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Longevity genes fight back at cancer

August 17, 2006 By Helen Pilcher This article courtesy of Nature News.

Long-lived worms hint at new ways to tackle tumours.

Genetic mutations that increase lifespan also seem to be particularly good at fighting tumours, a worm study suggests. The finding could shed light on why cancer risk increases as we get older, and may also suggest new targets for cancer therapeutics.

You might expect that genes that promote long life and fight cancer would go hand-in-hand: a gene that protects against tumours would help to stop cancer from killing you, after all, so you would probably live longer. But it seems that the relationship is more complicated than that. Genes that make some animals live longer through non-cancer-related mechanisms also seem to have a particular skill for suppressing tumours.

Cynthia Kenyon and colleagues from the University of California, San Francisco, studied the link in the tiny transparent worm Caenorhabditis elegans, a species that doesn't usually get cancer.

Some genetic mutations in these worms are known to boost lifespan by affecting processes such as hormone signalling, food intake and respiration. Inactivating a gene called daf-2, for example, which is involved in regulating insulin, more than doubles the animals' lifespan from around 17 to 35 days.

When the researchers genetically altered the worms so that they were susceptible to cancer, inactivating daf-2 still let the worms live to 35 days and restricted tumour growth to half the expected size. "These animals still live twice as long as normal even though they've got a tumour," says Kenyon. "It's really amazing."

Knockout round

To perform the study, the team first had to knock out a tumour suppressor gene called gld-1 in the worms, causing cells in the animals' gonads to divide rapidly and form germ-line tumours. Left alone, these cancer cells break out of the gonad and fill the body, killing the worm at around 9 days old.

They then investigated the effects of a handful of different 'longevity' genes in the tumour-ridden animals, to assess the effects on lifespan and tumour growth. All of the longevity mutations tested increased the worms' lifespans even though they had cancer, the team reports in Science1.

In the daf-2 example, the link isn't too mysterious. Researchers have long known that insulin boosts tumour growth in rats. And when tumour-bearing rats are made diabetic, decreasing insulin levels, tumour growth slows. "The study is another example of the intimate tie-in between insulin and tumorigenesis," says David Kritchevsky from the Wistar Institute in Philadelphia, Pennsylvania, who studies the effects of diet on cancer.

In the worms, lowering insulin levels seems to slow cell division and increase apoptosis - the process by which some cells are able to commit suicide with a particular impact on tumour cells.

The results suggest that tumour cells are generally more susceptible to the effects of longevity-causing mutations than normal cells. So investigating these long-life mechanisms might provide better ways to target cancer. Drugs created this way might even have the side effect of prolonging life, beyond the usual limit for someone without cancer.

Of mice and worms

The authors also hope that their work will help researchers to fathom exactly why aged animals are so much more prone to cancer than young ones.

The worm study makes for a great start in this direction: the short lifespan of the worms makes for a quick study of old age. But other experts add that other, more human-like models will need to be studied to unpick what's really going on.

Biologist Siegfried Hekimi from McGill University in Montreal, Canada, who studies C. elegans, cautions that the laboratory-engineered worm tumours are very different to naturally occurring mammalian ones: they aren't created by the same mechanism, nor do they spread the same way. So this one study is hard to generalize from. "It tells us that these pathways should be studied in vertebrates," he says. "Only then might we be able to explain how ageing relates to cancer," he says.

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  1. Pinkston J. M., Garigan D., Hansen M.& Kenyon C. Science, 313. 971 - 975 (2006).


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