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Cancer-proof mice live longer

July 18, 2007 By Ewen Callaway This article courtesy of Nature News.

An extra copy of a tumour-killing gene helps mice to stay young.

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A protein known to keep cancer at bay now also looks to be a fountain of youth. Mice with an extra copy of the tumour-killing gene that pumps out this protein live longer than those with just one copy, and are better at combating the cell damage that causes ageing.

The finding hints that a drug designed to boost the tumour suppressor, called p53, could work as an anti-ageing treatment for people, says Manuel Serrano, a biologist at Spanish National Cancer Research Centre in Madrid. Serrano's team publish their work in this week's Nature1.

The conclusion seems to stand in direct contradiction to previous work2, which showed that a boost in p53 kept mice cancer free but also caused them to age more quickly. But there's a key difference between these studies, the researchers say: in the new work, the normal regulatory mechanisms remain in place, so p53 is churned out only when needed. This seems to turn an ageing protein into a youth-preserving one.

"It's a very impressive effect," says Larry Donehower of Baylor University in Houston, who led the older work. "It's very hopeful because it says under some circumstances you can get the best of both worlds."

Double duty

First discovered in a 1979 study of tumour-causing viruses, p53 is one of the world's most researched proteins, with tens of thousands of papers written about it so far. When triggered by DNA damage or other stressors, p53 instructs cells to commit suicide or to stop dividing — nipping cancers in the bud. Researchers have now discovered that the protein also uses a gentler strategy to keep us healthy — it turns on cellular production of antioxidants, which mop up damaging molecules.

To determine whether this subtler role of p53 could slow ageing, Serrano's lab bred mice with an extra copy of p53, along with the usual gene that helps to regulate how much protein it produces. These mice produce more p53 protein when prompted to by cellular stress, such as DNA damage or lack of oxygen.

As expected, mice with the extra copy of p53 had fewer tumours than regular mice, and their cells were less likely to turn cancerous when grown in a Petri dish. On average, the transgenic mice lived 16% longer than normal mice: 118 days versus 137. By comparison, mice on a calorie-restricted diet — another lifespan booster — get a 20% bump in life expectancy.

But the age boost wasn't just an effect of fewer mice dying of cancer. When the researchers looked only at cancer-free mice in the study, they found that these transgenic mice lived 25% longer, on average, than normal ones. The oldest mice in both groups died at about the same age, but more of the transgenic mice lived into their golden years than the normal ones.

When the researchers looked more closely at the youthful mice, they found higher levels of genes that combat oxidative damage than in regular rodents. The mice with extra p53 also held up better against a lethal dose of paraquat, a drug that causes oxidative damage.

Live long and prosper

Donehower's study in 2002 had indicated that high levels of p53 can cause mice to age faster, as an abundance of the protein seemed to curb the growth and repair of all sorts of cells — not just cancerous ones. But those mice had a mutation that caused the protein to always be activated, says Donehower. He says he is now convinced that an extra copy of the normal p53 gene can forestall ageing.

So might patients some day pop a pill that fights cancer and keeps them young? "That's the million dollar question," Serrano says. Several cancer drugs targeting p53 are in clinical trials. His lab is testing one of them in mice. If this study is any indication, the key will be to find a drug that doesn't let p53 run amuck.

References

  1. Matheu, A. et al. Nature 448, 375-379 (2007).
  2. Tyner, S. et al. Nature 415, 45-53 (2002).

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