May 2, 2007
Studies have shown that severe calorie restriction markedly extends lifespan in mice and many other species - but the reasons for this remained elusive.
But now US research on nematode worms, published in Nature, has uncovered a gene linked to this unusual effect.
In the future, the find could lead to drugs that mimic the consequences of calorie restriction but negate the need for severe fasting regimes.
The life-lengthening properties of reducing calorie intake were first discovered in the 1930s, when laboratory rodents fed a severely reduced diet were found to outlive their well-fed peers.
Since then, this effect has been observed on organisms as diverse as yeast, flies, worms and dogs.
The consequences for humans of cutting calorie intake by about 60% while maintaining levels of vital nutrients are still unclear, although this extreme diet has a number of followers.
Andrew Dillin, an author of the paper and an associate professor at the Salk Institute for Biological Studies, said: "If you reduce food too much, you go towards starvation and live less long. If you overeat you will succumb to obesity and have a short lifespan. Dietary restriction is really a sweet-spot between the two.
"But for 72 years, we have not known how it works."
A study using nematode worms (Caenorhabditis elegans) revealed that a gene called pha-4 played a key role.
The team found worms that had their pha-4 genes removed showed no enhanced longevity while on the restricted diet.
But they discovered that the opposite experiment - over-expressing levels of pha-4 in the worms - increased longevity when on the restricted diet.
"This is the first gene we have found that is absolutely essential to the longevity response to dietary restriction," explained Dr Dillin.
"We finally have genetic evidence to unravel the underlying molecular programme required for increased longevity in response to calorie restriction."
Although the study was carried out on worms, the finding could also be important for other species.
Mammals, including humans, possessed genes that were highly similar to the pha-4 gene, explained Dr Dillin.
These genes play a key role in development, and then in later life in the regulation of glucagon, a hormone that has a major role in maintaining glucose levels in blood - especially during fasting.
In fact, scientists believe the life-increasing effect of dietary restriction may be linked to boosting chances of survival through times of food scarcity.
"Pha-4 may be the primordial gene to help an animal overcome stressful conditions to live a long time through dietary restriction conditions," explained Dr Dillin.
Scientists now plan to look at the gene in other species.
Should the longevity link also apply to humans, it could open the door to the development of drugs that mimic the effects of calorie restriction while allowing people to maintain their normal diet, the scientists said.
Professor Richard Miller of the Institute of Gerontology at the University of Michigan, commented: "It is really hard to guess whether the connections that we see between the pha-4 system and calorie restriction in worms will have parallels in mammals, whose repertoire of responses to various forms of long- and short-term food shortages are far more complex than those of worms.
"But the Dillin paper provides both motivation to look and also clues about where to look. I think it's likely to be influential, even if the implications for mammals do eventually turn out to be a cul-de-sac - which they might or might not."