Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations
Open accessAbstract
Cancer is a disease of aging. The accumulation of mutations in individual cells over a lifetime is thought to be the reason. In this work, we explored an additional hypothesis: could p53 function decline with age, which would contribute to an enhanced mutation frequency and tumorigenesis in the aging process? The efficiency of the p53 response to γ-irradiation was found to decline significantly in various tissues of aging mice from several inbred strains, including lower p53 transcriptional activity and p53-dependent apoptosis. This decline resulted from a decreased stabilization of the p53 protein after stress. The function of the Ataxia-telangiectasia mutated (ATM) kinase declined significantly with age, which may then be responsible for the decline of the p53 response to radiation. Declining p53 responses to other stresses were also observed in the cultured splenocytes from aging mice. Interestingly, the time of onset of this decreased p53 response correlated with the life span of mice; mice that live longer delay their onset of decreased p53 activity with time. These results suggest an enhanced fixation of mutations in older individuals because of the declining fidelity of p53-mediated apoptosis or senescence in response to stress, and they suggest a plausible explanation for the correlation between tumorigenesis and the aging process.
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?
ROS levels in cells may be regulated by ATM kinase, and age-related declines in ATM expression can increase ROS.
“Levels of ROS in cells may also be regulated by ataxia telangiectasia mutated (ATM) kinase, and age-related declines in expression of ATM can result in an increase in ROS in cells (77,78).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [77]
As p53 response efficiency declines during aging, aerobic glycolysis is increased as well as the proinflammatory SASP via NF-κB signaling.
“As the p53 response efficiency declines during aging [228], aerobic glycolysis is increased as well as the proinflammatory SASP via NF-κB signaling [155].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [228]
Signaling from ATM and the response of other DNA repair proteins declines with age.
“For example, signaling from the DNA damage kinase, ATM, and the response of other DNA repair proteins declines with age (Feng et al., 2007, Gorbunova et al., 2007).”
From Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression (2011) · cites this paper as Feng et al., 2007
There is a decrease in p53 function with age.
“Similarly, there is a decrease in p53 function with age (Feng et al., 2007).”
From Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression (2011) · cites this paper as Feng et al., 2007
Cites
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466 · 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 · see citing works
The plasticity of aging: insights from long-lived mutants
Kenyon, C. (2005) · Cell · doi:10.1016/j.cell.2005.02.002 · Cited by 1,338 · see citing works
p16INK4a induces an age-dependent decline in islet regenerative potential
Krishnamurthy, J., Ramsey, M. R., Ligon, K. L., Torrice, C., Koh, A., Bonner-Weir, S., & Sharpless, N. E. (2006) · Nature · doi:10.1038/nature05092 · Cited by 1,003 · 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
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
AMP-Activated Protein Kinase (AMPK) Controls the Aging Process via an Integrated Signaling Network
Salminen, A., & Kaarniranta, K. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2011.12.005 · Cited by 860 · see citing works
Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function
Hu, W., Zhang, C., Wu, R., Sun, Y., Levine, A., & Feng, Z. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001006107 · Cited by 862 · see citing works
Self-citationCauses, consequences, and reversal of immune system aging
Montecino-Rodriguez, E., Berent-Maoz, B., & Dorshkind, K. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64096 · Cited by 793 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
DNA damage checkpoints in stem cells, ageing and cancer
Sperka, T., Wang, J., & Rudolph, K. L. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3420 · Cited by 393 · see citing works
Paradoxical suppression of cellular senescence by p53
Demidenko, Z. N., Korotchkina, L. G., Gudkov, A. V., & Blagosklonny, M. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002298107 · Cited by 273 · see citing works
Regulation of the aging process by autophagy.
Salminen, A., & Kaarniranta, K. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.03.004 · Cited by 270 · see citing works
Do DNA Double-Strand Breaks Drive Aging?
White, R. R., & Vijg, J. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.08.004 · Cited by 232 · see citing works
Stressin’ Sestrins take an aging fight
Budanov, A. V., Lee, J. H., & Karin, M. (2010) · EMBO Molecular Medicine · doi:10.1002/emmm.201000097 · Cited by 208 · see citing works
The many faces of p53: something for everyone
Levine, A. J. (2019) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjz026 · Cited by 163 · see citing works
Self-citationLiu, L., Charville, G. W., Cheung, T. H., Yoo, B., Santos, P. J., Schroeder, M., & Rando, T. A. (2018) · Cell Stem Cell · doi:10.1016/j.stem.2018.08.019 · Cited by 156 · see citing works
Apoptosis and aging: increased resistance to apoptosis enhances the aging process
Salminen, A., Ojala, J., & Kaarniranta, K. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0597-y · Cited by 158 · see citing works
Eischen, C. M. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026096 · Cited by 161 · see citing works
The effects of p53 on whole organism longevity are mediated by autophagy
Tavernarakis, N., Pasparaki, A., Tasdemir, E., Maiuri, M. C., & Kroemer, G. (2008) · Autophagy · doi:10.4161/auto.6730 · Cited by 132 · 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
The p53 pathway in hematopoiesis: lessons from mouse models, implications for humans
Pant, V., Quintás-Cardama, A., & Lozano, G. (2012) · Blood · doi:10.1182/blood-2012-05-356014 · Cited by 129 · see citing works
Hirota, Y., Cha, J., Yoshie, M., Daikoku, T., & Dey, S. K. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1108180108 · Cited by 125 · see citing works
DNA repair and aging: The impact of the p53 family
Nicolai, S., Rossi, A., Di Daniele, N., Melino, G., Annicchiarico-Petruzzelli, M., & Raschellà, G. (2015) · Aging · doi:10.18632/aging.100858 · Cited by 118 · see citing works
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 · see citing works
Aylon, Y., & Oren, M. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.10.002 · Cited by 106 · 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
Dasatinib plus quercetin prevents uterine age-related dysfunction and fibrosis in mice
Cavalcante, M. B., Saccon, T. D., Nunes, A. D. C., Kirkland, J. L., Tchkonia, T., Schneider, A., & Masternak, M. M. (2020) · Aging · doi:10.18632/aging.102772 · Cited by 80 · see citing works
Reversing the aging stromal phenotype prevents carcinoma initiation
Lewis, D. A., Travers, J. B., Machado, C., Somani, A.-K., & Spandau, D. F. (2011) · Aging · doi:10.18632/aging.100318 · Cited by 66 · see citing works
Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression
Lushnikova, T., Bouska, A., Odvody, J., Dupont, W. D., & Eischen, C. M. (2011) · Oncogene · doi:10.1038/onc.2011.172 · Cited by 40 · see citing works
Jodar, L., Mercken, E. M., Ariza, J., Younts, C., Gonzalez-Reyes, J. A., Alcain, F. J., Buron, I., de Cabo, R., & Villalba, J. M. (2011) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glq181 · Cited by 33 · see citing works
- Authors
- Feng, Z., Hu, W., Teresky, A. K., Hernando, E., Cordon-Cardo, C., & Levine, A. J.
- Affiliations
- Rutgers Cancer Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Department of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY 10021; and
- Institute for Advanced Study (US)
- Corresponding author
- Levine, Arnold J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-10-16
- Volume
- 104
- Issue
- 42
- Pages
- 16633-16638
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2034252
- OpenAlex
- W2009986955
- Cited by
- 264
- References
- 5
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 8 · 2023: 13 · 2022: 11 · 2021: 13 · 2020: 12 · 2019: 12 · 2018: 8 · 2017: 8 · 2016: 14 · 2015: 14 · 2014: 14 · 2013: 20 · 2012: 16
- FWCI
- 11.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA087497, CA087497)
- 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
- aging, ATM kinase, radiation-induced apoptosis, p53 transcriptional activity, mutation accumulation, senescence, lifespan, inbred mouse strains, splenocytes
- MeSH terms
- Aging, Animals, DNA-Binding Proteins, Female, Male, Mutation, Neoplasms, Transcription, Genetic, Tumor Suppressor Protein p53, Mutagenesis, Cheirogaleidae, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Mice, Ataxia Telangiectasia Mutated Proteins
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
