Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations

Zhaohui Feng, Wenwei Hu, Angelika K. Teresky, Eva Hernando, Carlos Cordon-Cardo, Arnold J. Levine

Research output: Contribution to journalArticlepeer-review

199 Scopus citations

Abstract

Cancer is a disease of aging. The accumulation of mutations in individual cells over a lifetime is thought to be the reason. In this work, we explored an additional hypothesis: could p53 function decline with age, which would contribute to an enhanced mutation frequency and tumorigenesis in the aging process? The efficiency of the p53 response to γ-irradiation was found to decline significantly in various tissues of aging mice from several inbred strains, including lower p53 transcriptional activity and p53-dependent apoptosis. This decline resulted from a decreased stabilization of the p53 protein after stress. The function of the Ataxia-telangiectasia mutated (ATM) kinase declined significantly with age, which may then be responsible for the decline of the p53 response to radiation. Declining p53 responses to other stresses were also observed in the cultured splenocytes from aging mice. Interestingly, the time of onset of this decreased p53 response correlated with the life span of mice; mice that live longer delay their onset of decreased p53 activity with time. These results suggest an enhanced fixation of mutations in older individuals because of the declining fidelity of p53-mediated apoptosis or senescence in response to stress, and they suggest a plausible explanation for the correlation between tumorigenesis and the aging process.

Original languageEnglish (US)
Pages (from-to)16633-16638
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number42
DOIs
StatePublished - Oct 16 2007

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Apoptosis
  • Ataxia-telangiectasia mutated (ATM)
  • Tumorigenesis

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