Sci. Aging Knowl. Environ., 24 August 2005
Vol. 2005, Issue 34, p. nf68
[DOI: 10.1126/sageke.2005.34.nf68]


Family Feud

Protein relative of p53 has opposite influence on aging

R. John Davenport

Siblings sometimes have contrasting personalities despite similar appearances. The tumor-preventing molecule p53 accelerates aging, but new results suggest that a related protein retards it. Mice without the protein, called p63, age unusually quickly, and their cells divide sluggishly. The findings bolster the notion that dwindling stem cell stores promote physical deterioration.

The p53 protein guards against cancer by spurring damaged cells to either commit suicide or enter a non-dividing state known as senescence. But overactive p53 accelerates mouse aging, even though the animals resist cancer (see Campisi Perspective and "Tumor-Free, But Not in the Clear"). The protein might hasten an animal's demise by annihilating stem cells necessary to replenish weathered tissues. Scientists have recently found other proteins that resemble p53, but they don't understand what these molecules do. In a new study, Keyes and colleagues investigated the workings of p63.

Mice with a single copy of the p63 gene died prematurely and displayed signs of rapid aging. They lost weight and hair, and their spines warped. The team then probed how the absence of p63 disrupted animals. Mice without p63 die at birth, so the researchers generated a line of mice that carried two copies of p63 and develop normally. But the scientists could remove both copies from skin cells--which normally produce the p63 protein--by feeding the mice a compound that activates a DNA-clipping enzyme. The team raised the rodents to 8 months of age--roughly middle age--and then fed them the p63-eradicating compound. Like animals with one copy of p63, the rodents exhibited hallmarks of rapid aging. In addition, fewer of the animals' skin cells divided. The p63-devoid animals produced unusually large amounts of protein from several genes that flip on during senescence. Moreover, the genes were especially active in parts of hair follicles that contain stem cells, which normally have the capacity to reproduce. The findings suggest that senescence of stem cells might contribute to the apparent rapid aging of the animals.

Because p53 can spur cell senescence, the team next asked whether senescence caused by the absence of p63 required p53. The team mated animals without the p53 gene to those with removable p63. Offspring missing both genes still showed signs of rampant senescence, suggesting that the p53 protein isn't necessary.

The study is important because it "implicates other p53 family members in the aging process," says cancer biologist Lawrence Donehower of Baylor College of Medicine in Houston, Texas. Finding senescent cells where stem cells should be "is a provocative observation," says cancer researcher Norman Sharpless of the University of North Carolina, Chapel Hill. Skeptics might say that p63's absence fouls up tissues but doesn't speed aging, he cautions, so "putting p63 in the aging pantheon will require more work." For instance, scientists should determine whether p63 shuts down in older animals or people, or remains active in individuals that live unusually long, he says. In addition, researchers will need to clarify how the p63 protein interacts with other molecules, such as p53, that control senescence, studies that should help explain the disparate behaviors in this family.

August 24, 2005
  1. W. M. Keyes et al., p63 deficiency activates a program of cellular senescence and leads to accelerated aging. Genes Dev., 17 August 2005 [e-pub ahead of print]. doi:10.1101/gad.342305[Abstract/Free Full Text]
Citation: R. J. Davenport, Family Feud. Sci. Aging Knowl. Environ. 2005 (34), nf68 (2005).

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