper
“In many tissues, irreversibly cell cycle-arrested senescent cells accumulate during normal aging.”
From Aging of hematopoietic stem cells (2018) · cites this paper as [56]
In the citing paper
“In healthy aging, common cellular stresses can yield primary senescent cells that diminish tissue-repair capacity due to cell cycle arrest in progenitor cells and increase production of proinflammatory and matrix-degrading molecules (3, 4).”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Natural lung aging is associated with molecular and physiological changes that cause alterations in lung function, diminished pulmonary remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases.”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Exposure to extrinsic time-related effects, such as chronic exposure to atmospheric pollution, dusts, particulates, and gases, induce low-level insults to cellular function and accelerate aging of the lung (3).”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Age-associated changes in intrinsic mechanisms that aid in cell regeneration and repair, such as depletion of adult stem cell reservoirs, mitochondrial dysfunction, increased oxidative stress, and telomere shortening, contribute to an inability of lung cells to maintain baseline homeostasis.”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Senescent cells display a genetic and morphologic phenotype that is distinct from growth-competent cells and can have a detrimental impact on neighboring cells, structural components, and composition of the extracellular matrix (ECM) (3).”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing.”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [12]
In the citing paper
“However, excessive accumulation of senescent cells causally shortens the healthy lifespan [11] and drives organ ageing [12], age-related organ deterioration/disorders [13,14], tissue dysfunction and chronic diseases, including cardiovascular diseases (CVDs) [15,16], cancer [2], neurodegenerative diseases [17,18] and osteoarthritis [19].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [12]
In the citing paper
“An age-associated increase in NK cell senescence has been shown to impair antiviral immune responses in response to influenza (3, 128).”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Age-associated impairments in innate and adaptive immune responses in the lung may contribute to increased susceptibility of older persons developing an asthma exacerbation (3, 19, 107, 109, 110).”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Further, age-associated changes in genomic instability, telomere shortening, epigenetic alterations, cellular senescence, impaired autophagy, and mitochondrial dysfunction may promote IPF development and progression (3, 12, 62, 84, 88, 89, 116, 145).”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Age-associated immunosenescence and cellular senescence in response to exposure to cigarette smoke can greatly impact COPD pathogenesis (3, 19, 86).”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Age-associated alterations in immune surveillance, specifically decreased innate and adaptive immune responses, and dysfunctional immune response regulation can be responsible for increased lung pathology in response to infectious stimuli (3, 62, 106, 110, 114, 135).”
From Aging and Lung Disease (2020) · cites this paper as [3]
In the citing paper
“Cellular senescence, a process that essentially entails permanent proliferative arrest of cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related diseases and hence is a target of therapeutic interventions (3).”
From Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice (2021) · cites this paper as [3]
In the citing paper
“Importantly, removal of senescent cells promotes healthy aging in mice, making senescence‐associated inflammatory signaling an attractive target of therapeutic intervention for aging and age‐related disease (Tilstra et al, 2012; Childs et al, 2015; Baker et al, 2016; Ogrodnik et al, 2021).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Childs et al, 2015
In the citing paper
“Notably, SA-β-gal in diverse types of senescent cells is one widely used marker for identifying senescence in vitro and in vivo, which is linked to the increased content of lysosomes.20–23”
From Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice (2020) · cites this paper as [20]
In the citing paper
“While SA-β-gal is widely used as a marker of cellular senescence,20–22”
From Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice (2020) · cites this paper as [20]
In the citing paper
“A challenge in targeting senescence is the apparent heterogeneity of this cellular state, wherein a variety of insults may incite senescence, the inflammatory secretory phenotype is modified depending on cell type, and the senescent phenotype may even change based on the stage of senescence [22–24].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [23]
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Citations
Cites
1 retracted
Dual Role of Interleukin-6 in Regulating Insulin Sensitivity in Murine Skeletal Muscle
Nieto-Vazquez, I., Fernández-Veledo, S., de Alvaro, C., & Lorenzo, M. (2008) · Diabetes · doi:10.2337/db07-1062 · Cited by 209
RetractedThe serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508
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
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The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670
Self-citationChimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia
Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., Teachey, D. T., Chew, A., Hauck, B., Wright, J. F., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1215134 · Cited by 3,509
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van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
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Flagged first, then by citations
Research works printed but not linked: 1
- Baker, D.J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836 (2008). · DOI · Paper page
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
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
Naturally 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 2,876
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Self-citationWound healing: cellular mechanisms and pathological outcomes
Wilkinson, H. N., & Hardman, M. J. (2020) · Open Biology · doi:10.1098/rsob.200223 · Cited by 1,975
Senescence in Health and Disease
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Metadata
- Authors
- Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M.
- Affiliations
- Mayo Clinic (US)
- Venue
- Nature Medicine
- Published
- 2015-12
- Volume
- 21
- Issue
- 12
- Pages
- 1424-1435
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4748967
- OpenAlex
- W2193792657
- Cited by
- 2,363
- References
- 170
- Citations by year
- 2026: 257 · 2025: 278 · 2024: 275 · 2023: 278 · 2022: 259 · 2021: 266 · 2020: 246 · 2019: 191 · 2018: 153 · 2017: 106 · 2016: 51 · 2015: 1
- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- National Institute on Aging (AG41122-01P2, P01AG041122, R37AG013925)
- National Cancer Institute (R01CA166347, R01CA096985)
- 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, aging, age-related diseases, senescent cells, senescence induction, senolytics, anti-aging therapy, paracrine signaling, autocrine signaling, proliferative arrest
- MeSH terms
- Aging, Animals, Disease, Health, Humans, Longevity, Signal Transduction, Cellular Senescence
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