The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
Anti‐aging activity of the Ink4/Arf locus
Abstract
Summary: The proteins encoded by the Ink4/Arf locus, p16 Ink4a , p19 Arf and p15 Ink4b are major tumour suppressors that oppose aberrant mitogenic signals. The expression levels of the locus are progressively increased during aging and genome‐wide association studies have linked the locus to a number of aging‐associated diseases and frailty in humans. However, direct measurement of the global impact of the Ink4/Arf locus on organismal aging and longevity was lacking. In this work, we have examined the fertility, cancer susceptibility, aging and longevity of mice genetically modified to carry one ( Ink4/Arf ‐tg) or two ( Ink4/Arf ‐tg/tg) intact additional copies of the locus. First, increased gene dosage of Ink4/Arf impairs the production of male germ cells, and in the case of Ink4/Arf ‐tg/tg mice results in a Sertoli cell‐only‐like syndrome and a complete absence of sperm. Regarding cancer, there is a lower incidence of aging‐associated cancer proportional to the Ink4/Arf gene dosage. Interestingly, increased Ink4/Arf gene dosage resulted in lower scores in aging markers and in extended median longevity. The increased survival was also observed in cancer‐free mice indicating that cancer protection and delayed aging are separable activities of the Ink4/Arf locus. In contrast to these results, mice carrying one or two additional copies of the p53 gene ( p53 ‐tg and p53 ‐tg/tg) had a normal longevity despite their increased cancer protection. We conclude that the Ink4/Arf locus has a global anti‐aging effect, probably by favouring quiescence and preventing unnecessary proliferation.
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“mice with a mild and systemic increase in p16Ink4a, p19Arf or p53 tumor suppressors exhibit extended longevity, which cannot be accounted for by their lower cancer incidence”
From The Hallmarks of Aging (2013) · cites this paper as Matheu et al., 2009
In the citing paper
“A moderate enhancement of the senescence-inducing tumor suppressor pathways may extend longevity”
From The Hallmarks of Aging (2013) · cites this paper as Matheu et al., 2009
Citations
Cites
Ink4a/Arf expression is a biomarker of aging
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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×
“First, male sterility has not been reported for a variety of genetic modifications that upregulate p53 (Garcia-Cao et al., 2002; Tyner et al., 2002; Matheu et al., 2004; Mendrysa et al., 2006; Matheu et al., 2007), although there is one exception (Maier et al., 2004).”
BackgroundStem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006) · Nature · doi:10.1038/nature05159 · Cited by 1,106
Cellular Senescence in Aging Primates
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The Regulation of INK4/ARF in Cancer and Aging
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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 · cited 3×
“It is interesting to note that the effects of a transgenic allele constitutively overexpressing p16 (from 2- to 20-fold depending on the tissue), were minimal or absent in the pancreatic islets and in the neural stem cells of old mice (Krishnamurthy et al., 2006; Molofsky et al., 2006).”
BackgroundIncreasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing
Molofsky, A. V., Slutsky, S. G., Joseph, N. M., He, S., Pardal, R., Krishnamurthy, J., Sharpless, N. E., & Morrison, S. J. (2006) · Nature · doi:10.1038/nature05091 · Cited by 972 · cited 3×
“It is interesting to note that the effects of a transgenic allele constitutively overexpressing p16 (from 2- to 20-fold depending on the tissue), were minimal or absent in the pancreatic islets and in the neural stem cells of old mice (Krishnamurthy et al., 2006; Molofsky et al., 2006).”
BackgroundRegulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all
Gil, J., & Peters, G. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1987 · Cited by 843
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BackgroundZindy, F., Quelle, D. E., Roussel, M. F., & Sherr, C. J. (1997) · Oncogene · doi:10.1038/sj.onc.1201178 · Cited by 574
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Metadata
- Authors
- Matheu, A., Maraver, A., Collado, M., Garcia‐Cao, I., Cañamero, M., Borras, C., Flores, J. M., Klatt, P., Viña, J., & Serrano, M.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2009-03-26
- Volume
- 8
- Issue
- 2
- Pages
- 152-161
- ISSN
- 1474-9718
- 1474-9726
- Cited by
- 94
- References
- 16
- Language
- en
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