Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions

Ramirez, Ruben D.; Morales, Carmela P.; Herbert, Brittney-Shea; Rohde, Jeffrey M.; Passons, Christina; Shay, Jerry W.; Wright, Woodring E.

doi:10.1101/gad.859201

Cited by 444Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions

Open access

Ramirez, Ruben D., Morales, Carmela P., Herbert, Brittney-Shea, Rohde, Jeffrey M., Passons, Christina, Shay, Jerry W., Wright, Woodring E.·2001·Genes & Development

DOI 10.1101/gad.859201PMC PMC312628

Open this paper in CoChat — free account Open PDF

Abstract

Telomere shortening is the mechanism underlying replicative aging in fibroblasts. A variety of reports now claim that inactivation of the p16 INK4a/pRB pathway is required in addition to telomere maintenance for the immortalization of cells such as skin keratinocytes and breast epithelial cells. We here show that the premature growth arrest of these cell types can be explained by an inadequate culture environment. Providing mesenchymal/epithelial interactions by cultivating the telomerase-expressing cells on feeder layers avoids the growth arrest associated with increased p16 INK4a. These results do not support a telomere-independent mechanism of replicative aging.

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

Crossref · 10.1101/gad.859201

Cites

0 citation errors · 0 not checkable

Statistics

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?

Telomere-dependent replicative senescence is thought to depend primarily on the p53 pathway.
“Likewise, telomere-dependent replicative senescence is thought to depend primarily on the p53 pathway (Ramirez et al., 2001; Herbig et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Ramirez et al., 2001
The Discussion says short telomeres can trigger a DNA-damage signal and that p53 may mediate the resulting growth arrest. It also names p16 and does not say the process depends primarily on p53, so the claim overstates the pathway's specified role. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Cellular senescence in vitro may occur without detectable DNA damage response.
“although cellular senescence in vitro may also occur without detectable DDR [31,32].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [31]
Telomerase activation and telomere-length maintenance allow bypass of senescence and lead to cell immortalization.
“Telomerase activation and the resulting telomere-length maintenance leads to the bypass of senescence and ultimately to cell immortalization23,26,27.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [26]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Telomeres shorten during ageing of human fibroblasts
Harley, C. B., Futcher, A. B., & Greider, C. W. (1990) · Nature · doi:10.1038/345458a0 · Cited by 5,750 · see citing works
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · cited 3× · see citing works
“The same argument applies to the premature cellular senescence induced by Ras ( Serrano et al. 1997 ).”
Background
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., & Wright, W. E. (1998) · Science · doi:10.1126/science.279.5349.349 · Cited by 4,975 · see citing works
Self-citation
Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA
Blasco, M. A., Lee, H.-W., Hande, M. P., Samper, E., Lansdorp, P. M., DePinho, R. A., & Greider, C. W. (1997) · Cell · doi:10.1016/s0092-8674(01)80006-4 · Cited by 2,108 · see citing works
TRF2 Protects Human Telomeres from End-to-End Fusions
van Steensel, B., Smogorzewska, A., & de Lange, T. (1998) · Cell · doi:10.1016/s0092-8674(00)80932-0 · Cited by 1,709 · see citing works
Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells
Kiyono, T., Foster, S. A., Koop, J. I., McDougall, J. K., Galloway, D. A., & Klingelhutz, A. J. (1998) · Nature · doi:10.1038/23962 · Cited by 1,206 · cited 3× · see citing works
“2; Kiyono et al. 1998).”
BackgroundInfluential
Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span
Vaziri, H., & Benchimol, S. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70109-5 · Cited by 1,003 · see citing works
Cellular Senescence
Sherr, C. J., & DePinho, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00046-5 · Cited by 745 · see citing works
Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts
Robles, S. J., & Adami, G. R. (1998) · Oncogene · doi:10.1038/sj.onc.1201862 · Cited by 498 · see citing works
Genetic and Epigenetic Changes in Human Epithelial Cells Immortalized by Telomerase
Farwell, D. G., Shera, K. A., Koop, J. I., Bonnet, G. A., Matthews, C. P., Reuther, G. W., Coltrera, M. D., McDougall, J. K., & Klingelhutz, A. J. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65025-0 · Cited by 196 · see citing works
Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion
Khan, S. H., Moritsugu, J., & Wahl, G. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3266 · Cited by 103 · see citing works

Flagged first, then by citations

Research works printed but not linked: 4

Dimri, G.P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E.E., Linskens, M., Rubelj, I., Pereira-Smith, O., et al. 1995. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. 92: 9363-9367.
Hayflick, L. 1980. Cell Aging. In Annual Review of Gerontology and Geriatrics, Vol. 1 (ed. C. Eisdorfer), pp. 26-67. Springer, New York, NY.
Parchment, R.E., Lewellyn, A., Swartzendruber, D., and Pierce, G.B. 1990. Serum amine oxidase activity contributes to crisis in mouse embryo cell lines. Proc. Natl. Acad. Sci. 87: 4340-4344.
Rheinwald, J.G. 1989. Methods for clonal growth and serial cultivation of normal human epidermal keratinocytes and mesothelial cells. In Cell growth and division: A practical approach (ed. R. Baserga), pp. 81-94. IRL, Oxford, UK.

Sorted by citations

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 · see citing works
Oxidative stress shortens telomeres
von Zglinicki, T. (2002) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(02)02110-2 · Cited by 2,524 · see citing works
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 2,359 · see citing works
“In these bcells, the high levels of ROS produced by RAS (Irani et 2al., 1997) may trigger senescence by the p53 pathway. eLikewise, telomere-dependent replicative senescence is thought to depend primarily on the p53 pathway (Ramirez et al., 2001; Herbig et al., 2004).”
Background
The essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038 · see citing works
“1995), while the replicative potential of human melanocytes and epithelial cells depends largely on the composition of the culture medium used, as well as on the use of feeder layers (Ramirez et al. 2001; Bennett and Medrano 2002; Bennett 2003).”
BackgroundInfluential
Four faces of cellular senescence
Rodier, F., & Campisi, J. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201009094 · Cited by 2,016 · see citing works
“Nonetheless, between the two models, the mice However, the evolutionary theory of antagonistic pleiotropy stipulates that a biological process can be both beneficial and deleterious, depending on the age of the organism (Williams, 1957; Rauser et al., 2006).”
Cellular 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 · see citing works
“It is possible to cancel the INK4a/ ARF clock if culture conditions are finely tuned to avoid mitogenic overstimulation (Ramirez et al., 2001; Woo and Poon, 2004).”
The RB and p53 pathways in cancer
Sherr, C. J., & McCormick, F. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00102-2 · Cited by 1,690 · see citing works
“Stress stemming from a nonphysiologic cell culture environment generates signals that activate p16Ink4a synthesis (Sherr and DePinho, 2000), but its induction can be retarded, or even eliminated, by changing conditions in which primary cells are grown (Ramirez et al., 2001).”
Background
Reversal of human cellular senescence: roles of the p53 and p16 pathways
Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., & Campisi, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg417 · Cited by 1,457 · see citing works
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 · see citing works
“A systemic proinflammatory state that occurs with aging (termed inflammaging) (125) has been implicated in the induction of senescence in the chondrocytes, a condition that is responsible of osteoarthrosis, and in additional aging-related disorders linked to inflammation (155, 265, 313) (see sect.”
Background
Pancreatic cancer biology and genetics
Bardeesy, N. M., & DePinho, R. A. (2002) · Nature reviews. Cancer · doi:10.1038/nrc949 · Cited by 1,144 · see citing works
“When primary cells are placed into culture, INK4A -transcript expression is induced, and this seems to be a stress response to the inappropriate growth environment that is associated with in vitro cultur”
Background
Living on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
The INK4a/ARF network in tumour suppression
Sherr, C. J. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35096061 · Cited by 984 · see citing works
Modelling the molecular circuitry of cancer
Hahn, W. C., & Weinberg, R. A. (2002) · Nature reviews. Cancer · doi:10.1038/nrc795 · Cited by 936 · see citing works
Human Telomerase and Its Regulation
Cong, Y.-S., Wright, W. E., & Shay, J. W. (2002) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.66.3.407-425.2002 · Cited by 898 · see citing works
“Recent studies demonstrated that expression of human telomerase alone is sufficient for the immortalization of diverse cell types and for allowing transformed cells to escape from crisis (24, 191, 199, 263).”
BackgroundSelf-citation
Regulation of Telomerase by Telomeric Proteins
Smogorzewska, A., & de Lange, T. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.071403.160049 · Cited by 796 · see citing works
Telomeres in cancer: tumour suppression and genome instability
Maciejowski, J., & de Lange, T. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.171 · Cited by 745 · see citing works
Senescence and immortalization: role of telomeres and telomerase
Shay, J. W., & Wright, W. E. (2004) · Carcinogenesis · doi:10.1093/carcin/bgh296 · Cited by 729 · see citing works
Self-citation
Fighting against Skin Aging: The Way from Bench to Bedside
Zhang, S., & Duan, E. (2018) · Cell Transplantation · doi:10.1177/0963689717725755 · Cited by 739 · see citing works
Tumor suppression by Ink4a-Arf: progress and puzzles.
Lowe, S. W., & Sherr, C. J. (2003) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00013-8 · Cited by 699 · see citing works
Role of Telomeres and Telomerase in Aging and Cancer
Shay, J. W. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0062 · Cited by 668 · see citing works
Self-citation
Immortalization of Human Bronchial Epithelial Cells in the Absence of Viral Oncoproteins
Ramirez, R., Sheridan, S., Girard, L., Sato, M., Kim, Y., Pollack, J., Peyton, M., Zou, Y. S., Kurie, J., Dimaio, J. M., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-3703 · Cited by 666 · see citing works
“We reported previously that premature growth arrest in epidermal keratinocytes and human mammary epithelial cells when cultivated in vitro was associated with up-regulation of the cyclin-dependent kinase (Cdk) inhibitor, p16 (9, 10).”
BackgroundMethodInfluentialSelf-citation
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 · see citing works
“Our findings are of additional relevance since in both in vitro and in ex vivo studies, an increased expression of p16 has been causally related to inadequate growth conditions (Ramirez et al., 2001), DNA double strand breaks (Robles & Adami, 1998) and the occurrence of cervical and other epidermal cancers (Fiedler et…”
Background
Oxidative stress in cell culture: an under‐appreciated problem?
Halliwell, B. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00235-7 · Cited by 534 · see citing works
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527 · see citing works
“When primary cells are placed into culture, INK4A expression is induced via a presumed stress response to the inappropriate growth environment associated with in vitro culture (Sherr and DePinho 2000; Ramirez et al. 2001).”
Tumor Suppressor and Aging Biomarker p16INK4a Induces Cellular Senescence without the Associated Inflammatory Secretory Phenotype
Coppé, 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 · see citing works
Hallmarks of senescence in carcinogenesis and cancer therapy
Shay, J. W., & Roninson, I. B. (2004) · Oncogene · doi:10.1038/sj.onc.1207518 · Cited by 502 · see citing works
Self-citation
SINAT5 promotes ubiquitin-related degradation of NAC1 to attenuate auxin signals
Xie, Q., Guo, H., Dallman, G., Fang, S.-Y., Weissman, A., & Chua, N. (2002) · Nature · doi:10.1038/nature00998 · Cited by 494 · see citing works
Different telomere damage signaling pathways in human and mouse cells
Smogorzewska, A., & de Lange, T. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf433 · Cited by 482 · see citing works
“However, when the same cells are grown under optimal conditions, p16 is not induced and telomerase-mediated telomere maintenance is suf®cient to endow cells with in®nite replicative potential (Ramirez et al., 2001).”
Background
Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation
Bardeesy, N. M., Sinha, M., Hezel, A. F., Signoretti, S., Hathaway, N. A., Sharpless, N. E., Loda, M. F., Carrasco, D. R., & DePinho, R. A. (2002) · Nature · doi:10.1038/nature01045 · Cited by 418 · see citing works
“The phenomenon of passage-induced senescence in MEFs has been attributed to the activation of a cellular stress response elicited by in vitro growth condition”
Background
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 · see citing works
“Abbreviations Aβ amyloid-beta AD Alzheimer’s disease Akt protein kinase B ALL acute lymphocytic leukemia APP amyloid beta precursor protein ATF6α activating transcription factor 6 isoform α ATM ataxia-telangiectasia mutated BBB blood-brain barrier Bcl-2 B-cell lymphoma 2 CDK cyclin-dependent kinase CDKI cyclin-depende…”
BackgroundInfluential
Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1
Itahana, K., Zou, Y., Itahana, Y., Martinez, J.-L., Beausejour, C., Jacobs, J. J. L., van Lohuizen, M., Band, V., Campisi, J., & Dimri, G. P. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.389-401.2003 · Cited by 438 · see citing works
“p16 is induced by a variety of stimuli (45), including DNA”
Background
Putting the stress on senescence
Serrano, M., & Blasco, M. A. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00278-7 · Cited by 413 · see citing works
Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury.
Souza, R., Huo, X., Mittal, V., Schuler, C. M., Carmack, S. W., Zhang, H.-Y., Zhang, X., Yu, C.-H., Hormi-Carver, K. K., Genta, R., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.07.055 · Cited by 410 · see citing works
When cells get stressed: an integrative view of cellular senescence
Ben-Porath, I., & Weinberg, R. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420663 · Cited by 404 · see citing works
Cellular senescence, cancer and aging: the telomere connection
Campisi, J., Kim, S.-H., Lim, C.-S., & Rubio, M. (2001) · Experimental Gerontology · doi:10.1016/s0531-5565(01)00160-7 · Cited by 400 · see citing works
Cellular senescence in naevi and immortalisation in melanoma: a role for p16?
Gray-Schopfer, V. C., Cheong, S. C., Chong, H., Chow, J., Moss, T., Abdel-Malek, Z. A., Marais, R., Wynford-Thomas, D., & Bennett, D. C. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603283 · Cited by 394 · see citing works
Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney
Melk, A., Schmidt, B. M. W., Takeuchi, O., Sawitzki, B., Rayner, D. C., & Halloran, P. F. (2004) · Kidney International · doi:10.1111/j.1523-1755.2004.00438.x · Cited by 362 · see citing works
Telomeres: Cancer to Human Aging
Stewart, S. A., & Weinberg, R. A. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.22.010305.104518 · Cited by 336 · see citing works
“F or p er so na l u se o nl y. conditions of growth (including those that induce the expression of the p16INK4A and p21Waf1 cell cycle inhibitors), and high oxidative stress levels (Ramirez et al. 2001, Sherr & DePinho 2000, Wei et al. 2001, Wright & Shay 2002, and references in all).”
Background
Historical claims and current interpretations of replicative aging
Wright, W. E., & Shay, J. W. (2002) · Nature Biotechnology · doi:10.1038/nbt0702-682 · Cited by 355 · see citing works
“However, this stress-responsive pathway was not activated when human epidermal keratinocytes or mammary epithelial cells were grown on feeder layers, and under those conditions both cell types could be immortalized by telomeras”
BackgroundSelf-citation
Telomerase and differentiation in multicellular organisms: Turn it off, turn it on, and turn it off again
Forsyth, N. R., Wright, W. E., & Shay, J. W. (2002) · Differentiation · doi:10.1046/j.1432-0436.2002.690412.x · Cited by 345 · see citing works
Self-citation
Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo
Kaeser, M., & Iggo, R. (2001) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.012283399 · Cited by 346 · see citing works
Mechanisms of cellular senescence in human and mouse cells.
Itahana, K., Campisi, J., & Dimri, G. P. (2004) · Biogerontology · doi:10.1023/b:bgen.0000017682.96395.10 · Cited by 338 · see citing works
“Consistent with this view, it was recently reported that p16 can be repressed by manipulating culture conditions (Ramirez et al. 2001).”
Background
Telomerase: A target for cancer therapeutics
Shay, J. W., & Wright, W. E. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00159-9 · Cited by 330 · see citing works
“This resulted in telomere length stabilization and the direct immortalization of cells without oncogenic transformation (Morales et al., 1999; Harley, 2002) as long as cells are cultured in adequate conditions ( Ramirez et al., 2001 ).”
BackgroundSelf-citation
A Two-Stage, p16 INK4A - and p53-Dependent Keratinocyte Senescence Mechanism That Limits Replicative Potential Independent of Telomere Status
Rheinwald, J. G., Hahn, W. C., Ramsey, M. R., Wu, J. Y., Guo, Z., Tsao, H., De Luca, M., Catricalà, C., & O'Toole, K. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.14.5157-5172.2002 · Cited by 338 · see citing works
“Because a recent report (52) concluded that p16-related se-”
BackgroundResultInfluential
Omeprazole Blocks Eotaxin-3 Expression by Oesophageal Squamous Cells from Patients with Eosinophilic Oesophagitis and GORD
Cheng, E., Zhang, X., Huo, X., Yu, C.-H., Zhang, Q.-Y., Wang, D. H., Spechler, S., & Souza, R. (2012) · Gut · doi:10.1136/gutjnl-2012-302250 · Cited by 339 · see citing works
Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor
Chapman, S., Liu, X., Meyers, C., Schlegel, R., & McBride, A. A. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42297 · Cited by 314 · see citing works
Characterization of growth and differentiation in a telomerase-immortalized human corneal epithelial cell line.
Robertson, D. M., Li, L., Fisher, S., Pearce, V. P., Shay, J. W., Wright, W. E., Cavanagh, H., & Jester, J. (2005) · Investigative Ophthalmology and Visual Science · doi:10.1167/iovs.04-0528 · Cited by 304 · see citing works
“Alternatively, it has been reported that p16 induction can be bypassed under appropriate culture conditions.(10,31,32) To examine the role of p16 in hTCEpi immortalization, we assessed p16 expression in hTCEpi cells at early, middle, and late passages.”
Self-citation
Cellular senescence in human myoblasts is overcome by human telomerase reverse transcriptase and cyclin‐dependent kinase 4: consequences in aging muscle and therapeutic strategies for muscular dystrophies
Zhu, C., Mouly, V., Cooper, R. N., Mamchaoui, K., Bigot, A., Shay, J. W., Santo, J. P. D., Butler-Browne, G. S., & Wright, W. E. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00306.x · Cited by 301 · see citing works
“This behaviour is characteristic of cells grown under conditions inadequate for their long-term proliferation, where stress/damage checkpoints are induced before telomere shortening becomes limiting (Sherr & DePinho, 2000; Wright & Shay, 2000; Ramirez et al ., 2001; Forsyth et al ., 2003).”
BackgroundSelf-citation
Does a Sentinel or a Subset of Short Telomeres Determine Replicative Senescence?
Zou, Y., Sfeir, A., Gryaznov, S. M., Shay, J. W., & Wright, W. E. (2004) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-03-0207 · Cited by 293 · see citing works
“Fetal lung fibroblasts exhibited stasis (growth arrest due to inadequate culture conditions; Ramirez et al., 2001; Drayton and Peters, 2002; Wright and Shay, 2002) rather than pure telomere-based replicative senescence using standard tissue culture media in room oxygen (Forsyth et al., 2003).”
BackgroundSelf-citation
Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor
Lee, M., & Vasioukhin, V. I. (2008) · Journal of Cell Science · doi:10.1242/jcs.016634 · Cited by 276 · see citing works
“However, recent studies demonstrated that this might be due to inferior culture conditions (Papini et al., 2003; Ramirez et al., 2001).”
Background
Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16ink4a
Kosar, M., Bartkova, J., Hubackova, S., Hodny, Z., Lukas, J., & Bartek, J. (2011) · Cell Cycle · doi:10.4161/cc.10.3.14707 · Cited by 283 · see citing works
Reversal of Senescence in Mouse Fibroblasts through Lentiviral Suppression of p53
Dirac, A. M. G., & Bernards, R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300023200 · Cited by 254 · see citing works
Replicative senescence: a critical review
Cristofalo, V. J., Lorenzini, A., Allen, R. G., Torres, C. A., & Tresini, M. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.07.010 · Cited by 275 · see citing works
“However, another report indicated that both mammary epithelial cells and keratinocytes could be immortaliazed with hTERT alone if the appropriate growth conditions were provided (Ramirez et al., 2001).”
Background
Immortalization and transformation of primary human airway epithelial cells by gene transfer
Lundberg, A., Randell, S., Stewart, S. A., Elenbaas, B., Hartwell, K. A., Brooks, M., Fleming, M., Olsen, J., Miller, S., Weinberg, R., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205550 · Cited by 267 · see citing works
“It remains possible, however, that culture conditions and other factors also play an important role in determining replicative lifespan (Ramirez et al., 2001).”
Background
Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc−/− mice with short telomeres
Samper, E., Flores, J. M., & Blasco, M. A. (2001) · The EMBO Reports · doi:10.1093/embo-reports/kve174 · Cited by 263 · see citing works
“Conversely, re-introduction of telomerase activity in cultured human primary cells results in telomere maintenance and immortal growth (Bodnar et al., 1998; Jiang et al., 1999; Morales et al., 1999; Ramirez et al., 2001).”
Background
Expression of Human Telomerase (hTERT) Does Not Prevent Stress-induced Senescence in Normal Human Fibroblasts but Protects the Cells from Stress-induced Apoptosis and Necrosis
Gorbunova, V. A., Seluanov, A., & Pereira‐Smith, O. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202671200 · Cited by 253 · see citing works
Loss of linker histone H1 in cellular senescence
Funayama, R., Saito, M., Tanobe, H., & Ishikawa, F. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200604005 · Cited by 241 · see citing works
“Such a stress-induced state is called premature senescence or stress-induced senescence (Serrano et al., 1997; Ramirez et al., 2001).”
Background
Cell culture, oxidative stress, and antioxidants: Avoiding pitfalls
Halliwell, B. B. (2014) · Biomedical Journal · doi:10.4103/2319-4170.128725 · Cited by 222 · see citing works
Downregulation of Wnt Signaling Is a Trigger for Formation of Facultative Heterochromatin and Onset of Cell Senescence in Primary Human Cells
Ye, X., Zerlanko, B. J., Kennedy, A. L., Gowrishankar, B., Zhang, R., & Adams, P. D. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.05.034 · Cited by 227 · see citing works
“Senescence is also caused by cellular stresses, inadequate growth conditions, and shortened telomeres that result from repeated rounds of cell division (Campisi, 2005; Ramirez et al., 2001).”
Background
Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence
Jacobs, J. J. L., & de Lange, T. (2004) · Current Biology · doi:10.1016/j.cub.2004.12.025 · Cited by 237 · see citing works
Senescence-specific gene expression fingerprints reveal cell-type-dependent physical clustering of up-regulated chromosomal loci
Zhang, H., Pan, K.-H., & Cohen, S. N. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2627983100 · Cited by 209 · see citing works
Cell cycle status in human corneal endothelium
Joyce, N. C. (2005) · Experimental Eye Research · doi:10.1016/j.exer.2005.06.012 · Cited by 202 · see citing works
Development of cystic fibrosis and noncystic fibrosis airway cell lines
Zabner, J., Karp, P., Seiler, M. P., Phillips, S. L., Mitchell, C. J., Saavedra, M., Welsh, M. J., & Klingelhutz, A. J. (2003) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00355.2002 · Cited by 178 · see citing works
Growth retardation and premature aging phenotypes in mice with disruption of the SNF2-like gene, PASGPreprint
Sun, L.-Q., Lee, D. W., Zhang, Q., Xiao, W., Raabe, E. H., Meeker, A. K., Miao, D., Huso, D. L., & Arceci, R. J. (2004) · Genes & Development · doi:10.1101/gad.1176104 · Cited by 182 · see citing works
“This physiological response appears to trigger growth inhibition via activation of tumor suppressor genes, such as p16, p19, p53, and p21 (Alcorta et al. 1996; Kiyono et al. 1998; Stein et al. 1999; Ramirez et al. 2001; Randle et al. 2001; Rheinwald et al. 2002; Schmitt et al. 2002; Tyner et al. 2002).”
Background
Telomerase is not an oncogene
Harley, C. B. (2002) · Oncogene · doi:10.1038/sj.onc.1205076 · Cited by 193 · see citing works
Telomere biology in Metazoa
Gomes, N. M. V., Shay, J. W., & Wright, W. E. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.07.031 · Cited by 186 · see citing works
Self-citation
Immortalized Epithelial Cells Derived From Human Colon Biopsies Express Stem Cell Markers and Differentiate In Vitro
Roig, A. I., Eskiocak, U., Hight, S. K., Kim, S. B., Delgado, O., Souza, R. F., Spechler, S. J., Wright, W. E., & Shay, J. W. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.11.052 · Cited by 177 · see citing works
Self-citation
Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging
Adams, P. D. (2007) · Gene · doi:10.1016/j.gene.2007.04.020 · Cited by 174 · see citing works
“As well as activated oncogenes, senescence is caused by shortened telomeres that result from repeated rounds of cell division, and inadequate in vitro growth conditions and other cellular stresses (20,59,101,136).”
Background
Stable Cellular Senescence Is Associated with Persistent DDR Activation
Fumagalli, M., Rossiello, F., Mondello, C., & d’Adda di Fagagna, F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110969 · Cited by 183 · see citing works
“S2 and [45]) that has been observed associated with growth arrest in cells grown under inadequate conditions, such as exposure to oxidative stress or strong mitogenic stimuli [50–52].”
Background
Human lung epithelial cell cultures for analysis of inhaled toxicants: Lessons learned and future directions
Hiemstra, P. S., Grootaers, G., van der Does, A. M., Krul, C. A. M., & Kooter, I. M. (2017) · Toxicology in Vitro · doi:10.1016/j.tiv.2017.11.005 · Cited by 210 · see citing works
“It has been demonstrated that premature growth arrest of other epithelial cells (keratinocytes and mammary epithelial cells) is associated with increases in the cyclindependent kinase (Cdk) inhibitor p16INK4a (Ramirez et al., 2001).”
Background
Definition of pRB- and p53-Dependent and -Independent Steps in HIRA/ASF1a-Mediated Formation of Senescence-Associated Heterochromatin Foci
Ye, X., Zerlanko, B. J., Zhang, R., Somaiah, N., Lipinski, M., Salomoni, P., & Adams, P. D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01592-06 · Cited by 161 · see citing works
“As well as activated oncogenes, senescence is caused by shortened telomeres that result from repeated rounds of cell division, cellular stresses, and inadequate growth conditions (11, 32, 52, 66).”
Background
Real-time in vivo imaging of p16Ink4a reveals cross talk with p53
Yamakoshi, K., Takahashi, A., Hirota, F., Nakayama, R., Ishimaru, N., Kubo, Y., Mann, D. J., Ohmura, M., Hirao, A., Saya, H., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200904105 · Cited by 172 · see citing works
“However, because human p16Ink4a gene expression is also induced by tissue culture–imposed stress (Ramirez et al., 2001; Benanti and Galloway, 2004; Ince et al., 2007; Shay and Wright, 2007), it remains unclear whether the induction of human p16Ink4a gene expression in tissuecultured cells truly…”
Regulation of growth arrest in senescence: Telomere damage is not the end of the story
Herbig, U., & Sedivy, J. M. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.09.002 · Cited by 159 · see citing works
Developmental differences in the immortalization of lung fibroblasts by telomerase
Forsyth, N. R., Evans, A., Shay, J. W., & Wright, W. E. (2003) · Aging Cell · doi:10.1046/j.1474-9728.2003.00057.x · Cited by 156 · see citing works
“The p16/pRB pathway has been implicated in the growth arrest (stasis) that occurs when cells are grown under inadequate conditions ( Ramirez et al ., 2001; Drayton & Peters, 2002; Herbert et al ., 2002).”
BackgroundSelf-citation
Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survival
Kang, M., Kim, R., Kim, S., Yip, F., Shin, K., Dimri, G. P., Christensen, R., Han, T., & Park, N. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603529 · Cited by 163 · see citing works
“The extrinsic senescence is telomere-independent and triggered in cells after exposure to environmental factors, such as genotoxic stress, in vitro culture shock, and oncogenic stimuli (Serrano et al, 1997; Ramirez et al, 2001; Itahana et al, 2004; Chen et al, 2005; Dimri, 2005).”
Background
Cell senescence and cancer
Mathon, N. F., & Lloyd, A. C. (2001) · Nature reviews. Cancer · doi:10.1038/35106045 · Cited by 306 · see citing works
Immortalization with telomerase of the Nestin-positive cells of the human pancreas.
Lee, K. M., Nguyen, C., Ulrich, A., Pour, P., & Ouellette, M. (2003) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/s0006-291x(03)00086-x · Cited by 160 · see citing works
“Inappropriate tissue culture conditions can sometimes lead to the induction of M0, a form of premature senescence that hTERT alone fails to overcome [23–28].”
Background
Telomerase in cancer and aging
Granger, M. P., Wright, W. E., & Shay, J. W. (2002) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(01)00188-3 · Cited by 159 · see citing works
“The introduction of the catalytic protein (hTERT) component of telomerase into normal fibroblasts and epithelial cells prevents shortening of the telomeres, and results in immortalization [ 20 ].”
BackgroundSelf-citation
Molecular Distinctions between Stasis and Telomere Attrition Senescence Barriers Shown by Long-term Culture of Normal Human Mammary Epithelial Cells
Garbe, J. C., Bhattacharya, S., Merchant, B., Bassett, E., Swisshelm, K. L., Feiler, H. S., Wyrobek, A. J., & Stampfer, M. R. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0270 · Cited by 157 · see citing works
Cellular senescence and chromatin structure
Funayama, R., & Ishikawa, F. (2007) · Chromosoma · doi:10.1007/s00412-007-0115-7 · Cited by 150 · see citing works
“On the other hand, various forms of stress including DNA-damaging agents, oncogenic activation, and inadequate culture conditions acutely induce a state that is indistinguishable from replicative senescence (Ogryzko et al. 1996; Serrano et al. 1997; Ramirez et al. 2001).”
Premature Senescence of Balding Dermal Papilla Cells In Vitro Is Associated with p16INK4a Expression
Bahta, A. W., Farjo, N. P., FARJO, B. K., & Philpott, M. P. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701147 · Cited by 156 · see citing works
“Neither balding nor non-balding DPC expressed p53 (data not shown) suggesting that the senescence in balding DPC is mediated via the p16/Rb pathway and may therefore be associated with cellular stress and not replicative lifespan (Ramirez et al., 2001; Jacobs and de Lange, 2004).”
Background
Comparison of human mammary epithelial cells immortalized by simian virus 40 T-Antigen or by the telomerase catalytic subunit
Toouli, C., Huschtscha, L., Neumann, A. A., Noble, J. R., Colgin, L. M., Hukku, B., & Reddel, R. (2002) · Oncogene · doi:10.1038/sj.onc.1205014 · Cited by 149 · see citing works
“, 1994), and the induction of telomerase activity (Elenbaas et al., 2001; Farwell et al., 2000; Kiyono et al., 1998; Ramirez et al., 2001; Stampfer et al., 2001).”
BackgroundInfluential
Deoxycholic acid causes DNA damage while inducing apoptotic resistance through NF-κB activation in benign Barrett's epithelial cells.
Huo, X., Juergens, S., Zhang, X., Rezaei, D., Yu, C.-H., Strauch, E., Wang, J.-Y., Cheng, E., Meyer, F., Wang, D. H., et al. (2011) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00092.2011 · Cited by 148 · see citing works
“IEC-6 cells were cultured in DMEM with 10% FBS, and BAR-T cell lines were cocultured with a fibroblast feeder layer, as previously described (15, 26).”
Method
The Identification of Senescence-Specific Genes during the Induction of Senescence in Prostate Cancer Cells
Schwarze, S. R., Fu, V. X., Desotelle, J. A., Kenowski, M. L., & Jarrard, D. F. (2005) · Neoplasia · doi:10.1593/neo.05250 · Cited by 139 · see citing works
“SA-b-gal staining has been utilized to putatively identify this phenotype in aging human tissues and human cancers; however, this marker lacks specificity [19,20].”
Method
Increased gene dosage of Ink4a/Arf results in cancer resistance and normal agingPreprint
Matheu, A., Pantoja, C., Efeyan, A., Criado, L. M., Martín‐Caballero, J., Flores, J. M., Klatt, P., & Serrano, M. (2004) · Genes & Development · doi:10.1101/gad.310304 · Cited by 137 · see citing works
Role of Telomeres and Telomerase in the Pathogenesis of Human Cancer
Hahn, W. C. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.06.018 · Cited by 141 · see citing works
Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock
Munro, J., Barr, N. I., Ireland, H., Morrison, V., & Parkinson, E. K. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.01.017 · Cited by 141 · see citing works
Immortalisation and transformation revisited
Drayton, S. (2002) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(01)00271-4 · Cited by 126 · see citing works
Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformationPreprint
Woo, R. A., & Poon, R. Y. C. (2004) · Genes & Development · doi:10.1101/gad.1165204 · Cited by 123 · see citing works
A Comprehensive Review on Mesenchymal Stem Cell Growth and Senescence
Książek, K. (2009) · Rejuvenation Research · doi:10.1089/rej.2009.0830 · Cited by 131 · see citing works
“1 The seminal studies on the senescence of cultured fibroblasts by Hayflick and Moorhead 2,3 were reproduced extensively and broadened by a large number of investigators on other types of somatic cells, including lymphocytes 4 endothelial, 5 epithelial, 6 and mesothelial cells.”
Immortalization of Primary Human Prostate Epithelial Cells by c-Myc
Gil, J., Kerai, P., LLeonart, M. E., Bernard, D., Cigudosa, J. C., Peters, G. G., Carnero, A., & Beach, D. (2005) · Cancer Research · doi:10.1158/0008-5472.can-03-4030 · Cited by 129 · see citing works
CDK4 and cyclin D1 allow human myogenic cells to recapture growth property without compromising differentiation potential
Shiomi, K., Kiyono, T., Okamura, K., Uezumi, M., Goto, Y., Yasumoto, S., Shimizu, S., & Hashimoto, N. (2011) · Gene Therapy · doi:10.1038/gt.2011.44 · Cited by 130 · see citing works
Human UBN1 Is an Ortholog of Yeast Hpc2p and Has an Essential Role in the HIRA/ASF1a Chromatin-Remodeling Pathway in Senescent Cells
Gowrishankar, B., Somaiah, N., Zhang, R., Tang, Y., Hoffmann, J., Andrake, M., Ceulemans, H., Schultz, D., Marmorstein, R., & Adams, P. D. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01047-08 · Cited by 141 · see citing works
“Senescence is also caused by telomere attrition that results from repeated rounds of cell division (8, 45).”
Background
Molecular signaling and genetic pathways of senescence: Its role in tumorigenesis and aging
Zhang, H. (2006) · Journal of Cellular Physiology · doi:10.1002/jcp.20919 · Cited by 128 · see citing works
“However, these parameters lack the precise molecular basis and specificity (Robles and Adami, 1998; Severino et al., 2000; Ramirez et al., 2001; Romanov et al., 2001).”
BackgroundInfluential
Co-Expression of p16INK4A and Laminin 5 γ2 by Microinvasive and Superficial Squamous Cell Carcinomas in Vivo and by Migrating Wound and Senescent Keratinocytes in Culture
Natarajan, E., Saeb, M., Crum, C. P., Woo, S. B., McKee, P. H., & Rheinwald, J. G. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63677-2 · Cited by 114 · see citing works
“The mechanism responsible for inducing serial passage-related p16 expression in keratinocytes has not been characterized, although inadequate culture conditions hasten their p16related aging.(31) However, p16-dependent senescence in keratinocytes is clearly distinct from the telomere-sensitive, p53/p21-dependent repli…”
Background
NON‐CORONARY HEART DISEASE IN DIALYSIS PATIENTS: Hypertrophy and Fibrosis in the Cardiomyopathy of Uremia—Beyond Coronary Heart Disease
Groß, M.-L., & Ritz, E. (2008) · Seminars in Dialysis · doi:10.1111/j.1525-139x.2008.00454.x · Cited by 162 · see citing works
Molecular changes accompanying senescence and immortalization of cultured human mammary epithelial cells.
Yaswen, P., & Stampfer, M. (2002) · International Journal of Biochemistry and Cell Biology · doi:10.1016/s1357-2725(02)00047-x · Cited by 122 · see citing works
Genetic and Epigenetic Changes in Mammary Epithelial Cells May Mimic Early Events in Carcinogenesis
Tlsty, T. D., Crawford, Y., Holst, C. R., Fordyce, C., Zhang, J., McDermott, K. M., Kozakiewicz, K., & Gauthier, M. L. (2004) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1023/b:jomg.0000048773.95897.5f · Cited by 84 · see citing works
A three-dimensional model of differentiation of immortalized human bronchial epithelial cells
Vaughan, M. B., Ramirez, R. D., Wright, W. E., Minna, J. D., & Shay, J. W. (2006) · Differentiation · doi:10.1111/j.1432-0436.2006.00069.x · Cited by 114 · see citing works
Self-citation
Are there roles for brain cell senescence in aging and neurodegenerative disorders?
Tan, F. C. C., Hutchison, E. R., Eitan, E., & Mattson, M. P. (2014) · Biogerontology · doi:10.1007/s10522-014-9532-1 · Cited by 116 · see citing works
“…seen in response to long-term exposure to sub- cytotoxic doses of a number of stressors including oxidative stress (Chen et al. 1995), UVB radiation (Medrano et al. 1995), artificial and inadequate culture conditions ((Ramirez et al. 2001; Sherr and DePinho 2000) for a review; also see Fig.”

Authors: Ramirez, R. D., Morales, C. P., Herbert, B.-S., Rohde, J. M., Passons, C., Shay, J. W., & Wright, W. E.
Affiliations: The University of Texas Southwestern Medical Center (US)
ORCID: Herbert, Brittney-Shea
Shay, Jerry W.
Wright, Woodring E.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2001-02-15
Volume: 15
Issue: 4
Pages: 398-403
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.859201
PMC: PMC312628
OpenAlex: W2136840198
Cited by: 444
References: 0
Citations by year: 2026: 4 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 7 · 2017: 9 · 2016: 12 · 2015: 9 · 2014: 14 · 2013: 8 · 2012: 12
Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Ellison Medical Foundation
National Institute on Aging (AG 01228, R01AG001228)
Topics: Health Sciences › Medicine › Physiology › 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: replicative senescence, telomere shortening, telomerase, p16INK4a, retinoblastoma protein, cell immortalization, feeder layer, epithelial-mesenchymal interactions, keratinocytes, breast epithelial cells, fibroblasts, culture conditions
MeSH terms: Animals, Cell Division, Cell Line, Transformed, Culture Media, Epithelial Cells, Female, Fibroblasts, Humans, Mammary Glands, Animal, Skin, Keratinocytes, 3T3 Cells, Telomere, Cellular Senescence, Telomerase, Cyclin-Dependent Kinase Inhibitor p16, Mice

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

Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Record

About these checks