Modelling the p53/p66Shc Aging Pathway in the Shortest Living Vertebrate Nothobranchius Furzeri
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Oxidative stress induced by reactive oxygen species (ROS) increases during lifespan and is involved in aging processes. The p66Shc adaptor protein is a master regulator of oxidative stress response in mammals. Ablation of p66Shc enhances oxidative stress resistance both in vitro and in vivo. Most importantly, it has been demonstrated that its deletion retards aging in mice. Recently, new insights in the molecular mechanisms involving p66Shc and the p53 tumor suppressor genes were given: a specific p66Shc/p53 transcriptional regulation pathway was uncovered as determinant in oxidative stress response and, likely, in aging. p53, in a p66Shc-dependent manner, negatively downregulates the expression of 200 genes which are involved in the G2/M transition of mitotic cell cycle and are downregulated during physiological aging. p66Shc modulates the response of p53 by activating a p53 isoform (p44/p53, also named Delta40p53). Based on these latest results, several developments are expected in the future, as the generation of animal models to study aging and the evaluation of the use of the p53/p66Shc target genes as biomarkers in aging related diseases. The aim of this review is to investigate the conservation of the p66Shc and p53 role in oxidative stress between fish and mammals. We propose to approach this study trough a new model organism, the annual fish Nothobranchius furzeri, that has been demonstrated to develop typical signs of aging, like in mammals, including senescence, neurodegeneration, metabolic disorders and cancer.
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Several proapoptotic pathways (e.g., P53, p66Shc) enhance mPTP activity.
“In contrast, several proapoptotic pathways (e.g., P53, p66Shc) enhance mPTP activity [122,123,124,125].”
From The mitochondrial permeability transition: Nexus of aging, disease and longevity (2021) · cites this paper as [124]
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Kojima, T., Yoshikawa, Y., Takada, S., Sato, M., Nakamura, T., Takahashi, N., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., & Mori, N. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5080 · Cited by 25 · see citing works
Davidson, W. R., Kari, C., Ren, Q., Daróczi, B., Dicker, A. P., & Rodeck, U. (2010) · BMC Developmental Biology · doi:10.1186/1471-213x-10-102 · Cited by 23 · see citing works
Stoner, C. S., Pearson, G. D., Koç, A., Merwin, J. R., Lopez, N. I., & Merrill, G. F. (2009) · Biochemistry · doi:10.1021/bi900757q · Cited by 18 · see citing works
Jeon, H., & Lee, H. (2013) · FEBS Journal · doi:10.1111/febs.12153 · Cited by 17 · see citing works
Aoto, M., Sato, K.-I., Takeba, S., Horiuchi, Y., Iwasaki, T., Tokmakov, A. A., & Fukami, Y. (1999) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.0624 · Cited by 16 · see citing works
Bras, M. L., Bensaad, K., & Soussi, T. (2003) · Oncogene · doi:10.1038/sj.onc.1206424 · Cited by 13 · see citing works
Yamaguchi, F., Yamaguchi, K., Tokuda, M., & Brenner, S. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01210-7 · Cited by 11 · see citing works
Assessing Vascular Senescence in Zebrafish
Donnini, S., Giachetti, A., & Ziche, M. (2012) · Methods in molecular biology · doi:10.1007/978-1-62703-239-1_34 · Cited by 10 · see citing works
Molecular cloning and characterization of an adaptor protein Shc isoform from Xenopus laevis oocytes
Chesnel, F., Héligon, C., Richard‐Parpaillon, L., & Boujard, D. (2003) · Biology of the Cell · doi:10.1016/s0248-4900(03)00058-3 · Cited by 4 · see citing works
Flagged first, then by citations
1 of the 95 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Rottenberg, H., & Hoek, J. B. (2017) · Aging Cell · doi:10.1111/acel.12650 · Cited by 275 · see citing works
The African turquoise killifish: A research organism to study vertebrate aging and diapause
Hu, C., & Brunet, A. (2018) · Aging Cell · doi:10.1111/acel.12757 · Cited by 165 · see citing works
Mitochondria and Calcium Regulation as Basis of Neurodegeneration Associated With Aging
Müller, M., Ahumada-Castro, U., Sanhueza, M., González-Billault, C. E., Court, F. A., & Cárdenas, C. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00470 · Cited by 124 · see citing works
Kent, A. C., Baradie, K. B. Y. E., & Hamrick, M. W. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6626484 · Cited by 107 · see citing works
The mitochondrial permeability transition: Nexus of aging, disease and longevity
Rottenberg, H., & Hoek, J. B. (2021) · Cells · doi:10.3390/cells10010079 · Cited by 94 · see citing works
Matsui, H., Kenmochi, N., & Namikawa, K. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.015 · Cited by 70 · see citing works
Age-dependent increase of oxidative stress regulates microRNA-29 family preserving cardiac health
Heid, J., Cencioni, C., Ripa, R., Baumgart, M., Atlante, S., Milano, G., Scopece, A., Kuenne, C. T., Günther, S., Azzimato, V., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-16829-w · Cited by 69 · see citing works
Self-citationBamshad, C., Roudkenar, M. H., Abedinzade, M., Yousefzadeh-Chabok, S., Pourmohammadi-Bejarpasi, Z., Najafi-Ghalehlou, N., Sato, T., Tomita, K., Jahanian‐Najafabadi, A., Feizkhah, A., et al. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110106 · Cited by 47 · see citing works
Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases
Jęśko, H. M., & Strosznajder, R. P. (2016) · Folia Neuropathologica · doi:10.5114/fn.2016.62531 · Cited by 44 · see citing works
P66Shc-SIRT1 Regulation of Oxidative Stress Protects Against Cardio-cerebral Vascular Disease
Kong, X., Guan, J., Li, J., Wei, J., & Wang, R. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0073-2 · Cited by 36 · see citing works
Wang, Y., LIU, T., Pan, W., Chi, H., Chen, J., Yu, Z., & Chen, C. (2015) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2015.2921 · Cited by 17 · see citing works
Huang, K., Jiang, L., Huang, W., Li, X., Lu, Y., Jiang, J., Zhou, S., Wang, Y., & Xie, J. (2023) · Aquaculture · doi:10.1016/j.aquaculture.2023.739780 · Cited by 11 · see citing works
Effect of Polypeptides on Cell Proliferation and Apoptosis during Aging
Ryzhak, A. P., Chalisova, N. I., Linkova, N. S., Ничик, Т. Е., Дудков, А. В., Колчина, Н. В., Ryzhak, G. A., & Khalimov, R. I. (2017) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-017-3655-8 · Cited by 7 · see citing works
li, C., Winberg, S., Sun, C., & Schiöth, H. B. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103064 · Cited by 4 · see citing works
Guan, B., Qi, F., & Tian, Y. (2020) · Translational Andrology and Urology · doi:10.21037/tau.2020.01.34 · Cited by 1 · see citing works
Targeting p66Shc by natural-derived and synthetic compounds in organ toxicity
Yarmohammadi, F., Shabani, S., & Karimi, G. (2026) · Human & Experimental Toxicology · doi:10.1177/09603271261494653
- Authors
- Priami, C., De Michele, G., Cotelli, F., Cellerino, A., Giorgio, M., Pelicci, P. G., & Migliaccio, E.
- Affiliations
- University of Milan (IT)
- Scuola Normale Superiore (IT)
- European Institute of Oncology (IT)
- Venue
- Aging and Disease
- Publisher
- Aging and Disease
- Published
- 2015
- Volume
- 6
- Issue
- 2
- Pages
- 95
- ISSN
- 2152-5250 (ISSN-L)
- PMC
- PMC4365960
- OpenAlex
- W2034889054
- Cited by
- 16
- References
- 95
- Citations by year
- 2026: 2 · 2023: 2 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 1
- FWCI
- 0.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Aging and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scuola Normale Superiore di Pisa (submittedVersion, other-oa)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by)
- Funders
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- p53, p66Shc, aging, oxidative stress, reactive oxygen species, Nothobranchius furzeri, annual killifish, p53 isoforms, Δ40p53, transcriptional regulation, G2/M phase, senescence, neurodegeneration, aging biomarkers
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 ›
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