Journal
AGING CELL
Volume 8, Issue 2, Pages 152-161Publisher
WILEY
DOI: 10.1111/j.1474-9726.2009.00458.x
Keywords
anti-aging; antioxidant; ARF; cellular senescence; DNA damage; Ink4a; life-span studies; cancer; aging; tumor suppression; p16Ink4a; p53
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Funding
- Spanish Ministry of Education and Science (MEC) [(SAF2005-03018]
- 'Juan de la Cierva' Program (MEC)
- MC
- Government of Madrid (GsSTEM)
- European Union
- 'Marcelino Botin' Foundation
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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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