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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.
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“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.
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“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]
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“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]
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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]
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“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]
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“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
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“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
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“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
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“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]
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“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]
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“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]
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“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
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“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]
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“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
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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]
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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 301–400 of 1,003
Cudejko, C., Wouters, K., Fuentes, L., Hannou, S. A., Paquet, C., Bantubungi, K., Bouchaert, E., Vanhoutte, J., Fleury, S., Rémy, P., et al. (2011) · Blood · doi:10.1182/blood-2010-10-313106 · Cited by 133
Selective Targeting of Cancer Stem Cells
Körkaya, H., & Wicha, M. S. (2007) · BioDrugs · doi:10.2165/00063030-200721050-00002 · Cited by 126
Markers of cellular senescence in zero hour biopsies predict outcome in renal transplantation
Koppelstaetter, C., Schratzberger, G., Perco, P., Hofer, J., Mark, W., Öllinger, R., Oberbauer, R., Schwarz, C., Mitterbauer, C., Kainz, A., et al. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00398.x · Cited by 124
Age- and tissue-specific expression of senescence biomarkers in mice.
Hudgins, A. D., Tazearslan, C., Tare, A., Zhu, Y., Huffman, D., & Suh, Y. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00059 · Cited by 124
Yeast as a tool to identify anti-aging compounds
Zimmermann, A., Hofer, S. J., Pendl, T., Kainz, K., Madeo, F., & Carmona‐Gutiérrez, D. (2018) · FEMS Yeast Research · doi:10.1093/femsyr/foy020 · Cited by 126
Wong, E. S. M., Guezennec, X. L., Demidov, O. N., Marshall, N. T., Wang, S. T., Krishnamurthy, J., Sharpless, N. E., Dunn, N. R., & Bulavin, D. V. (2009) · Developmental Cell · doi:10.1016/j.devcel.2009.05.009 · Cited by 131
Self-citationFarr, J. N., Rowsey, J. L., Eckhardt, B. A., Thicke, B. S., Fraser, D. G., Tchkonia, T., Kirkland, J. L., Monroe, D. G., & Khosla, S. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3729 · Cited by 127
Nuclear DNA Damage as a Direct Cause of Aging
Best, B. P. (2009) · Rejuvenation Research · doi:10.1089/rej.2009.0847 · Cited by 129
Cellular senescence in lung cancer: Molecular mechanisms and therapeutic interventions
Jha, S. K., Rubis, G. D., Devkota, S. R., Zhang, Y., Adhikari, R., Jha, L. A., Bhattacharya, K., Mehndiratta, S., Gupta, G., Singh, S. K., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102315 · Cited by 138
Reprogramming the epigenome with vitamin C
Lee Chong, T., Ahearn, E. L., & Cimmino, L. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00128 · Cited by 120
Li, Y., Liu, L., & Tollefsbol, T. O. (2009) · The FASEB Journal · doi:10.1096/fj.09-149328 · Cited by 120
Revisiting the Hallmarks of Aging to Identify Markers of Biological Age
Guerville, F., Barreto, P. D. S., Ader, I., Andrieu, S., Casteilla, L., Dray, C., Fazilleau, N., Guyonnet, S., Langin, D., Liblau, R., et al. (2020) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2019.50 · Cited by 122
Lipids as Regulators of Cellular Senescence
Hamsanathan, S., & Gurkar, A. U. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.796850 · Cited by 131
Roles and mechanisms of cellular senescence in regulation of tissue homeostasis
Ohtani, N., & Hara, E. (2013) · Cancer Science · doi:10.1111/cas.12118 · Cited by 122
Inhibition of TGF-β Signaling Promotes Human Pancreatic β-Cell Replication
Dhawan, S., Dirice, E., Kulkarni, R. N., & Bhushan, A. (2016) · Diabetes · doi:10.2337/db15-1331 · Cited by 119
Liu, J., Yang, J.-R., Chen, X.-M., Cai, G.-Y., Lin, L.-R., & He, Y.-N. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00096.2014 · Cited by 117
Keyes, M. K., Jang, H., Mason, J. B., Liu, Z., Crott, J. W., Smith, D. E., Friso, S., & Choi, S. (2007) · Journal of Nutrition · doi:10.1093/jn/137.7.1713 · Cited by 116
Cancer Treatment-Induced Accelerated Aging in Cancer Survivors: Biology and Assessment
Wang, S., Prizment, A. E., Thyagarajan, B., & Blaes, A. H. (2021) · Cancers · doi:10.3390/cancers13030427 · Cited by 118
Senescent Cells: A Therapeutic Target in Cardiovascular Diseases
Suda, M., Paul, K. H., Minamino, T., Miller, J. D., Lerman, A., Ellison, G. M., Tchkonia, T., & Kirkland, J. L. (2023) · Cells · doi:10.3390/cells12091296 · Cited by 119
The great unravelling: chromatin as a modulator of the aging process
O’Sullivan, R. J., & Karlseder, J. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.08.001 · Cited by 120
Ito, M., Yurube, T., Kakutani, K., Maeno, K., Takada, T., Terashima, Y., Kakiuchi, Y., Takeoka, Y., Miyazaki, S., Kuroda, R., et al. (2017) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2017.08.019 · Cited by 117
Jin, H. J., Lee, H. J., Heo, J., Lim, J., Kim, M., Kim, M. K., Nam, H. Y., Hong, G. H., Cho, Y. S., Choi, S. J., et al. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6359 · Cited by 115
The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2
Chaib, S., López-Domínguez, J. A., Lalinde-Gutiérrez, M., Prats, N., Marin, I., Boix, O., García-Garijo, A., Meyer, K., Muñoz, M. I., Aguilera, M., et al. (2024) · Nature Cancer · doi:10.1038/s43018-023-00712-x · Cited by 114
Cell Senescence: A Challenge in Cartilage Engineering and Regeneration
Li, J., & Pei, M. (2012) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2011.0583 · Cited by 114
Muñoz-Nájar, U., & Sedivy, J. M. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3250 · Cited by 114
Comprehensive transcriptional landscape of aging mouse liver
White, R. R., Milholland, B., MacRae, S. L., Lin, M., Zheng, D., & Vijg, J. (2015) · BMC Genomics · doi:10.1186/s12864-015-2061-8 · Cited by 116
Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging
Wang, Q., Nie, L., Zhao, P., Zhou, X., Ding, Y., Chen, Q., & Wang, Q. (2021) · International Journal of Oral Science · doi:10.1038/s41368-021-00116-6 · Cited by 113
Cellular senescence: Its role in tumor suppression and aging
Ohtani, N., Mann, D. J., & Hara, E. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01123.x · Cited by 119
Cellular senescence in the lung across the age spectrum
Parikh, P., Wicher, S., Khandalavala, K., Pabelick, C. M., Britt, R. D., & Prakash, Y. S. (2019) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00424.2018 · Cited by 112
Tissue Depletion of Taurine Accelerates Skeletal Muscle Senescence and Leads to Early Death in Mice
Ito, T., Yoshikawa, N., Inui, T., Miyazaki, N., Schaffer, S. W., & Azuma, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107409 · Cited by 113
Reproductive Ageing: Inflammation, immune cells, and cellular senescence in the aging ovary
Isola, J. V. V., Hense, J. D., Osorio, C. A. P., Biswas, S., Alberola‐Ila, J., Ocañas, S. R., Schneider, A., & Stout, M. B. (2024) · Reproduction · doi:10.1530/rep-23-0499 · Cited by 115
Control of p53 and NF-κB signaling by WIP1 and MIF: Role in cellular senescence and organismal aging
Salminen, A., & Kaarniranta, K. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2010.10.012 · Cited by 111
Aging and induced senescence as factors in the pathogenesis of lung emphysema
Karrasch, S., Holz, O., & Jörres, R. A. (2008) · Respiratory Medicine · doi:10.1016/j.rmed.2008.04.013 · Cited by 114
Changes in the Transcriptome of Human Astrocytes Accompanying Oxidative Stress-Induced Senescence
Crowe, E. P., Tuzer, F., Gregory, B. D., Donahue, G., Gosai, S. J., Cohen, J., Leung, Y. Y., Yetkin, E., Nativio, R., Wang, L.-S., et al. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00208 · Cited by 110
Pei, X., Bai, F., Smith, M. D., Usary, J., Fan, C., Pai, S., Ho, I., Perou, C. M., & Xiong, Y. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.004 · Cited by 113
Calorie restriction-induced SIRT6 activation delays aging by suppressing NF-κB signaling
Zhang, N., Li, Z., Mu, W., Li, L., Liang, Y., Lu, M., Wang, Z., Qiu, Y., & Wang, Z. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1152427 · Cited by 110
Increased immunosuppression impairs tissue homeostasis with aging and age-related diseases
Salminen, A. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01988-7 · Cited by 111
Molecular Mechanisms of Fibrosis-Associated Promotion of Liver Carcinogenesis
Uehara, T., Ainslie, G. R., Kutanzi, K., Pogribny, I. P., Muskhelishvili, L., Izawa, T., Yamate, J., Kosyk, O., Shymonyak, S., Bradford, B. U., et al. (2013) · Toxicological Sciences · doi:10.1093/toxsci/kfs342 · Cited by 111
Treiber, N., Maity, P., Singh, K., Kohn, M., Keist, A. F., Ferchiu, F., Sante, L., Frese, S., Bloch, W., Kreppel, F., et al. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2010.00658.x · Cited by 109
Senescent cells and macrophages: key players for regeneration?
Elder, S. S., & Emmerson, E. (2020) · Open Biology · doi:10.1098/rsob.200309 · Cited by 114
MicroRegulators come of age in senescence
Gorospe, M., & Abdelmohsen, K. (2011) · Trends in Genetics · doi:10.1016/j.tig.2011.03.005 · Cited by 108
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Xu, J., Zhou, L., & Liu, Y. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.601325 · Cited by 113
Cellular senescence in pretransplant renal biopsies predicts postoperative organ function
McGlynn, L. M., Stevenson, K. S., Lamb, K. J., Zino, S., Brown, M., Prina, A., Kingsmore, D. B., & Shiels, P. G. (2008) · Aging Cell · doi:10.1111/j.1474-9726.2008.00447.x · Cited by 108
Topical hypochlorite ameliorates NF-κB–mediated skin diseases in mice
Leung, T. H., Zhang, L. F., Wang, J., Ning, S., Knox, S. J., & Kim, S. K. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70895 · Cited by 107
White, R. R., Milholland, B., de Bruin, A., Curran, S., Laberge, R.-M., van Steeg, H., Campisi, J., Maslov, A. Y., & Vijg, J. (2015) · Nature Communications · doi:10.1038/ncomms7790 · Cited by 107
Yao, H., & Rahman, I. (2012) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00175.2012 · Cited by 109
LncRNAs Regulatory Networks in Cellular Senescence
Pavan Kumar, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112615 · Cited by 109
The bright and dark side of extracellular vesicles in the senescence-associated secretory phenotype
Wallis, R., Mizen, H., & Bishop, C. L. (2020) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111263 · Cited by 111
Molecular and genetic insights into human ovarian aging from single-nuclei multi-omics analyses
Jin, C., Wang, X., Yang, J., Kim, S.-S., Hudgins, A. D., Gamliel, A., Pei, M., Contreras, D., Devos, M., Guo, Q., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00762-5 · Cited by 107
Premature senescence of human endothelial cells induced by inhibition of glutaminase
Unterluggauer, H., Mazurek, S., Lener, B., Hütter, E., EIGENBRODT, E., Zwerschke, W., & Jansen‐Dürr, P. (2008) · Biogerontology · doi:10.1007/s10522-008-9134-x · Cited by 109
Functional changes in beta cells during ageing and senescence
Aguayo‐Mazzucato, C. (2020) · Diabetologia · doi:10.1007/s00125-020-05185-6 · Cited by 107
Reshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies
D’Ambrosio, M., & Gil, J. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.05.010 · Cited by 111
Anti‐aging activity of the Ink4/Arf locus
Matheu, A., Maraver, A., Collado, M., Garcia‐Cao, I., Cañamero, M., Borras, C., Flores, J. M., Klatt, P., Viña, J., & Serrano, M. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00458.x · Cited by 94
Mechanistic links between aging and lung fibrosis
Thannickal, V. J. (2013) · Biogerontology · doi:10.1007/s10522-013-9451-6 · Cited by 109
Telomeres in aging and disease: lessons from zebrafish
Carneiro, M. C., de Castro, I. P., & Ferreira, M. G. (2016) · Disease Models & Mechanisms · doi:10.1242/dmm.025130 · Cited by 109
Epigenetic Regulation of Genomic Stability by Vitamin C
Brabson, J. P., Leesang, T. E., Mohammad, S., & Cimmino, L. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.675780 · Cited by 111
Sirt1 protects the heart from aging and stress
Hsu, C., Odewale, I., Alcendor, R. R., & Sadoshima, J. (2008) · Biological Chemistry · doi:10.1515/bc.2008.032 · Cited by 108
Absence of Thrombospondin-2 Causes Age-Related Dilated Cardiomyopathy
Swinnen, M., Vanhoutte, D., van Almen, G. C., Hamdani, N., Schellings, M. W. M., D’hooge, J., van der Velden, J., Weaver, M. S., Sage, E. H., BORNSTEIN, P. K., et al. (2009) · Circulation · doi:10.1161/circulationaha.109.863266 · Cited by 107
Targeting Senescent Cells in Fibrosis: Pathology, Paradox, and Practical Considerations
Schafer, M. J., Haak, A. J., Tschumperlin, D. J., & LeBrasseur, N. K. (2018) · Current Rheumatology Reports · doi:10.1007/s11926-018-0712-x · Cited by 106
Caloric restriction and cellular senescence
Fontana, L., Nehme, J., & Demaria, M. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2018.10.005 · Cited by 104
Cellular senescence and the skeleton: pathophysiology and therapeutic implications
Khosla, S., Farr, J. N., & Monroe, D. G. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154888 · Cited by 106
Reversal of Hepatocyte Senescence After Continuous In Vivo Cell Proliferation
Wang, M., Chen, F., Li, J., Liu, C.-C., Zhang, H., Xia, Y., Yu, B., You, P., Xiang, D., Lu, L., et al. (2014) · Hepatology · doi:10.1002/hep.27094 · Cited by 109
Navarro, H. G., Nabah, Y. N. A., Vinué, Á., Andrés‐Manzano, M. J., Collado, M., Serrano, M., & Andrés, V. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.01.026 · Cited by 105
Minamino, T., & Komuro, I. (2008) · Nature Clinical Practice Cardiovascular Medicine · doi:10.1038/ncpcardio1324 · Cited by 104
Signer, R. A. J., Montecino-Rodriguez, E., Witte, O. N., & Dorshkind, K. (2008) · Genes & Development · doi:10.1101/gad.1715808 · Cited by 102
Cellular hallmarks of aging emerge in the ovary prior to primordial follicle depletion
Ansere, V. A., Ali-Mondal, S., Sathiaseelan, R., Garcia, D. N., Isola, J. V. V., Henseb, J. D., Saccon, T. D., Ocañas, S. R., Tooley, K. B., Stout, M. B., et al. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2020.111425 · Cited by 101
Dynamic Chromatin Localization of Sirt6 Shapes Stress- and Aging-Related Transcriptional Networks
Kawahara, T. L. A., Rapicavoli, N. A., Wu, A. R., Qu, K., Quake, S. R., & Chang, H. Y. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002153 · Cited by 104
Acute Kidney Injury as a Condition of Renal Senescence
Andrade, L., Rodrigues, C. E., Gomes, S. A., & Noronha, I. L. (2018) · Cell Transplantation · doi:10.1177/0963689717743512 · Cited by 104
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Gerdes, E. O. W., Misra, A., Espíndola‐Netto, J. M., Tchkonia, T., & Kirkland, J. L. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111591 · Cited by 105
Tian, X., Azpurua, J., Ke, Z., Augereau, A., Zhang, Z. D., Vijg, J., Gladyshev, V. N., Gorbunova, V. A., & Seluanov, A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1418203112 · Cited by 105
Hepatic senescence, the good and the bad
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Ink4‐Arf locus in cancer and aging
Sherr, C. J. (2012) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.40 · Cited by 104
The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.09.001 · Cited by 101
Tamama, K., Kawasaki, H., Kerpedjieva, S. S., Guan, J., Ganju, R. K., & Sen, C. K. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22961 · Cited by 98
Li, Y., & Tollefsbol, T. O. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017421 · Cited by 99
Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid
Gutiérrez‐Fernández, A., Soria‐Valles, C., Osorio, F. G., Gutiérrez‐Abril, J., Garabaya, C., Aguirre, A., Fueyo, A., Fernández‐García, M. S., Puente, X. S., & López‐Otín, C. (2015) · The EMBO Journal · doi:10.15252/embj.201490594 · Cited by 96
DNA Damage: A Main Determinant of Vascular Aging
Bautista‐Niño, P. K., Portilla-Fernández, E., Vaughan, D. E., Danser, A. H. J., & Roks, A. J. M. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17050748 · Cited by 95
Hallmarks of cellular senescence: biology, mechanisms, regulations
Ajoolabady, A., Praticò, D., Bahijri, S., Tuomilehto, J. O., Uversky, V. N., & Ren, J. T. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01480-7 · Cited by 107
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Martin‐Gronert, M. S., & Ozanne, S. E. (2012) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-012-9210-z · Cited by 97
Lim, S., An, S. B., Jung, M., Joshi, H. P., Kumar, H., Kim, C., Song, S. Y., Lee, J., Kang, M., Han, I., et al. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202101483 · Cited by 95
Challenges in developing Geroscience trials
Rolland, Y., Sierra, F., Ferrucci, L., Barzilai, N., de Cabo, R., Mannick, J. B., Oliva, A. A., Evans, W. J., Angioni, D., Barreto, P. D. S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39786-7 · Cited by 98
Zhang, J., Wan, L., Dai, X., Sun, Y., & Wei, W. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.02.001 · Cited by 98
Waaijer, M. E. C., Gunn, D. A., Adams, P. D., Pawlikowski, J. S., Griffiths, C. E. M., van Heemst, D., Slagboom, P. E., Westendorp, R. G. J., & Maier, A. B. (2015) · The Journals of Gerontology Series A · doi:10.1093/gerona/glv114 · Cited by 95
Islet biology, the CDKN2A/B locus and type 2 diabetes risk
Kong, Y., Sharma, R. B., Nwosu, B. U., & Alonso, L. C. (2016) · Diabetologia · doi:10.1007/s00125-016-3967-7 · Cited by 97
β cell aging and age-related diabetes
Zhu, M., Liu, X., Liu, W., Lu, Y., Cheng, J., & Chen, Y. (2021) · Aging · doi:10.18632/aging.202593 · Cited by 96
Sleep and biological aging: A short review
Carroll, J., & Prather, A. A. (2021) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2021.03.021 · Cited by 95
Can blocking inflammation enhance immunity during aging?
Chambers, E. S., & Akbar, A. N. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.03.016 · Cited by 92
Repair of senescent myocardium by mesenchymal stem cells is dependent on the age of donor mice
Khan, M., Mohsin, S., Khan, S. N., & Riazuddin, S. A. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00998.x · Cited by 93
The role of senescence in cancer development
Mavrogonatou, E., Pratsinis, H., & Kletsas, D. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.06.018 · Cited by 95
Chang-Panesso, M. (2021) · Pediatric Nephrology · doi:10.1007/s00467-020-04849-0 · Cited by 97
Cluett, C., McDermott, M. M., Guralnik, J. M., Ferrucci, L., Bandinelli, S., Miljkovic, I., Zmuda, J. M., Li, R., Tranah, G. J., Harris, T. B., et al. (2009) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.108.825935 · Cited by 93
The p53 tumor suppressor protein regulates hematopoietic stem cell fate
Asai, T., Liu, Y., Bae, N., & Nimer, S. D. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22561 · Cited by 102
Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota
Kawamoto, S., Uemura, K., Hori, N., Takayasu, L., Konishi, Y., Katoh, K., Matsumoto, T., Suzuki, M., Sakai, Y., Matsudaira, T., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01145-5 · Cited by 91
Cellular Senescence in Ageing, Age-Related Disease and Longevity
Sikora, E., Bielak-Żmijewska, A., & Mosieniak, G. (2013) · Current Vascular Pharmacology · doi:10.2174/1570161111666131219094045 · Cited by 92
Significance of taurine transporter (TauT) in homeostasis and its layers of regulation (Review)
Baliou, S., Kyriakopoulos, A. M., Goulielmaki, M., Panayiotidis, M. I., Spandidos, D. A., & Zoumpourlis, V. (2020) · Molecular Medicine Reports · doi:10.3892/mmr.2020.11321 · Cited by 91
Ning, Y., Cai, G., Zhuo, L., Gao, J., Dong, D. F., Cui, S., Feng, Z., Shi, S., Bai, X., Sun, X., et al. (2013) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2013.11.006 · Cited by 91
Extracellular vesicles and aging
Robbins, P. D. (2017) · Stem Cell Investigation · doi:10.21037/sci.2017.12.03 · Cited by 93
Skin equivalents: skin from reconstructions as models to study skin development and diseases
Ali, N., Hosseini, M., Vainio, S. J., Taı̈eb, A., Cario, M., & Rezvani, H. R. (2015) · British Journal of Dermatology · doi:10.1111/bjd.13886 · Cited by 90
Cheng, H., Fan, X., Lawson, W. E., Paueksakon, P., & Harris, R. C. (2015) · Kidney International · doi:10.1038/ki.2015.69 · Cited by 89
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
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