Anti-aging activity of the Ink4/Arf locus |
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Authors: | Ander Matheu † Antonio Maraver Manuel Collado Isabel Garcia-Cao Marta Cañamero Consuelo Borras Juana M Flores Peter Klatt Jose Viña Manuel Serrano |
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Institution: | Tumor Suppression Group; Comparative Pathology Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Department of Physiology, University of Valencia, Valencia, Spain; Department of Animal Surgery and Medicine, Complutense University, Madrid, Spain |
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Abstract: | The proteins encoded by the Ink4/Arf locus, p16Ink4a, p19Arf and p15Ink4b 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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Keywords: | anti-aging antioxidant ARF cellular senescence DNA damage Ink4a life-span studies cancer aging tumor suppression p16Ink4a p53 |
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