Insights into aging obtained from p53 mutant mouse models

Annals of the New York Academy of Sciences
Melissa DumbleLawrence A Donehower

Abstract

Cancer suppression is an integral component of longevity in organisms with renewable tissues. A number of genes in the mammalian genome function in cancer prevention, and some of these have been directly implicated in longevity assurance. One such longevity assurance gene is the tumor suppressor p53, a transcription factor that is mutated or dysregulated in most human cancers. Early studies have linked p53 to the induction of cellular senescence, whereas recent reports implicate it as a potential regulator of organismal aging. We have shown by gene inactivation studies that loss of p53 function enhances tumor susceptibility and reduces longevity in the mouse. A recent serendipitously generated p53 mutant allele resulted in a hypermorphic version of p53 that displays increased cancer resistance, yet also mediates decreased longevity. The reduced longevity is accompanied by the accelerated onset of a variety of aging phenotypes. These include a 20% decrease in median life span, early osteoporosis, lordokyphosis, organ atrophy, delayed wound healing, and a reduced regenerative response after various stresses. Since the initial characterization of these mutant mice, we have attempted to elucidate the underlying molecular and cellul...Continue Reading

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Citations

Nov 6, 2009·Carcinogenesis·Roger R Reddel
Nov 15, 2007·The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences·Huber R Warner
May 12, 2010·Cold Spring Harbor Perspectives in Biology·Lawrence A Donehower
Aug 7, 2007·PLoS Biology·Stuart M ChambersMargaret A Goodell
Oct 15, 2013·Pathobiology of Aging & Age Related Diseases·Paul Hasty, Barbara A Christy
Feb 4, 2010·Clinical Lipidology·Merlijn BazuineSamuel W Cushman
Jun 22, 2011·Mechanisms of Ageing and Development·Ari Barzilai
Mar 19, 2008·Mechanisms of Ageing and Development·Han LiPaul Hasty
Feb 8, 2005·Biochemical and Biophysical Research Communications·Jill L Carrington
May 13, 2005·Mechanisms of Ageing and Development·Vera Gorbunova, Andrei Seluanov
Feb 18, 2005·The Journal of Biological Chemistry·Shino NemotoToren Finkel

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