Scientists find the gene that decides how long we live

[Al-khiyal]

3 May 2007 -- Scientists have come a step closer to understanding the secret of a long, healthy life with the discovery of a gene that plays a central role in the ageing process.

The gene appears to be critical in extending the lifespan of animals that are subjected to a calorie-restricted diet - when they are slightly starved of high-calorie food but are given all the other nutrients they need.

It is well established that calorie-restricted diets lead to longer maximum lifespans in practically every animal in which they have been studied, although the evidence it not as strong for humans.

The latest study focussed on a gene common to nematode worms, mice and humans. When the gene was blocked in the worms, the benefits of a calorie-restricted diet were lost and the worms lived shorter lives. Similarly, when the scientists were able to stimulate the gene they found that they could enhance the longevity of the worms so that their extended lifespans came close to matching those worms on a calorie-restricted diet.

Scientists believe that the findings could unlock a genetic treasure-chest of potential pharmacological targets for developing drugs that can extend the human lifespan without having to follow a rigorous and difficult diet.

"After 72 years of not knowing how calorie restriction works, we finally have genetic evidence to unravel the underlying molecular programme required for increased longevity in response to calorie restriction," said Andrew Dillin, of the Salk Institute in San Diego, California. "It's likely to play a role in the human condition, although we still don't know whether calorie restriction really works in humans. Studies in primates suggest it does."

The first experiments in calorie-restricted diets go back to the 1930s. Laboratory rats and mice fed a severely calorie-restricted diet, but with normal levels of vitamins and minerals, lived almost twice as long as rodents with unrestricted access to food. Experiments with other creatures found that the phenomenon appeared to be ubiquitous in the animal kingdom. Some scientists suggested it was an evolutionary adaptation to surviving hard times until enough food became available.

The longevity-associated gene identified by Dr Dillin and his colleagues is known as PHA-4 - the name of the protein for which the gene is responsible. The same gene also exists in mice and humans and is known as the Foxa family of genes. Both PHA-4 and Foxa are involved in the complex process of glucose metabolism. In mammals, the gene is linked with a hormone called glucagon which increases levels of glucose in the bloodstream to maintain the body's energy balance especially during fasting.

Scientists from Louisiana State University are monitoring a group of 48 overweight men and women aged between 25 and 50. The study found that those who were able to cut down on their calorie intake improved in terms of metabolic markers that are linked to longer living.

The accepted view among scientists is that there is probably an absolute upper limit to human lifespan of no more than about 125 years - the oldest person with an authenticated birth record was a Frenchwoman called Jeanne Calment, who died aged 122 years, five months and 14 days. People in the West are living longer, but the extra years are not necessarily healthy ones - an ageing population is leading to a dramatic rise in senile dementia.

There has been a dramatic increase in longevity over the past couple of centuries due to improvements in housing and sanitation, nutrition and health.

Some 60 per cent of boys and 70 per cent of girls born in 1981 are expected to survive to celebrate their 75th birthday in 2056. In 1881, only a third of girls and just one in five boys reached the same age.

Scientists find the gene that decides how long we live

[Al-khiyal]

May 4, 2007 -- Scientists have identified a gene that makes roundworms live longer when they eat less, a finding they hope could lead to drugs that promote human longevity but without the pain of strict dieting, according to a study published Thursday.

Roundworms are excellent subjects for longevity research because they usually only live three weeks, making any increment in life span quickly apparent. Although people and worms took divergent evolutionary paths about 600 million years ago, they retain many genetic mechanisms in common, including the insulin-signaling control of metabolism and, quite possibly, the ancient survival mechanism of living longer to ride out famines.

This mechanism has been retained by mice, which live a third longer if fed a healthy but very low-calorie diet. Most people find it impossible to stay on such a diet, so researchers would like to stimulate the life-extension mechanism with a drug instead. But first they need to identify the genetic pathway through which the mechanism is set off so that possible drugs can be tested first in mice and then, perhaps, in people.

Disrupting a gene that mediates the insulin-signaling pathway in roundworms is one way of making them live longer. But researchers have been unsure whether this is the pathway involved in achieving the low-calorie and longer-life effect.

In what may prove to be a major clarification of the issue, researchers at the Salk Institute for Biological Studies in California reported in the Thursday issue of the journal Nature the existence of a life-extending genetic pathway, which they believe is the one naturally set off by dietary restriction.

The Salk Institute team, led by Siler Panowski and Andrew Dillin, said the new pathway was mediated by a gene already known from its role in building the worm's gut while the worm was an embryo. This new pathway works independently of the insulin-signaling pathway, they said, although it shares several genetic elements and is dedicated just to the famine response.

"This may be the primordial gene that regulates nutrients and helps the animal live a long time through dietary restriction," Dillin said. "We think it likely to play a role in the human condition."

The gene has exact counterparts in mammals, three of them, in fact, because the gene tripled at some point in mammalian evolution. The three genes in mice and in people are known as FoxA 1, 2 and 3. The Fox genes are a large family of master regulator genes that control other genes.

The Salk Institute has applied for a patent based on use of the FoxA genes, Dillin said.

Klaus Kaestner, a researcher at the University of Pennsylvania who has long studied the FoxA genes, said the finding was "very significant and will open new avenues for investigation."

For his own work, Kaestner has already engineered strains of mice in which the FoxA-1 and FoxA-2 genes can be switched off. He said he had shipped some of the mice to the Salk Institute team, which would test whether the FoxA genes mediate the diet-related longevity response in mice. If mice on restricted diets do not live longer when their FoxA gene is switched off, that would indicate the genes play an essential role in extending the life of the mice.

Leonard Guarente, a longevity researcher at the Massachusetts Institute of Technology, said the newfound role of the worm gene was not the only mechanism involved in life extension and that "the way in which it will fit into the whole story is not clear yet."

After many decades of being regarded among scientists as a backwater, research on longevity has been enjoying renewed interest.

The stakes are high: a drug that mimicked the effects of caloric restriction in people could lead to significant increases in life span.

But much work remains to be done in roundworms and mice to define the genetic pathway and its possible side effects in people, like reduced fertility.

Gene links longevity and diet, scientists say