Sunday, August 20, 2006

Longevity genes and cancer

Scientists have identified a number of genes that seem to have some effect on an animal's longevity. Mostly they have been found in small, short-lived creatures whose longevity is easily studied, such as mice, fruit flies, or roundworms (C. elegans), though they frequently have analogues in humans. See here for an earlier discussion.

Of course, any gene which is important for inhibiting cancer, such as the well-known p53, will tend to improve longevity, for obvious reasons. But surprisingly, there are some longevity genes which don't have such an obvious relation to cancer, and may lengthen expected life span even when cancer is present.

Longevity genes fight cancer at its source
Over the years, biologists have discovered a handful of genes in roundworms, mice and flies that bestow a dramatic increase in lifespan on the organism that carries it – sometimes up to twice their normal life expectancy.

These genes are involved in diverse biochemical pathways including those for growth hormones, insulin, food intake and caloric restriction. But it is thought that they are all have a role in how the body responds to stress.

Julie Pinkston at the University of California in San Francisco, US, and colleagues, wondered if these longevity genes had something else in common: the power to fight cancer – a notoriously age-related disease.

Pinkston manipulated a C. elegans gene to make the worm more susceptible to cancer, and she also introduced a mutated version of the daf-2 insulin-like receptor gene, known to be longevity-enhancing. Worms with both mutations, even though they developed tumors, still lived twice as long as unmutated worms. Apparently the mutated daf-2 was doing something in addition to preventing tumors from forming.

The something else seems to be related to apoptosis:
Daf-2 seemed to protect against the lethal cancer by stimulating apoptosis – programmed cell death – which tumour cells usually avoid, the researchers say.

It's understandable that a gene which stimulates apoptosis helps fight cancer. The question is whether stimulating apoptosis also has harmful side effects. Apparently not so much in this case, if longevity is doubled anyhow.

But there's more to it than that:
One hallmark of cancerous growth is a rapid acceleration of cell division. Daf-2 also decreased the number of cell divisions in the roundworms by 50% compared to what was expected for those with the gld-1 gene, Pinkston says.

Other longevity-releated gene mutations are known in C. elegans, and when these mutations were present, the longevity effect also occurred:
The team then used the same process to test three other known longevity genes in turn against the life-shortening gld-1 gene. These three double-mutant worms also lived longer than normal roundworms. Each of the three genes (eat-2, isp-1 and clk-1) suppressed cell division, even though they did not appear to increase apoptosis.

Again, it would seem that suppressing cell division with these mutations is a net benefit for longevity, despite the need for some cell division outside of tumors. Perhaps they simply cause an animal's life cycle to proceed at a slower pace.

But roundworms are rather simple animals. One wonders how such an effect would play out in a human...

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Other references:

Longevity genes fight back at cancer
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