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
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
Cellular senescence: when bad things happen to good cells
Campisi, J., & d'Adda di Fagagna, F. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2233 · Cited by 4,441
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
“Additionally, the expression of p16 Ink4a is known to increase with ageing in several rodent and human tissue”
Aging, Cellular Senescence, and Cancer
Campisi, J. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183653 · Cited by 2,954
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623
Cellular senescence in aging and age-related disease: from mechanisms to therapy
Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M. (2015) · Nature Medicine · doi:10.1038/nm.4000 · Cited by 2,363
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.11.012 · Cited by 2,045
“p16 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-b-gal) activity (Dimri et al.”
Four faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,070
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., & Kirkland, J. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64098 · Cited by 1,774
Senescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766
Self-citationCellular senescence in cancer and aging.
Collado, M., Blasco, M. A., & Serrano, M. (2007) · Cell · doi:10.1016/j.cell.2007.07.003 · Cited by 1,708
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622
Genetics and biology of pancreatic ductal adenocarcinomaPreprint
Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. M., & DePinho, R. A. (2006) · Genes & Development · doi:10.1101/gad.1415606 · Cited by 1,611
Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.031 · Cited by 1,454
Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.08.069 · Cited by 1,383
“Work that led to the discovery of senolytics was prompted by a 2004 article showing that the age-related increase in senescent cells is delayed by interventions that increase healthspan: caloric restriction or the Prop-1 deficiency in long-lived Amesmice [31].”
BackgroundReactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Takubo, K., Matsuoka, S., Miyamoto, K., Ohmura, M., Naka, K., Hosokawa, K., Ikeda, Y., et al. (2006) · Nature Medicine · doi:10.1038/nm1388 · Cited by 1,362
Inflammatory networks during cellular senescence: causes and consequences.
Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.03.003 · Cited by 1,354
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse
Demaria, M., O'Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A. M., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0241 · Cited by 1,338
Self-citationSenescent cells: an emerging target for diseases of ageing
Childs, B. G., Gluscevic, M., Baker, D. J., Laberge, R.-M., Marquess, D., Dananberg, J., & van Deursen, J. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.116 · Cited by 1,284
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270
Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines
Rea, I. M., Gibson, D. S., McGilligan, V., McNerlan, S. E., Alexander, H. D., & Ross, O. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00586 · Cited by 1,267
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study
Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Hashmi, S. K., Prata, L., Masternak, M. M., Kritchevsky, S. B., Musi, N., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2018.12.052 · Cited by 1,261
“The idea for developing agents to target senescent cells was based on a key study showing that age-related senescent cell burden in mice was reduced by both caloric restriction and a lifespan-extending mutation [13].”
BackgroundHumphreys, B. D. (2017) · Annual Review of Physiology · doi:10.1146/annurev-physiol-022516-034227 · Cited by 1,263
Senescence and aging: Causes, consequences, and therapeutic avenues
McHugh, D., & Gil, J. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201708092 · Cited by 1,233
Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232
Senolytic drugs: from discovery to translation
Kirkland, J. L., & Tchkonia, T. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13141 · Cited by 1,227
Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart
Alcendor, R. R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., Tian, B., Wagner, T., Vatner, S. F., & Sadoshima, J. (2007) · Circulation Research · doi:10.1161/01.res.0000267723.65696.4a · Cited by 1,147
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006) · Nature · doi:10.1038/nature05159 · Cited by 1,106
Self-citationForging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104
Self-citationSindrilaru, A., Peters, T., Wieschalka, S., Baican, C., Baican, A., Peter, H., Hainzl, A., Schatz, S., Qi, Y., Schlecht, A., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44490 · Cited by 1,100
Fat tissue, aging, and cellular senescence
Tchkonia, T., Morbeck, D. E., Von Zglinicki, T., Van Deursen, J., Lustgarten, J., Scrable, H., Khosla, S., Jensen, M. D., & Kirkland, J. L. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00608.x · Cited by 1,094
Lamin B1 loss is a senescence-associated biomarker
Freund, A., Laberge, R.-M., Demaria, M., & Campisi, J. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-10-0884 · Cited by 1,046
Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.015 · Cited by 1,032
Feedback between p21 and reactive oxygen production is necessary for cell senescence
Passos, J. F., Nelson, G., Wang, C., Richter, T., Simillion, C., Proctor, C. J., Miwa, S., Olijslagers, S., Hallinan, J., Wipat, A., et al. (2010) · Molecular Systems Biology · doi:10.1038/msb.2010.5 · Cited by 1,019
“There is evidence that senescence-marker-positive cells increase with age in various tissues (Dimri et al, 1995; Krishnamurthy et al, 2004; Herbig et al, 2006; Wang et al, 2009) and in age-related diseases including atherosclerosis (Minamino and Komuro, 2007) and diabetes (Sone and Kagawa, 2005).”
Cellular senescence: a translational perspective
Kirkland, J. L., & Tchkonia, T. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.04.013 · Cited by 1,013
The Regulation of INK4/ARF in Cancer and Aging
Kim, W. Y., & Sharpless, N. E. (2006) · Cell · doi:10.1016/j.cell.2006.10.003 · Cited by 1,009
Self-citationp16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003
Self-citationKotake, Y., Nakagawa, T., Kitagawa, K., Suzuki, S., Liu, N., Kitagawa, M., & Xiong, Y. (2011) · Oncogene · doi:10.1038/onc.2010.568 · Cited by 1,001
The common biology of cancer and ageing
Finkel, T., Serrano, M., & Blasco, M. A. (2007) · Nature · doi:10.1038/nature05985 · Cited by 988
An aged immune system drives senescence and ageing of solid organs
Yousefzadeh, M. J., Flores, R. R., Zhu, Y., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., Cui, Y., Angelini, L., Lee, K.-A., McGowan, S. J., et al. (2021) · Nature · doi:10.1038/s41586-021-03547-7 · Cited by 972
Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J. (2006) · Nature · doi:10.1038/nature05091 · Cited by 972
Self-citationThe Ink4/Arf locus is a barrier for iPS cell reprogramming
Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Cañamero, M., Blasco, M. A., & Serrano, M. (2009) · Nature · doi:10.1038/nature08290 · Cited by 968
Levine, M. E. (2012) · The Journals of Gerontology Series A · doi:10.1093/gerona/gls233 · Cited by 897
Burd, C. E., Jeck, W. R., Liu, Y., Sanoff, H. K., Wang, Z., & Sharpless, N. E. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001233 · Cited by 909
Self-citationStems Cells and the Pathways to Aging and Cancer
Rossi, D. J., Jamieson, C. H. M., & Weissman, I. L. (2008) · Cell · doi:10.1016/j.cell.2008.01.036 · Cited by 895
Jang, Y.-Y., & Sharkis, S. J. (2007) · Blood · doi:10.1182/blood-2007-05-087759 · Cited by 894
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855
Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all
Gil, J., & Peters, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1987 · Cited by 843
How stem cells age and why this makes us grow old
Sharpless, N. E., & DePinho, R. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2241 · Cited by 743
Self-citationCole, J. H., Ritchie, S. J., Bastin, M. E., Hernández, M. C. V., Maniega, S. M., Royle, N. A., Corley, J., Pattie, A., Harris, S. E., Zhang, Q., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.62 · Cited by 848
Cellular senescence and tumor suppressor gene p16
Rayess, H., Wang, M. B., & Srivatsan, E. S. (2012) · International Journal of Cancer · doi:10.1002/ijc.27316 · Cited by 825
Senescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798
Causes, consequences, and reversal of immune system aging
Montecino-Rodriguez, E., Berent-Maoz, B., & Dorshkind, K. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64096 · Cited by 793
Biomarkers, oxidative stress and autophagy in skin aging
Gu, Y., Han, J., Jiang, C., & Zhang, Y. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101036 · Cited by 797
Salminen, A., Kauppinen, A., & Kaarniranta, K. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2011.12.006 · Cited by 763
Mechanisms and therapeutic implications of cellular senescence in osteoarthritis
Coryell, P. R., Diekman, B. O., & Loeser, R. F. (2021) · Nature Reviews Rheumatology · doi:10.1038/s41584-020-00533-7 · Cited by 761
Identification of HSP90 inhibitors as a novel class of senolytics
Fuhrmann-Stroissnigg, H., Ling, Y. Y., Zhao, J., McGowan, S. J., Zhu, Y., Brooks, R. W., Grassi, D., Gregg, S. Q., Stripay, J. L., Dorronsoro, A., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00314-z · Cited by 701
DNA damage response and cellular senescence in tissues of aging mice
Wang, C., Jurk, D., Maddick, M., Nelson, G., Martin‐Ruiz, C., & Von Zglinicki, T. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00481.x · Cited by 696
Senescent cells as a source of inflammatory factors for tumor progression
Davalos, A. R., Coppe, J.-P., Campisi, J., & Desprez, P.-Y. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9220-9 · Cited by 636
Cellular senescence: a key therapeutic target in aging and diseases
Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158450 · Cited by 631
Nishino, J., Kim, I., Chada, K. K., & Morrison, S. J. (2008) · Cell · doi:10.1016/j.cell.2008.09.017 · Cited by 638
Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer
Herranz, D., Muñoz-Martin, M., Cañamero, M., Mulero, F., Martinez-Pastor, B., Fernandez-Capetillo, O., & Serrano, M. (2010) · Nature Communications · doi:10.1038/ncomms1001 · Cited by 612
Mechanisms of Stem Cell Self-Renewal
He, S., Nakada, D., & Morrison, S. J. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.042308.113248 · Cited by 644
Jurk, D., Wang, C., Miwa, S., Maddick, M., Korolchuk, V., Tsolou, A., Gonos, E. S., Thrasivoulou, C., Jill Saffrey, M., Cameron, K., et al. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00870.x · Cited by 598
Tissue damage and senescence provide critical signals for cellular reprogramming in vivo
Mosteiro, L., Pantoja, C., Alcazar, N., Marión, R. M., Chondronasiou, D., Rovira, M., Fernandez-Marcos, P. J., Muñoz-Martin, M., Blanco-Aparicio, C., Pastor, J., et al. (2016) · Science · doi:10.1126/science.aaf4445 · Cited by 589
Astrocyte Senescence as a Component of Alzheimer’s Disease
Bhat, R., Crowe, E. P., Bitto, A., Moh, M., Katsetos, C. D., Garcia, F. U., Johnson, F. B., Trojanowski, J. Q., Sell, C., & Torres, C. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045069 · Cited by 586
Chang, A. M., & Halter, J. B. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00366.2002 · Cited by 585
Cardiac Myocyte Cell Cycle Control in Development, Disease, and Regeneration
Ahuja, P., Sdek, P., & MacLellan, W. R. (2007) · Physiological Reviews · doi:10.1152/physrev.00032.2006 · Cited by 568
Identification of senescent cells in the bone microenvironment
Farr, J. N., Fraser, D. G., Wang, H., Jaehn, K., Ogrodnik, M. B., Weivoda, M. M., Drake, M. T., Tchkonia, T., LeBrasseur, N. K., Kirkland, J. L., et al. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2892 · Cited by 562
p16 INK4A is a robust in vivo biomarker of cellular aging in human skin
Ressler, S., Bartkova, J., Niederegger, H., Bartek, J., Scharffetter‐Kochanek, K., Jansen‐Dürr, P., & Wlaschek, M. (2006) · Aging Cell · doi:10.1111/j.1474-9726.2006.00231.x · Cited by 557
Vascular Cell Senescence: Contribution to Atherosclerosis
Minamino, T., & Komuro, I. (2007) · Circulation Research · doi:10.1161/01.res.0000256837.40544.4a · Cited by 542
The Clinical potential of Senolytic Drugs
Kirkland, J. L., Tchkonia, T., Zhu, Y., Niedernhofer, L. J., & Robbins, P. D. (2017) · Journal of the American Geriatrics Society · doi:10.1111/jgs.14969 · Cited by 539
Rodier, F., Muñoz, D. P., Teachenor, R., Chu, V., Le, O., Bhaumik, D., Coppé, J.-P., Campeau, E., Beauséjour, C. M., Kim, S.-H., et al. (2011) · Journal of Cell Science · doi:10.1242/jcs.071340 · Cited by 535
Molecular and physiological manifestations and measurement of aging in humans
Khan, S. S., Singer, B. D., & Vaughan, D. E. (2017) · Aging Cell · doi:10.1111/acel.12601 · Cited by 530
The role of cellular senescence in ageing and endocrine disease
Khosla, S., Farr, J. N., Tchkonia, T., & Kirkland, J. L. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0335-y · Cited by 523
Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock
Rando, T. A., & Chang, H. Y. (2012) · Cell · doi:10.1016/j.cell.2012.01.003 · Cited by 520
Methods to Detect Biomarkers of Cellular Senescence
Itahana, K., Campisi, J., & Dimri, G. P. (2007) · Methods in molecular biology · doi:10.1007/978-1-59745-361-5_3 · Cited by 535
Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives
Baker, D. J., & Petersen, R. C. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95145 · Cited by 514
Romagosa, C., Simonetti, S., López-Vicente, L., Mazo, A., Lleonart, M. E., Castellvi, J., & Ramon y Cajal, S. (2011) · Oncogene · doi:10.1038/onc.2010.614 · Cited by 509
Expression of p16 INK4a in peripheral blood T‐cells is a biomarker of human aging
Liu, Y., Sanoff, H. K., Cho, H., Burd, C. E., Torrice, C., Ibrahim, J. G., Thomas, N. E., & Sharpless, N. E. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00489.x · Cited by 509
Self-citationCoppé, J.-P., Rodier, F., Patil, C. K., Freund, A., Desprez, P.-Y., & Campisi, J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.257071 · Cited by 506
Strategies for targeting senescent cells in human disease
Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021) · Nature Aging · doi:10.1038/s43587-021-00121-8 · Cited by 501
Calder, P. C., Bosco, N., Bourdet‐Sicard, R., Capuron, L., Delzenne, N. M., Dore, J. M., Franceschi, C., Lehtinen, M. J., Recker, T., Salvioli, S., et al. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.09.001 · Cited by 524
Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant Mice
Tomás-Loba, A., Flores, I., Fernández-Marcos, P. J., Cayuela, M. L., Maraver, A., Tejera, A., Borrás, C., Matheu, A., Klatt, P., Flores, J. M., et al. (2008) · Cell · doi:10.1016/j.cell.2008.09.034 · Cited by 484
DNA damage, cellular senescence and organismal ageing: causal or correlative?
Chen, J.-H., Hales, C. N., & Ozanne, S. E. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm681 · Cited by 507
Advances in pathogenesis and therapeutic strategies for osteoporosis
Song, S., Guo, Y., Yang, Y., & Fu, D. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108168 · Cited by 476
Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes
Aguayo-Mazzucato, C., Andle, J., Lee, T. B., Midha, A., Talemal, L., Chipashvili, V., Hollister-Lock, J., van Deursen, J., Weir, G., & Bonner-Weir, S. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.05.006 · Cited by 469
Motif module map reveals enforcement of aging by continual NF-κB activity
Adler, A. S., Sinha, S., Kawahara, T. L. A., Zhang, J. Y., Segal, E., & Chang, H. Y. (2007) · Genes & Development · doi:10.1101/gad.1588507 · Cited by 466
Le Maitre, C. L., Freemont, A. J., & Hoyland, J. A. (2007) · Arthritis Research & Therapy · doi:10.1186/ar2198 · Cited by 457
“A number of studies have shown increased levels of p16INK4a with increased occurrence of senescence [ 32 ,33].”
Aging Hallmarks and the Role of Oxidative Stress
Maldonado, E., Morales, S., Urbina, F., & Solari, A. (2023) · Antioxidants · doi:10.3390/antiox12030651 · Cited by 491
Ageing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448
“This evidence has established p16INK4a as a widely-accepted marker of ageing and cellular senescence [81,82].”
BackgroundAging and Autophagy in the Heart
Shirakabe, A., Ikeda, Y., Sciarretta, S., Zablocki, D., & Sadoshima, J. (2016) · Circulation Research · doi:10.1161/circresaha.116.307474 · Cited by 448
AGEMAP: A Gene Expression Database for Aging in Mice
Zahn, J. M., Poosala, S., Owen, A. B., Ingram, D. K., Lustig, A., Carter, A., Weeraratna, A. T., Taub, D. D., Gorospe, M., Mazan-Mamczarz, K., et al. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030201 · Cited by 431
Cellular senescence: a link between cancer and age-related degenerative disease?
Campisi, J., Andersen, J. K., Kapahi, P., & Melov, S. (2011) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2011.09.001 · Cited by 421
Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model
Burd, C. E., Sorrentino, J. A., Clark, K. S., Darr, D. B., Krishnamurthy, J., Deal, A. M., Bardeesy, N., Castrillon, D. H., Beach, D. H., & Sharpless, N. E. (2013) · Cell · doi:10.1016/j.cell.2012.12.010 · Cited by 419
Self-citationIs HIV a Model of Accelerated or Accentuated Aging?
Pathai, S., Bajillan, H., LANDAY, A. L., & High, K. P. (2013) · The Journals of Gerontology Series A · doi:10.1093/gerona/glt168 · Cited by 437
The ageing immune system: is it ever too old to become young again?
Dorshkind, K. A., Montecino‐Rodriguez, E., & Signer, R. A. J. (2008) · Nature reviews. Immunology · doi:10.1038/nri2471 · Cited by 424
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
