p53: The Tradeoff Between Cancer Protection and Longevity

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No. 2 • April 2005

p53: The Tradeoff Between Cancer Protection and Longevity

The p53 protein, being intensively studied for its cancer-suppressive function (p53 is mutated in about half of all human cancers1), is also linked to longevity. A recent mouse model in which the animals were engineered to have an increased function of p53 showed the expected decrease in cancer incidence, but the mice also aged prematurely.2,3 However, in a different mouse model in which genetically engineered (in a different way) mice had extra p53 activity, the mice had an enhanced DNA damage response, were tumor-resistant, and aged normally.4

It is now believed that p53 is a key regulatory protein that balances the need for cell proliferation against the need for cancer suppression (by reducing cellular proliferation).5 Cellular senescence, an important part of the aging process at the cellular level, is an irreversible arrest of proliferation, though cells can continue to survive for a lengthy period of time. The accumulation of senescent cells (including stem cells) contributes to aging. Hence, it would appear that a certain amount of p53 activity is essential to prevent cancer, but too much activity leads to reduced tissue renewal and repair, stem cell deletion, and organismal aging.

We now have human data on this balancing act of p53.1,6 In a study of polymorphic variation in the human p53 gene,6 scientists discovered that replacing the arginine at position 72 with a proline results in a human p53 with less apoptosis-inducing potential (reduced suppression of cancer). In a formal meta-analysis of the published literature, the scientists found that carriers of the TP53 codon 72 Pro/Pro (two alleles with the arginine replaced by proline) have an increased cancer risk compared to Arg/Arg carriers (no replacement of arginine by proline). Finally, they found that in a prospective study of 1226 people aged 85 years and over, carriers of the Pro/Pro genotype (that is, p53 with a reduced suppression of cancer) had a 41% increased survival despite a 2.54-fold increased proportional mortality from cancer.6 The result is a significant decrease in mortality from all causes but cancer and a nonsignificant increase in mortality from cancer. Hence, the authors suggest, “… human p53 protect[s] against cancer but at a cost of longevity.” This is an example of antagonistic pleiotropy, where adaptations that increase fitness in early life lead to reduced survival in old age.

Not much is known about manipulable factors that affect p53 expression. One paper7 reports that statins (HMG-CoA reductase inhibitors) attenuated the p53 response to DNA damage in HepG2 cell culture. Some research has been published on possible anticancer effects of statins. How a possible decreased p53 response to DNA damage might fit in with that is unclear. In a different paper,8 it was reported that glucocorticoid receptor activation resulted in enhancement of p53 activity and inhibition of neural cell proliferation. As the authors note, “… it merits mention that glucocorticoids are used to reduce inflammation and edema in neuro-oncology; a hitherto unrecognized benefit of such treatment may be proliferation arrest.” On the other hand, chronic exposure to high levels of glucocorticoids might be expected to damage the brain by suppressing neurogenesis, such as occurs in depression.


  1. Donehower. p53: guardian and suppressor of longevity? Exp Gerontol 40:7-9 (2005).
  2. Ferbeyre and Lowe. The price of tumour suppression? Nature 415:26-7 (2002).
  3. Tyner et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415:45-53 (2002).
  4. Garcia-Cao et al. “Super p53” mice exhibit enhanced DNA damage response, are tumor-resistant, and age normally. EMBO J 21(22):6225-35 (2002).
  5. Campisi. Fragile fugue: p53 in aging, cancer, and IGF signaling. Nature Med 10(3):231-2 (2004).
  6. Heemst et al. Variation in the human TP53 gene affects old age survival and cancer mortality. Exp Gerontol 40:11-15 (2005).
  7. Paajarvi et al. HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage. FASEB J 19:476-8 (2005).
  8. Crochemore et al. Enhancement of p53 activity and inhibition of neural cell proliferation by glucocorticoid receptor activation. FASEB J 16:761-70 (2002).

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