The DOI matches its Crossref record; 64 of the 64 references it cites were found in a registry or an index.
Ink4a/Arf expression is a biomarker of aging
Open accessAbstract
The Ink4a/Arf locus encodes 2 tumor suppressor molecules, p16INK4a and Arf, which are principal mediators of cellular senescence. To study the links between senescence and aging in vivo, we examined Ink4a/Arf expression in rodent models of aging. We show that expression of p16INK4a and Arf markedly increases in almost all rodent tissues with advancing age, while there is little or no change in the expression of other related cell cycle inhibitors. The increase in expression is restricted to well-defined compartments within each organ studied and occurs in both epithelial and stromal cells of diverse lineages. The age-associated increase in expression of p16INK4a and Arf is attenuated in the kidney, ovary, and heart by caloric restriction, and this decrease correlates with diminished expression of an in vivo marker of senescence, as well as decreased pathology of those organs. Last, the age-related increase in Ink4a/Arf expression can be independently attributed to the expression of Ets-1, a known p16INK4a transcriptional activator, as well as unknown Ink4a/Arf coregulatory molecules. These data suggest that expression of the Ink4a/Arf tumor suppressor locus is a robust biomarker, and possible effector, of mammalian aging.
Overview
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
Verification
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?
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
“p16INK4a also increases with age and is a robust senescence marker in numerous mouse and human tissues (Krishnamurthy et al., 2004; Ressler et al., 2006), often coinciding with another prominent senescence marker, senescence-associated beta-galactosidase (SA-β-gal) activity (Dimri et al., 1995).”
From An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA (2014) · cites this paper as Krishnamurthy et al., 2004
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
“A key study demonstrating that caloric restriction, which increases health span and life span, decreases the accumulation of Sncs (18)”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [18]
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
“Nevertheless, it was reported that caloric restriction reduces p16 levels and the transcriptional expression of genes associated with cellular senescence, including SASP genes, in mice and in the colon of healthy human individuals256,257.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [256]
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
“Additionally, the expression of p16Ink4a is known to increase with ageing in several rodent and human tissues8.”
From Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders (2011) · cites this paper as [8]
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 ovaries from mice of advanced reproductive age, cells classified as senescent are characterized by increased expression of Cdkn2a (refs. 238–240), Cdkn1a, Serpine1 and Hmgb1 (ref. 239).”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [238]
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
“There is, however, intriguing evidence that, similar to p19/ARF, the levels of p16 expression and incidence of p16-positive cells increase with age in many mouse and rat tissues (Zindy et al., 1997; Krishnamurthy et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
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
“Of particular importance, caloric restriction, which retards aging in rodents and other species, attenuated the accumulation of p16-positive cells (Krishnamurthy et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
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 addition, expression of Ets-1, a transcriptional activator of p16 (Ohtani et al., 2001), correlated with p16 expression, although absolute levels of Ets-1 did not necessarily increase with age (Krishnamurthy et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
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
“p16 is considered the best marker of senescent cells, and its expression is upregulated in many tissues during ageing [10 -12].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
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
“Furthermore, as the most important risk factor for cancer, ageing is associated with the steady accumulation of senescent cells [10 -12]”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
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
“Moreover, these two genes share an enhancer and regulation at the chromatin level; therefore, both genes are upregulated in many tissues during aging and reflect chromatin-level regulation [10].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
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 levels of p16INK4a (and to a lower extent also p19ARF) correlate with the chronological age of essentially all tissues analyzed, both in mice and humans”
From The Hallmarks of Aging (2013) · cites this paper as Krishnamurthy et al., 2004
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“p16 is a key trigger of cellular senescence16, and its expression increases with aging in several rodent and primate tissues17–19, suggesting its potential use as a biomarker of mammalian aging.”
From Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial (2024) · cites this paper as [18]
The cited source says what the claim attributes to it.
In the citing paper
“However, at least some cells express p16 in vivo (Krishnamurthy et al., 2004), during long-term culture (Benanti and Galloway, 2004), and at elevated levels upon replicative senescence (Alcorta et al., 1996; Hara et al., 1996; Brenner et al., 1998; Stein et al., 1999; Itahana et al., 2003).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
The cited source says what the claim attributes to it.
In the citing paper
“At least in rodents, the expression of ARF increases with age (Krishnamurthy et al., 2004), suggesting that cells with chronic p53 activity might accumulate.”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Krishnamurthy et al., 2004
The cited source says what the claim attributes to it.
In the citing paper
“p16 is considered the best marker of senescent cells, and its expression is upregulated in many tissues during ageing [10 -12].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
The cited source says what the claim attributes to it.
In the citing paper
“Interestingly, the expression levels of p16 and Ets1 simultaneously increase and are positively correlated during aging [10].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [10]
In the citing paper
“In young tissues, the CDKN2A locus is normally expressed at a very low undetectable level whereas it becomes derepressed leading to a high-level of expression upon aging (Krishnamurthy et al., 2004).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Krishnamurthy et al., 2004
In the citing paper
“This evidence has established p16INK4a as a widely-accepted marker of ageing and cellular senescence [81,82].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [82]
In the citing paper
“Importantly, p16 INK4A is a biomarker of natural aging, as its expression increases in a variety of tissues with time (28).”
From Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives (2018) · cites this paper as [28]
In the citing paper
“senescent cells persist and accumulate during ageing82 and they display an abnormal secretory phenotype characterized by the presence of inflammatory cytokines that contributes to inflammageing.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [82]
In the citing paper
“Senescent cells are more common in the normal tissues of aged individuals, especially in certain tissue types, such as skin and adipose tissue [38,39,40].”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [38]
In the citing paper
“Increased expression of tumor suppressor proteins such as p16 Ink4a and ARF also occurs in aging cells from multiple tissues (79,80).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [79]
In the citing paper
“because an age-related increase in expression of both of these tumorsuppressor genes has been reported in numerous tissues, 13”
From Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a (2012) · cites this paper as [13]
In the citing paper
“This is in accordance with previous reports, which have found that p16INK4A levels correlate with chronological age in most tissues analyzed, both in mice (Baker et al., 2016, Krishnamurthy et al., 2004) and in humans (Ressler et al., 2006).”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Krishnamurthy et al., 2004
In the citing paper
“p16Ink4a is differentially expressed in aging tissues and has been shown to restrict islet growth (27,28).”
From Adaptive β-Cell Proliferation Is Severely Restricted With Advanced Age (2009) · cites this paper as [27]
In the citing paper
“The two genes are largely coregulated in rodents, although some stimuli can selectively regulate p16 or ARF alone [128], whereas co-regulation of human p16 and p14ARF is uncommon [123].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [128]
In the citing paper
“Senescent cells share distinct detectable features, including the activation of the senescence-associated β-galactosidase (SA-β-gal) [28] and the transcriptional upregulation of cyclin-dependent kinase inhibitors (i.e., p16Ink4a, p19Arf and p21waf1/cip1) [65, 74].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [65]
In the citing paper
“senescent cells are viable for long periods of time and thereby accumulate with age in various organs and tissues5–7.”
From A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells (2020) · cites this paper as [5]
In the citing paper
“Increased expression of p16 and Arf has been implicated in mediating induction of senescence in a variety of cells including HSCs and is the most robust biomarker of senescence cells besides SA-β-gal staining.8,24,25”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [25]
In the citing paper
“Senescent cells accumulated in different tissues of aged mice,4,40,41 which was consistent with our observation that SA-β-gal-positive cells increased in aged livers, kidneys and lungs (Supplementary information, Fig. S5a–c).”
From Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice (2020) · cites this paper as [41]
In the citing paper
“It is well established that the CDKN2a locus is activated during organismal ageing in both rodents and humans, and the levels of p16INK4a constitute an impressively good overall biomarker of ageing 16, 17”
From The common biology of cancer and ageing (2007) · cites this paper as [16]
In the citing paper
“strategies such as caloric restriction, which extend lifespan, also seem to reverse the age-dependent increase in p16INK4a transcription 16, 18”
From The common biology of cancer and ageing (2007) · cites this paper as [16]
In the citing paper
“The CDKN2a locus is normally expressed at very low levels in most tissues of young organisms 16”
From The common biology of cancer and ageing (2007) · cites this paper as [16]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., et al. (2004) · Science · doi:10.1126/science.1094637 · Cited by 3,239
Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase
Cohen, H. Y., Miller, C., Bitterman, K. J., Wall, N. R., Hekking, B., Kessler, B., Howitz, K. T., Gorospe, M., de Cabo, R., & Sinclair, D. A. (2004) · Science · doi:10.1126/science.1099196 · Cited by 1,924
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871
Pagano, M., Tam, S. W., Theodoras, A. M., Beer‐Romero, P., Sal, G. D., Chau, V., Yew, P. R., Draetta, G. F., & Rolfe, M. (1995) · Science · doi:10.1126/science.7624798 · Cited by 1,815
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
Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A., & van Lohuizen, M. (1999) · Nature · doi:10.1038/16476 · Cited by 1,580
Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19
Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., & Sherr, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80452-3 · Cited by 1,566
p53 mutant mice that display early ageing-associated phenotypes
Tyner, S. D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., et al. (2002) · Nature · doi:10.1038/415045a · Cited by 1,459 · cited 1×
“For example, excess activity of p53 has been shown to induce premature aging in mice in multiple tissue types (5, 6).”
BackgroundBmi-1 determines the proliferative capacity of normal and leukaemic stem cells.
Lessard, J., & Sauvageau, G. (2003) · Nature · doi:10.1038/nature01572 · Cited by 1,452
Flagged first, then by citations
Research works printed but not linked: 6
- Nielsen, 1999, Lab Invest., 79, 1137
- Kanavaros, 2001, Histol. Histopathol., 16, 1005
- Meng, 2003, Cancer Res., 63, 5414
- Sherr, 2000, Cancer Res., 60, 3689
- Ruas, 1998, Biochim. Biophys. Acta., 1378, F115
- 10.1210/en.141.7.2608 · DOI · Paper page
Cited by
Sorted by citations
Items 601–700 of 1,003
Sundar, I. K., Rashid, K., Gerloff, J., Li, D., & Rahman, I. (2018) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2017-0390oc · Cited by 52
Targeting Cell Senescence for the Treatment of Age-Related Bone Loss
Pignolo, R. J., Samsonraj, R. M., Law, S. F., Wang, H., & Chandra, A. (2019) · Current Osteoporosis Reports · doi:10.1007/s11914-019-00504-2 · Cited by 52
Stem Cells Use Distinct Self-renewal Programs at Different AgesPreprint
Levi, B. P., & Morrison, S. J. (2008) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2008.73.049 · Cited by 54
Nalapareddy, K., Jiang, H., Gutierrez, L. M. G., & Rudolph, K. L. (2008) · Experimental Gerontology · doi:10.1016/j.exger.2008.09.002 · Cited by 50
p16INK4a/Ki‐67 co‐expression specifically identifies transformed cells in the head and neck region
Prigge, E., Tóth, C., Dyckhoff, G., Wagner, S., Müller, F., Wittekindt, C., Freier, K., Plinkert, P. K., Hoffmann, J., Vinokurova, S., et al. (2014) · International Journal of Cancer · doi:10.1002/ijc.29130 · Cited by 53
PTEN controls β‐cell regeneration in aged mice by regulating cell cycle inhibitor p16 ink4a
Zeng, N., Yang, K., Bayan, J., He, L., Aggarwal, R., Stiles, J. W., Hou, X., Medina, V., Abad, D., Palian, B. M., et al. (2013) · Aging Cell · doi:10.1111/acel.12132 · Cited by 50
Chronic Inflammation Potentiates Kidney Aging
Mei, C., & Zheng, F. (2009) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2009.07.002 · Cited by 50
Boquoi, A., Arora, S., Chen, T., Litwin, S., Koh, J., & Enders, G. H. (2014) · Aging Cell · doi:10.1111/acel.12279 · Cited by 52
Impaired autophagic function in rat islets with aging
Liu, Y., Shi, S., Gu, Z., Du, Y., Liu, M., Yan, S., Gao, J., Li, J., Shao, Y., Zhong, W., et al. (2012) · AGE · doi:10.1007/s11357-012-9456-0 · Cited by 51
Wu, C.-L., Wang, Y., Jin, B., Chen, H., Xie, B., & Mao, Z.-B. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.661785 · Cited by 50
Aberrant expression of p16INK4a in human cancers – a new biomarker?
Inoue, K., & Fry, E. A. (2018) · Cancer Reports and Reviews · doi:10.15761/crr.1000145 · Cited by 51
Senescent Microvesicles: A Novel Advance in Molecular Mechanisms of Atherosclerotic Calcification
Alique, M., Ramírez-Carracedo, R., Bodega, G., Carracedo, J., & Ramı́rez, R. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19072003 · Cited by 50
Sessions, G. A., Copp, M. E., Liu, J., Sinkler, M. A., D’Costa, S., & Diekman, B. O. (2019) · The FASEB Journal · doi:10.1096/fj.201900815rr · Cited by 52
Afzaal, A., Rehman, K., Kamal, S., & Akash, M. S. H. (2022) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.23047 · Cited by 49
Cellular Senescence and Periodontitis: Mechanisms and Therapeutics
Chen, S., Zhou, D., Liu, O., Chen, H., Wang, Y., & Zhou, Y. (2022) · Biology · doi:10.3390/biology11101419 · Cited by 51
The paradox of senescent-marker positive cancer cells: challenges and opportunities
O’Sullivan, E. A., Wallis, R., Mossa, F., & Bishop, C. L. (2024) · npj Aging · doi:10.1038/s41514-024-00168-y · Cited by 50
Marcoux, S., Lê, O., Langlois-Pelletier, C., Laverdière, C., Hatami, A., Robaey, P., & Beausejour, C. M. (2013) · Radiation Oncology · doi:10.1186/1748-717x-8-252 · Cited by 49
Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma
Liu, H., Huang, C., Lin, T., Tsai, C.-Y., Chen, S.-Y. T., Liu, A., Chen, W.-H., Wei, H.-J., Wang, M.-F., Williams, D. F., et al. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.08.034 · Cited by 51
Cathepsin K knockout alleviates aging‐induced cardiac dysfunction
Hua, Y., Robinson, T. J., Cao, Y., Shi, G., Ren, J. T., & Nair, S. (2015) · Aging Cell · doi:10.1111/acel.12276 · Cited by 49
Role of lncRNAs in Cellular Aging
Degirmenci, U., & Sun, L. (2016) · Frontiers in Endocrinology · doi:10.3389/fendo.2016.00151 · Cited by 49
p53 induces senescence through Lamin A/C stabilization-mediated nuclear deformation
Yoon, M.-H., Kang, S., Lee, S. J., Woo, T., Oh, A.-Y., Park, S., Ha, N., & Park, B.-J. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1378-7 · Cited by 52
Senolytics: Potential for Alleviating Diabetes and Its Complications
Palmer, A. K., Tchkonia, T., & Kirkland, J. L. (2021) · Endocrinology · doi:10.1210/endocr/bqab058 · Cited by 50
Are skin senescence and immunosenescence linked within individuals?
Waaijer, M. E. C., Goldeck, D., Gunn, D. A., van Heemst, D., Westendorp, R. G. J., Pawelec, G., & Maier, A. B. (2019) · Aging Cell · doi:10.1111/acel.12956 · Cited by 48
Chanda, D., Rehan, M., Smith, S. R., Dsouza, K. G., Wang, Y., Bernard, K. F., Kurundkar, D., Memula, V., Kojima, K., Mobley, J. A., et al. (2021) · eLife · doi:10.7554/elife.68049 · Cited by 50
Brauer, E., Lange, T., Keller, D., Görlitz, S., Cho, S., Keye, J., Gossen, M., Petersen, A., & Kornak, U. (2022) · Aging Cell · doi:10.1111/acel.13744 · Cited by 50
Senolytic therapeutics: An emerging treatment modality for osteoarthritis
Ansari, M. M., Ghosh, M., Lee, D., & Son, Y. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102275 · Cited by 49
Macoska, J. A. (2011) · Differentiation · doi:10.1016/j.diff.2011.04.003 · Cited by 49
Despars, G., Carbonneau, C. L., Bardeau, P., Coutu, D. L., & Beausejour, C. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073206 · Cited by 49
Sarlak, G., & Vincent, B. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9123-4 · Cited by 48
p16INK4A Influences the Aging Phenotype in the Living Skin Equivalent
Adamus, J. E., Aho, S., Meldrum, H., Bosko, C. A., & Lee, J.-M. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.468 · Cited by 48
p16INK4a protects against dysfunctional telomere–induced ATR-dependent DNA damage responses
Wang, Y., Sharpless, N. E., & Chang, S. S. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69574 · Cited by 49
Self-citationReuschenbach, M., Pauligk, C., Karbach, J., Rafiyan, M., Kloor, M., Prigge, E., Sauer, M., Al‐Batran, S., Kaufmann, A. M., Schneider, A., et al. (2016) · Cancer · doi:10.1002/cncr.29925 · Cited by 48
Bassaneze, V., Miyakawa, A. A., & Krieger, J. E. (2007) · Analytical Biochemistry · doi:10.1016/j.ab.2007.08.016 · Cited by 48
Accelerated senescence in kidneys of low-birth-weight rats after catch-up growth
Luyckx, V. A., Compston, C. A., Simmen, T., & Mueller, T. (2009) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00462.2009 · Cited by 48
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
Bhatia, B., Multani, A. S., Patrawala, L., Chen, X., Calhoun‐Davis, T., Zhou, J., Schroeder, L., Schneider‐Broussard, R., Shen, J., Pathak, S., et al. (2008) · International Journal of Cancer · doi:10.1002/ijc.23222 · Cited by 47
Crosstalk between gut microbiota and cellular senescence: a vicious cycle leading to aging gut
Kawamoto, S., & Hara, E. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.12.004 · Cited by 47
Mouse Models of Accelerated Cellular Senescence
Yousefzadeh, M. J., Melos, K. I., Angelini, L. A., Burd, C. E., Robbins, P. D., & Niedernhofer, L. J. (2018) · Methods in molecular biology · doi:10.1007/978-1-4939-8931-7_17 · Cited by 48
The Zebrafish as an Emerging Model to Study DNA Damage in Aging, Cancer and Other Diseases
Cayuela, M. L., Claes, K., Ferreira, M. G., Henriques, C. M., Eeden, F. V., Varga, M., Vierstraete, J., & Mione, M. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00178 · Cited by 50
Pawlikowski, J. S., Adams, P. D., & Nelson, D. M. (2013) · Journal of Cell Science · doi:10.1242/jcs.109728 · Cited by 52
Berent-Maoz, B., Montecino-Rodriguez, E., Signer, R. A. J., & Dorshkind, K. (2012) · Blood · doi:10.1182/blood-2011-12-400002 · Cited by 46
Gil, T., Zheng, H., Lee, H. G., Shin, J.-W., Hwang, S. W., Jang, K.-M., & Jeon, O. H. (2022) · Aging · doi:10.18632/aging.204204 · Cited by 47
Subcellular structure, heterogeneity, and plasticity of senescent cells
Bitencourt, T. C., Vargas, J. E., Silva, A. O., Fraga, L. R., & Filippi‐Chiela, E. C. (2024) · Aging Cell · doi:10.1111/acel.14154 · Cited by 46
Kanaki, T., Makrantonaki, E., & Zouboulis, C. C. (2016) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-016-9392-x · Cited by 49
de Jonge, H. J. M., de Bont, E. S. J. M., Valk, P. J. M., Schuringa, J. J., Kies, M. P., Woolthuis, C. M., Delwel, R., Veeger, N. J. G. M., Vellenga, E., Löwenberg, B., et al. (2009) · Blood · doi:10.1182/blood-2009-03-212688 · Cited by 46
Functional Genomics of the 9p21.3 Locus for Atherosclerosis: Clarity or Confusion?
Chen, H.-H., Almontashiri, N. A. M., Antoine, D., & Stewart, A. F. R. (2014) · Current Cardiology Reports · doi:10.1007/s11886-014-0502-7 · Cited by 45
Mechanisms involved in hematopoietic stem cell aging
Fujino, T., Asada, S., Goyama, S., & Kitamura, T. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04356-5 · Cited by 49
PML, SUMOylation, and Senescence
Ivanschitz, L., de Thé, H., & Bras, M. L. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00171 · Cited by 45
Gromley, A., Churchman, M. L., Zindy, F., & Sherr, C. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0902310106 · Cited by 46
The role of cellular senescence in aging through the prism of Koch-like criteria
Yanai, H., & Fraifeld, V. E. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2017.10.004 · Cited by 45
Age-Related Changes in the Fibroblastic Differon of the Dermis: Role in Skin Aging
Zorina, A. I., Zorin, V. L., Kudlay, D. A., & Kopnin, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116135 · Cited by 46
Altered senescence, apoptosis, and DNA damage response in a mutant p53 model of accelerated aging
Hinkal, G. W., Gatza, C. E., Parikh, N., & Donehower, L. A. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2009.01.001 · Cited by 45
Cellular senescence is increased in airway smooth muscle cells of elderly persons with asthma
Aghali, A., Khalfaoui, L., Lagnado, A. B., Drake, L. Y., Teske, J. J., Pabelick, C. M., Passos, J. F., & Prakash, Y. S. (2022) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00146.2022 · Cited by 44
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
Cellular senescence and the blood–brain barrier: Implications for aging and age-related diseases
Knopp, R. C., Erickson, M. A., Rhea, E. M., Reed, M. J., & Banks, W. A. (2023) · Experimental Biology and Medicine · doi:10.1177/15353702231157917 · Cited by 47
Cardiomyocyte senescence and the potential therapeutic role of senolytics in the heart
Zhai, P., & Sadoshima, J. (2024) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2024.06 · Cited by 46
The regulation of pre- and post-maturational plasticity of mammalian islet cell mass
Mezza, T., & Kulkarni, R. (2014) · Diabetologia · doi:10.1007/s00125-014-3251-7 · Cited by 45
Sosińska, P., Mikuła‐Pietrasik, J., Ryżek, M., Naumowicz, E., & Książek, K. (2014) · Biogerontology · doi:10.1007/s10522-014-9505-4 · Cited by 44
Li, D., de Glas, N. A., & Hurria, A. (2015) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2015.08.003 · Cited by 44
miRNAs in stem cell aging and age-related disease
Choi, S. W., Lee, J. Y., & Kang, K. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.08.013 · Cited by 46
Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice
Mikawa, R., Suzuki, Y., Baskoro, H., Kanayama, K., Sugimoto, K., Sato, T., & Sugimoto, M. (2018) · Aging Cell · doi:10.1111/acel.12827 · Cited by 44
Yurube, T., Buchser, W., Moon, H. J., Hartman, R. A., Takayama, K., Kawakami, Y., Nishida, K., Kurosaka, M., Vo, N. V., Kang, J. D., et al. (2019) · European Spine Journal · doi:10.1007/s00586-019-05910-9 · Cited by 44
Jeremias, G., Gonçalves, F. J. M., Pereira, J. L., & Asselman, J. (2020) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.12589 · Cited by 48
Kurauti, M. A., Soares, G. M., Marmentini, C., Bronczek, G. A., Branco, R. C. S., & Boschero, A. C. (2021) · Vitamins and hormones · doi:10.1016/bs.vh.2020.12.010 · Cited by 47
Suelves, N., Saleki, S., Ibrahim, T., Palomares, D., Moonen, S., Koper, M. J., Vrancx, C., Vadukul, D. M., Papadopoulos, N., Viceconte, N., et al. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01578-x · Cited by 43
Single-cell transcriptomic analysis uncovers diverse and dynamic senescent cell populations
Wechter, N., Rossi, M., Anerillas, C., Tsitsipatis, D., Piao, Y., Fan, J., Martindale, J. L., De, S., Mazan-Mamczarz, K., & Gorospe, M. (2023) · Aging · doi:10.18632/aging.204666 · Cited by 43
Exosomes and Micro-RNAs in Aging Process
Hamdan, Y., Mazini, L., & Malka, G. (2021) · Biomedicines · doi:10.3390/biomedicines9080968 · Cited by 43
Role of key regulators of the cell cycle in maintenance of hematopoietic stem cells
Matsumoto, A., & Nakayama, K. I. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.07.004 · Cited by 43
Transgenic and Knockout Mice Models to Reveal the Functions of Tumor Suppressor Genes
Taneja, P., Zhu, S., Maglic, D., Fry, E. A., Kendig, R. D., & Inoue, K. (2011) · Clinical Medicine Insights Oncology · doi:10.4137/cmo.s7516 · Cited by 44
DNA double strand break responses and chromatin alterations within the aging cell
Klement, K., & Goodarzi, A. A. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.09.003 · Cited by 48
Maï, M. E., Marzullo, M., de Castro, I. P., & Ferreira, M. G. (2020) · eLife · doi:10.7554/elife.54935 · Cited by 47
Autophagy regulates the localization and degradation of p16 INK4a
Coryell, P., Goraya, S. K., Griffin, K. A., Redick, M. A., Sisk, S. R., & Purvis, J. E. (2020) · Aging Cell · doi:10.1111/acel.13171 · Cited by 44
A natural product solution to aging and aging-associated diseases
Yang, C., Zhang, W., Dong, X., Fu, C., Yuan, J., Xu, M., Liang, Z. C., Qiu, C., & Xu, C. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107673 · Cited by 43
Keeping zombies alive: The ER-mitochondria Ca2+ transfer in cellular senescence
Ahumada-Castro, U., Puebla-Huerta, A., Cuevas-Espinoza, V., Lovy, A., & Cárdenas, C. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2021.119099 · Cited by 45
Human disease biomarker panels through systems biology
Smith, B. J., Silva-Costa, L. C., & Martins‐de‐Souza, D. (2021) · Biophysical Reviews · doi:10.1007/s12551-021-00849-y · Cited by 44
Hribal, M. L., Presta, I., Procopio, T., Marini, M. A., Stančáková, A., Kuusisto, J., Andreozzi, F., Hammarstedt, A., Jansson, P., Grarup, N., et al. (2011) · Diabetologia · doi:10.1007/s00125-010-2038-8 · Cited by 43
Premature Skin Aging Features Rescued by Inhibition of NADPH Oxidase Activity in XPC-Deficient Mice
Hosseini, M., Mahfouf, W., Serrano-Sanchez, M., Raad, H., Harfouche, G., Bonneu, M., Claverol, S., Mazurier, F., Rossignol, R., Taieb, A., et al. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.511 · Cited by 42
Dulic, V. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_2 · Cited by 42
Targeting Cellular Senescence for Age-Related Diseases: Path to Clinical Translation
Wyles, S. P., Tchkonia, T., & Kirkland, J. L. (2021) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0000000000009669 · Cited by 42
The entrancing role of dietary polyphenols against the most frequent aging‐associated diseases
Shah, M. A., Faheem, H. I., Hamid, A., Yousaf, R., Haris, M., Saleem, U., Shah, G. M., Alhasani, R. H., Althobaiti, N. A., Alsharif, I., et al. (2023) · Medicinal Research Reviews · doi:10.1002/med.21985 · Cited by 43
Ristori, S., Bertoni, G., Bientinesi, E., & Monti, D. (2025) · Nutrients · doi:10.3390/nu17111837 · Cited by 43
Translational research in immune senescence: Assessing the relevance of current models
High, K. P., Akbar, A. N., & Nikolich‐Žugich, J. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.007 · Cited by 42
Zhou, L., Chen, X., Liu, T., Zhu, C., Si, M., Jargstorf, J., Mao, L., Pan, G., Gong, Y., Luo, Z., et al. (2017) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.2422 · Cited by 42
Cellular senescence: from anti-cancer weapon to anti-aging target
Yuan, L., Alexander, P. B., & Wang, X. (2020) · Science China Life Sciences · doi:10.1007/s11427-019-1629-6 · Cited by 42
Redd1 knockdown prevents doxorubicin-induced cardiac senescence
Huang, P., Bai, L., Liu, L., Fu, J. F., Wu, K., Liu, H., Liu, Y., Qi, B., & Qi, B. (2021) · Aging · doi:10.18632/aging.202972 · Cited by 43
Senescence-mediated anticancer effects of quercetin
Özsoy, S., Becer, E., & Vatansever, H. S. (2022) · Nutrition Research · doi:10.1016/j.nutres.2022.04.007 · Cited by 43
The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence
Shafqat, S., Arana‐Chicas, E., Shafqat, A., & Hashmi, S. K. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158452 · Cited by 43
AgeAnno: a knowledgebase of single-cell annotation of aging in human
Huang, K., Gong, H., Guan, J., Zhang, L., Hu, C., Zhao, W., Huang, L., Zhang, W., Kim, P., & Zhou, X. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac847 · Cited by 43
Profiling influences of senescent and aged fibroblasts on prostate carcinogenesis
Dean, J. P., & Nelson, P. S. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604087 · Cited by 43
A quantitative model for age-dependent expression of the p16INK4a tumor suppressor
Tsygankov, D., Liu, Y., Sanoff, H. K., Sharpless, N. E., & Elston, T. C. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0904405106 · Cited by 43
Self-citationPignolo, R. J. (2023) · Comprehensive physiology · doi:10.1002/cphy.c220012 · Cited by 48
Kang, D., Lee, J., Yook, G., Jeong, S., Shin, J., Kim, M.-S., Kim, Y., Jung, H., Ahn, J., Kim, T., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-55085-1 · Cited by 41
Graf, M., Hartmann, N., Reichwald, K., & Englert, C. (2012) · Experimental Gerontology · doi:10.1016/j.exger.2012.02.012 · Cited by 42
ARF induction in response to DNA strand breaks is regulated by PARP1
Orlando, G., Khoronenkova, S. V., Dianova, I. I., Parsons, J. L., & Dianov, G. L. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1185 · Cited by 43
Hajjar, J. E., Chatoo, W., Hanna, R., Nkanza, P., Tétreault, N., Tse, Y. C., Wong, T. P., Abdouh, M., & Bernier, G. (2019) · Scientific Reports · doi:10.1038/s41598-018-37444-3 · Cited by 46
Nie, D., Zhang, J., Zhou, Y., Sun, J., Wang, W., & Wang, J. H. (2021) · Stem Cells International · doi:10.1155/2021/6638249 · Cited by 41
Cellular senescence promotes cancer metastasis by enhancing soluble E-cadherin production
Kawaguchi, K., Komoda, K., Mikawa, R., Asai, A., & Sugimoto, M. (2021) · iScience · doi:10.1016/j.isci.2021.103022 · Cited by 42
Effects of rhein lysinate on D-galactose-induced aging mice
Zhen, Y., Lin, Y., Li, K., ZHANG, G.-L., ZHAO, Y.-F., Wang, M., Jing-bo, W., Wei, J., & Hu, G. (2015) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2015.2858 · Cited by 41
Wong, G. C., & Chow, H. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220203 · Cited by 41
Cellular senescence and neurodegeneration
Holloway, K., Neherin, K., Dam, K. U., & Zhang, H. (2023) · Human Genetics · doi:10.1007/s00439-023-02565-x · Cited by 40
Metadata
- Authors
- Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Southern Illinois University Carbondale (US)
- SIU Medicine (US)
- UNC Lineberger Comprehensive Cancer Center (US)
- Corresponding author
- Sharpless, Norman E.
- Venue
- Journal of Clinical Investigation
- Published
- 2004-11-01
- Volume
- 114
- Issue
- 9
- Pages
- 1299-1307
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC524230
- OpenAlex
- W2073429636
- Semantic Scholar
- 5b25e72d000d08a468fd5e9b4a1b4c8009757274
- Cited by
- 1,486
- References
- 64
- Citations by year
- 2026: 32 · 2025: 51 · 2024: 86 · 2023: 76 · 2022: 75 · 2021: 94 · 2020: 100 · 2019: 91 · 2018: 78 · 2017: 82 · 2016: 80 · 2015: 77 · 2014: 74 · 2013: 76 · 2012: 72
- FWCI
- 19.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sidney Kimmel Foundation for Cancer Research
- Sidney Kimmel Foundation
- National Institutes of Health
- National Institute on Aging (AG 19899, R01AG019899)
- National Cancer Institute (K08CA090679, CA090679)
- 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 › Oncology › Cancer-related Molecular Pathways
- Keywords
- INK4a/ARF locus, p16INK4a, ARF, cellular senescence, aging, aging biomarkers, caloric restriction, ETS1, transcriptional regulation, tumor suppressor, kidney, ovary, heart, age-related diseases
- MeSH terms
- Aging, Animals, beta-Galactosidase, Cell Cycle, Disease Models, Animal, Humans, Immunohistochemistry, Models, Biological, Time Factors, Tissue Distribution, Biomarkers, Polymerase Chain Reaction, Cyclin-Dependent Kinase Inhibitor p16, Reverse Transcriptase Polymerase Chain Reaction, ADP-Ribosylation Factor 1, Caloric Restriction, Mice, Rats
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
