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
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
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
"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
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)