Anti-ageing breakthrough

The elixir of youth may ultimately be hidden in a poorly-understood gene that not only fosters longevity but enhances quality of life, according to a landmark study released Wednesday.

In a series of experiments on earthworms, a team of scientists at the Salk Institute in San Diego, California have identified for the first time a gene, known as PHA-4, which plays a critical role in prolonging life without tapping into insulin-regulating neural pathways that also control the ageing process.

Other molecular biologists hailed the study as a "breakthrough" that will change research agendas in the new but burgeoning field of longevity genetics.

Far more complicated in humans
But they also cautioned that duplicating the results in humans is far more complicated.

Only within the last decade have scientists understood that single genes can significantly affect ageing, once thought to be an uncontrollable process of decay.

"There are two major ways to prolong life," biologist Hugo Aguilaniu, one of the study's co-authors, explained in an interview.

One is to decrease sensitivity at the cellular level to insulin.

"This is already well known - genetically modified mice have been created that live twice as long as a result," he said.

But there are unwelcome side-effects, including stunted growth and reproductive malfunction.

Eat less, live longer
The other way is dietary restriction. "If you give an animal 70% of its normal intake, it will live 20 to 30% longer," said Aguilaniu.

In a human being, that adds up to an additional 15 to 20 years of life. A restricted diet, however, is not the same as near starvation, and must consist of a balanced mix of nutrients to be effective.

The link between eating less and living longer has been known for decades. "But we had no idea what the molecular actor of this process was," he said.

In the study, led by Andrew Dillin and published in the British journal Nature, C. elegans worms were fed a bacteria laced with genetic material that selectively switched off the PHA-4 gene. As suspected, the worms no longer enjoyed a longer lifespan when placed on a slimmed-down diet.

Gene tied to longevity
But while this first experiment showed that the gene was critical for diet-induced longevity, it did not prove that the PHA-4 directly triggered longer life, so another test was devised.

"When we over-expressed the gene" - making it more active that it would be naturally - "the animals lived longer, up to 20 or 30%," even when they ate normally, said Aguilaniu.

Adding dietary restrictions boosted longevity even further.

The researchers conducted a separate set of experiments to be sure that PHA-4 was acting independently from any insulin signalling pathways.

"What is most interesting is that diet-restricted animals are more dynamic. We like to talk not just about life span but 'health-span expansion' - being healthier over a longer period of time," Aguilaniu said.

The millimetre-long C. elegans worm is frequently used in the laboratory because it is easy for researchers to disrupt the functions of its nearly 20 000 genes to determine what they do.

Many, including PHA-4, have specific counterparts in humans.

Scientists familiar with the study described it as significant.

"It answers a question we have been asking for a long time," commented Martin Holzenberger, a researcher at France's National Institute for Health and Medical Research.

A breakthrough in understanding
"It is certainly a real breakthrough in our understanding of diet restriction," he said, adding that the study showed PHA-4 to be "a key gene" that regulates others.

Holzenberger said PHA-4, which corresponds to the "foxa" family of genes in humans, probably works on enzymes to reduce harmful oxidation in the cells. But he said the link between diet restriction and longevity remains poorly understood.

"The closer we get to humans, the more complicated it gets," he told AFP, pointing out that the technique that worked in worms can't be used on people.

Relevance remains theoretical
Aguilaniu agrees that the relevance for humans remains, for now, theoretical. "But all studies suggest that dietary restriction works the same way in worms as it does in mice or in men. As soon as we have a molecule that is specific, there are potential pharmaceutical applications."

Gary Ruvkun, a geneticist at Harvard in Massachusetts, also thinks the study could open up new avenues of research on ageing in humans. "There are homologues across all these organisms and one expects them to work in similar ways," he said.

He predicted that other researchers would start to look more carefully at the role of PHA-4, which was previously linked only to growth of the pharynx in the C. elegans. Indeed, Ruvkun said he had overlooked the gene in his own research because he assumed that deactivating it in experiments would simply kill the worm.

But Dillin and his colleagues discovered once the worm reaches adulthood, the gene changes function, regulating ageing instead of growth. – (Sapa-AFP)

Read more:
Anti-ageing Centre

May 2007

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