Modulation of mammalian life span by the short isoform of p53
Open accessAbstract
Overexpression of the short isoform of p53 (p44) has unexpectedly uncovered a role for p53 in the regulation of size and life span in the mouse. Hyperactivation of the insulin-like growth factor (IGF) signaling axis by p44 sets in motion a kinase cascade that clamps potentially unimpeded growth through p21Cip1. This suggests that pathways of gene activity known to regulate longevity in lower organisms are linked in mammals via p53 to mechanisms for controlling cell proliferation. Thus, appropriate expression of the short and long p53 isoforms might maintain a balance between tumor suppression and tissue regeneration, a major requisite for long mammalian life span.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
In mice, chronically active p53 both promotes cellular senescence and accelerates aging phenotypes.
“Moreover, in mice, chronically active p53 both promotes cellular senescence and accelerates aging phenotypes [ 31 , 32 ].”
From Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor (2008) · cites this paper as [31]
Cells from these modified mice were more susceptible to both p53-mediated apoptosis and p53-mediated senescence.
“Cells from these modified mice were more susceptible to both p53-mediated apoptosis (Tyner et al., 2002) and p53-mediated senescence (Maier et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Maier et al., 2004
In genetically modified mice, p53 function was enhanced either by low-level expression of an artificially truncated p53 protein or modest overexpression of a naturally occurring short isoform.
“Evidence for this idea comes from the phenotype of genetically modified mice in which p53 function was enhanced either by low-level expression of an artificially truncated p53 protein (Tyner et al., 2002; Maier et al., 2004) or modest overexpression of a naturally occurring short isoform (Maier et al., 2004).”
From Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors (2005) · cites this paper as Maier et al., 2004
p53 deficiency attenuates degenerative phenotypes associated with telomere dysfunction, whereas constitutively activated p53 accelerates ageing phenotypes.
“p53 deficiency markedly attenuates the degenerative phenotypes associated with telomere dysfunction, whereas constitutively activated p53 accelerates ageing phenotypes15-18.”
From Telomere dysfunction induces metabolic and mitochondrial compromise (2011) · cites this paper as [17]
Two mouse strains that express C-terminal p53 fragments along with full-length p53 show accelerated aging phenotypes and a lower incidence of malignancy.
“However, two mouse strains that express C-terminal p53 fragments along with full-length p53 have been reported to show accelerated aging phenotypes and a lower incidence of malignancy (Maier et al., 2004; Tyner et al., 2002”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Maier et al., 2004
Sirt6-deficient mice add to a growing but poorly understood connection between genomic instability and altered IGF-1 signalling, as insulin-IGF signalling is also perturbed in other mouse models of accelerated ageing, including animals with increased p53 activity and mice lacking the NER enzyme ERCC4.
“The Sirt6 -deficient mice therefore add to a growing but poorly understood connection between genomic instability and altered IGF-1 signalling, as insulin-IGF signalling is also perturbed in other mouse models of accelerated ageing, including animals with increased p53 activity 30 and mice lacking the NER enzyme ERCC4 39”
From The common biology of cancer and ageing (2007) · cites this paper as [30]
Mice genetically engineered to express altered isoforms of p53 with increased activity seem to be resistant to cancer but age prematurely.
“mice that are genetically engineered to express altered isoforms of p53 with increased activity seem to be resistant to cancer but age prematurely 29, 30”
From The common biology of cancer and ageing (2007) · cites this paper as [30]
Cites
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510 · see citing works
IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice
Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Géloën, A., Even, P. C., Cervera, P., & Le Bouc, Y. (2003) · Nature · doi:10.1038/nature01298 · Cited by 2,109 · see citing works
Lin, S.-J., Defossez, P.-A., & Guarente, L. (2000) · Science · doi:10.1126/science.289.5487.2126 · Cited by 1,775 · see citing works
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 2× · see citing works
“Our results confirm results reported last year that p53 status affects mammalian aging (Tyner et al. 2002).”
BackgroundResultReversal 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
Flagged first, then by citations
Cited by
Sorted by citations
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · see citing works
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
Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302 · see citing works
“accelerates aging phenotypes [31,32].”
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
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
“DNA-SCARS include dysfunctional telomeres or telomere dysfunction–induced foci (TIF; d’Adda di Fagagna et al., 2003; Takai et al., 2003; Herbig et al., 2004; Kim et al., 2004). replication fork collapse (Bartkova et al., 2006; Di Micco et al., 2006; Mallette et al., 2007).”
Senescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766 · see citing works
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
p53 Regulates Mitochondrial Respiration
Matoba, S., Kang, J.-G., Patino, W. D., Wragg, A., Boehm, M., Gavrilova, O., Hurley, P. J., Bunz, F., & Hwang, P. M. (2006) · Science · doi:10.1126/science.1126863 · Cited by 1,650 · see citing works
Telomere dysfunction induces metabolic and mitochondrial compromise
Sahin, E., Colla, S., Liesa, M., Moslehi, J., Müller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., et al. (2011) · Nature · doi:10.1038/nature09787 · Cited by 1,319 · see citing works
The common biology of cancer and ageing
Finkel, T., Serrano, M., & Blasco, M. A. (2007) · Nature · doi:10.1038/nature05985 · Cited by 988 · see citing works
DNA Repair, Genome Stability, and Aging
Lombard, D. B., Chua, K. F., Mostoslavsky, R., Franco, S., Gostissa, M., & Alt, F. W. (2005) · Cell · doi:10.1016/j.cell.2005.01.028 · Cited by 944 · see citing works
p53 isoforms can regulate p53 transcriptional activity
Bourdon, J.-C., Fernandes, K., Murray-Zmijewski, F., Liu, G., Diot, A., Xirodimas, D. P., Saville, M. K., & Lane, D. P. (2005) · Genes & Development · doi:10.1101/gad.1339905 · Cited by 810 · see citing works
Linking functional decline of telomeres, mitochondria and stem cells during ageing
Sahin, E., & DePinho, R. A. (2010) · Nature · doi:10.1038/nature08982 · Cited by 759 · see citing works
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 · see citing works
Vascular Cell Senescence: Contribution to Atherosclerosis
Minamino, T., & Komuro, I. (2007) · Circulation Research · doi:10.1161/01.res.0000256837.40544.4a · Cited by 542 · see citing works
Coping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522 · see citing works
Delayed ageing through damage protection by the Arf/p53 pathway
Matheu, A., Maraver, A., Klatt, P., Flores, I., Garcia-Cao, I., Borras, C., Flores, J. M., Viña, J., Blasco, M. A., & Serrano, M. (2007) · Nature · doi:10.1038/nature05949 · Cited by 466 · see citing works
The p53 network: cellular and systemic DNA damage responses in aging and Cancer
Reinhardt, H. C., & Schumacher, B. (2012) · Trends in Genetics · doi:10.1016/j.tig.2011.12.002 · Cited by 458 · see citing works
DNA damage responses and p53 in the aging process
Ou, H.-L., & Schumacher, B. (2018) · Blood · doi:10.1182/blood-2017-07-746396 · Cited by 377 · see citing works
The role of DNA damage and repair in aging through the prism of Koch-like criteria
Moskalev, A. A., Shaposhnikov, M. V., Plyusnina, E. N., Zhavoronkov, A., Budovsky, A., Yanai, H., & Fraifeld, V. E. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2012.02.001 · Cited by 387 · see citing works
Tarragó, M. G., Chini, C. C. S., Kanamori, K. S., Warner, G. M., Caride, A., de Oliveira, G. C., Rud, M., Samani, A., Hein, K. Z., Huang, R., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.016 · Cited by 384 · see citing works
Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation
Inomata, K., Aoto, T., Binh, N. T., Okamoto, N., Tanimura, S., Wakayama, T., Iseki, S., Hara, E., Masunaga, T., Shimizu, H., et al. (2009) · Cell · doi:10.1016/j.cell.2009.03.037 · Cited by 368 · see citing works
CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels
Chini, C. C. S., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., Gomez, L. S., Hogan, K. A., Tarragó, M. G., Puranik, A. S., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00298-z · Cited by 349 · see citing works
Coordination and communication between the p53 and IGF-1–AKT–TOR signal transduction pathways
Levine, A. J., Feng, Z., Mak, T. W., You, H., & Jin, S. (2006) · Genes & Development · doi:10.1101/gad.1363206 · Cited by 321 · see citing works
DNA damage response and metabolic disease
Shimizu, I., Yoshida, Y., Suda, M., & Minamino, T. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.008 · Cited by 286 · see citing works
Changes in Regenerative Capacity through Lifespan
Yun, M. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161025392 · Cited by 216 · see citing works
p53, ROS and senescence in the control of aging
Vigneron, A., & Vousden, K. H. (2010) · Aging · doi:10.18632/aging.100189 · Cited by 221 · see citing works
Tumor suppression and normal aging in mice with constitutively high p53 activity
Mendrysa, S. M., O'Leary, K. A., McElwee, M. K., Michalowski, J., Eisenman, R. N., Powell, D. A., & Perry, M. E. (2006) · Genes & Development · doi:10.1101/gad.1378506 · Cited by 210 · see citing works
Deconstructing p53 transcriptional networks in tumor suppression
Bieging, K. T., & Attardi, L. D. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.10.006 · Cited by 194 · see citing works
Kim, H., Chang, J., Shao, L., Han, L., Iyer, S., Manolagas, S. C., O'Brien, C. A., Jilka, R. L., Zhou, D., & Almeida, M. (2017) · Aging Cell · doi:10.1111/acel.12597 · Cited by 192 · see citing works
Cancer and ageing: convergent and divergent mechanisms
Serrano, M., & Blasco, M. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2242 · Cited by 182 · see citing works
Insulin/IGF-1 paradox of aging: Regulation via AKT/IKK/NF-κB signaling
Salminen, A., & Kaarniranta, K. (2010) · Cellular Signalling · doi:10.1016/j.cellsig.2009.10.006 · Cited by 177 · see citing works
Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program
Edwards, M. G., Anderson, R. M., Yuan, M., Kendziorski, C. M., Weindruch, R., & Prolla, T. A. (2007) · BMC Genomics · doi:10.1186/1471-2164-8-80 · Cited by 174 · see citing works
Insulin‐like growth factor‐1 regulates the <scp>SIRT</scp> 1‐p53 pathway in cellular senescence
Tran, D., Bergholz, J., Zhang, H., He, H., Wang, Y., Zhang, Y., Li, Q., Kirkland, J. L., & Xiao, Z. (2014) · Aging Cell · doi:10.1111/acel.12219 · Cited by 161 · see citing works
“Indeed, transgenic mice bearing hyperactive p53 alleles exhibit increased circulating levels of IGF1 and accelerated aging phenotypes (Tyner et al., 2002; Maier et al., 2004).”
BackgroundGenetics of Longevity and Aging
Vijg, J., & Suh, Y. (2005) · Annual Review of Medicine · doi:10.1146/annurev.med.56.082103.104617 · Cited by 142 · see citing works
p21 Both Attenuates and Drives Senescence and Aging in BubR1 Progeroid Mice
Baker, D. J., Weaver, R. L., & van Deursen, J. M. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.03.028 · Cited by 130 · see citing works
Sex-specific regulation of aging and apoptosis
Tower, J. (2006) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2006.05.001 · Cited by 125 · see citing works
Systemic DNA damage responses in aging and diseases
Ribezzo, F., Shiloh, Y., & Schumacher, B. (2016) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2015.12.005 · Cited by 116 · see citing works
Increased p53 activity does not accelerate telomere‐driven ageing
García‐Cao, I., García‐Cao, M., Tomás‐Loba, A., Martin‐Caballero, J., Flores, J. M., Klatt, P., Blasco, M. A., & Serrano, M. (2006) · The EMBO Reports · doi:10.1038/sj.embor.7400667 · Cited by 102 · see citing works
p53 at the crossroads between cancer and neurodegeneration
Lanni, C., Racchi, M., Memo, M., Govoni, S., & Uberti, D. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.02.034 · Cited by 95 · see citing works
Immunity and cognition: what do age-related dementia, HIV-dementia and ‘chemo-brain’ have in common?
Kipnis, J., Derecki, N. C., Yang, C., & Scrable, H. (2008) · Trends in Immunology · doi:10.1016/j.it.2008.07.007 · Cited by 90 · see citing works
Self-citationGannon, H. S., Donehower, L. A., Lyle, S., & Jones, S. N. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.02.007 · Cited by 87 · see citing works
Atas-Ozcan, H., Brault, V., Duchon, A., & Herault, Y. (2021) · Genes · doi:10.3390/genes12111833 · Cited by 78 · see citing works
Ohtani, N., Imamura, Y., Yamakoshi, K., Hirota, F., Nakayama, R., Kubo, Y., Ishimaru, N., Takahashi, A., Hirao, A., Shimizu, T., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706949104 · Cited by 73 · see citing works
Pekovic, V., & Hutchison, C. J. (2008) · Journal of Anatomy · doi:10.1111/j.1469-7580.2008.00928.x · Cited by 75 · see citing works
Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence
Collin, G., Huna, A., Warnier, M., Flaman, J.-M., & Bernard, D. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-0300-z · Cited by 71 · see citing works
Molecular and cellular aspects of age-related cognitive decline and Alzheimer’s disease
Hullinger, R., & Puglielli, L. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.05.008 · Cited by 68 · see citing works
The yin and yang of the Cdkn2a locus in senescence and aging
Baker, D. J., Jin, F., & van Deursen, J. M. (2008) · Cell Cycle · doi:10.4161/cc.7.18.6687 · Cited by 56 · see citing works
p53: Pro-aging or pro-longevity?
de Keizer, P. L. J., Laberge, R.-M., & Campisi, J. (2010) · Aging · doi:10.18632/aging.100178 · Cited by 48 · see citing works
Reassessing the role of p53 in cancer and ageing from an evolutionary perspective
Aranda-Anzaldo, A., & Dent, M. A. R. (2007) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2007.01.001 · Cited by 36 · see citing works
Removing all obstacles: A critical role for p53 in promoting tissue renewal
Schoppy, D. W., Ruzankina, Y., & Brown, E. J. (2010) · Cell Cycle · doi:10.4161/cc.9.7.11194 · Cited by 32 · see citing works
Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?
Chesnokova, V., & Pechnick, R. N. (2008) · Cell Cycle · doi:10.4161/cc.6446 · Cited by 19 · see citing works
Fiorini, A., Sultana, R., Barone, E., Cenini, G., Perluigi, M., Mancuso, C., Cai, J., Klein, J. B., St. Clair, D., & Butterfield, D. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049846 · Cited by 16 · see citing works
Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri
Priami, C., De Michele, G., Cotelli, F., Cellerino, A., Giorgio, M., Pelicci, P. G., & Migliaccio, E. (2015) · Aging and Disease · doi:10.14336/ad.2014.0228 · Cited by 16 · see citing works
What do we need to know and understand about p53 to improve its clinical value?
Salomao, N., Karakostis, K., Hupp, T., Vollrath, F., Vojtesek, B., & Fahraeus, R. (2021) · The Journal of Pathology · doi:10.1002/path.5677 · Cited by 15 · see citing works
Making Young Tumors Old: A New Weapon Against Cancer?
Sage, J. (2005) · Science of Aging Knowledge Environment · doi:10.1126/sageke.2005.33.pe25 · Cited by 9 · see citing works
- Authors
- Maier, B., Gluba, W., Bernier, B., Turner, T., Mohammad, K., Guise, T., Sutherland, A., Thorner, M., & Scrable, H.
- Affiliations
- University of Virginia (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2004-02-01
- Volume
- 18
- Issue
- 3
- Pages
- 306-319
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC338283
- OpenAlex
- W2142205521
- Cited by
- 586
- References
- 5
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 14 · 2023: 13 · 2022: 12 · 2021: 15 · 2020: 23 · 2019: 18 · 2018: 22 · 2017: 21 · 2016: 18 · 2015: 21 · 2014: 18 · 2013: 41 · 2012: 30
- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG020915, AG20915)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK07766, T32DK007766)
- National Center for Research Resources (R24RR011102, RR11102)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD034807)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- p44, longevity, insulin-like growth factor signaling, p21, cell proliferation, tumor suppression, tissue regeneration
- MeSH terms
- Aging, Animals, Bone and Bones, Cell Division, Cell Survival, Growth, Longevity, Mice, Transgenic, Somatomedins, Transfection, Signal Transduction, Genes, p53, Tumor Suppressor Protein p53, Protein Isoforms, 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
