Open AccessAnti‐aging activity of the Ink4/Arf locus
Author(s) -
Matheu Ander,
Maraver Antonio,
Collado Manuel,
GarciaCao Isabel,
Cañamero Marta,
Borras Consuelo,
Flores Juana M.,
Klatt Peter,
Viña Jose,
Serrano Manuel
Publication year - 2009
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/j.1474-9726.2009.00458.x
Subject(s) - biology , locus (genetics) , longevity , ageing , gene , genetics , allele
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.