4 January 2002

NATURE - GMO MICE AGE PREMATURELY

amidst speculation as to whether Dolly the Sheep's unusual early development of arthritis fits into a wider pattern of biological disruption through cloning and genetic engineering...
 

Cancer-proof mice age prematurely
Frailty could be the price old bodies pay for a cancer-free youth

JOHN WHITFIELD
Nature, 3 January 2002
http://www.nature.com/nsu/020101/020101-2.html

Too much of a cancer-preventing protein causes mice to age prematurely, researchers have found. The result suggests that mammals may have to strike a balance between stamping out cancer and succumbing to old age[1].

This is the first time that the p53 protein has been implicated in ageing. This protein is one of the cell's main defences, carrying out many functions to stop cells becoming cancerous, including halting cell division, repairing damaged DNA and triggering cell death.

Lawrence Donehower of Baylor College of Medicine, Houston, and colleagues were trying to knock the p53 gene out. Instead, they created mice with a chunk missing from one copy of the gene. Disappointed, the team "put the animals in the corner of our mouse colony and ignored them", says Donehower.

As the months passed, the researchers noticed that the mutants developed far fewer tumours than their normal counterparts. The partial version of p53 somehow caused the normal form of the gene to become hyperactive.

This protection came at a price. The mutants were normal up to a year old - middle-aged, in mouse terms. Then they went downhill fast.

The cancer-proof mice lost weight and muscle, developed hunched backs and brittle bones, their skin became thinner and their wounds took longer to heal. Their average lifespan was about 20 per cent shorter than that of normal mice - 96 weeks compared with 118 weeks.

It is widely thought that damage to cells - from radiation, for example - causes ageing. This finding suggests that "it may not be damage that's causing ageing, but the way the cells respond to it", says cell biologist Scott Lowe of Cold Spring Harbor Laboratory in New York State.

"It's a striking and provocative finding," says Lowe. "It changes the way we think about a lot of things."

The great divide

Donehower thinks that enhanced cancer defences shorten life span through their effect on stem cells. Adult bodies rely on stem cells to replenish skin, muscle and bone. Normally, p53 leaves these cells in peace, working only to stop cells embarking on malignant, runaway division.

In the mutants, however, the over-zealous molecule curbs cells that maintain the body. Tissues that don't contain rapidly dividing cells didn't show the same signs of ageing - the mice didn't develop cataracts, and their brains didn't degenerate abnormally.

This adds to our knowledge of how DNA repair interacts with ageing - "the jigsaw is coming together quite well", comments gerontologist Tom Kirkwood of the University of Newcastle upon Tyne, UK. But a lot more work needs to be done before we can say for sure why these mice age early, he adds.

High price

Frailty could be the price that our old bodies pay for a cancer-free youth. "During development and reproduction it is essential to have a vigorous anti-cancer mechanism," says ageing researcher Lenny Guarente, of the Massachusetts Institute of Technology. "But later in life this results in cell death and senescence, which results in organ degeneration."

Guarente has recently shown that a protein called Sir2, which he believes determines the rate of ageing, also interacts with p53. The new finding "strengthens our model", he says, although he warns that it can be hard to know whether premature ageing is really the same as natural ageing.

The balance between cancer and decrepitude might present a gloomy prospect for increasing human longevity, suggesting that a longer life span comes with a greater cancer risk.

Not necessarily, says Kirkwood. We could be able to pick a path through the molecular mechanisms of ageing without making cells more tumour-prone. "There's no reason why you shouldn't get greater defence against cancer and greater longevity."

References
Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature, 415, 45 - 53, (2002).

© Nature News Service / Macmillan Magazines Ltd 2001
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