Scientists unlock key to longer life

La Jolla, California: The day when humans could enjoy at least a partial “elixir of life”, a pill extending lifespan by up to 40 per cent, is now closer with the discovery of a “longevity gene”.

Scientists studying worms have found a gene that links eating less with longer life. This confirms earlier studies carried out over the last 70 years which have looked at dogs, mice, yeast, fruit flies and nematode worms, which have shown that a reduction in calorie intake by 60 per cent of normal, while maintaining a healthy diet of vitamins, minerals, and other nutrients, consistently prolongs life by up to 40 per cent.

That regime also reduces the risk of cancer, diabetes, and cardiovascular disease, while staving off age-related degeneration of the brain and nervous system.

Although some people are already imposing this strict diet on themselves, and primate experiments appear to back this longevity effect, it is still too early tell whether calorie restriction will have the same effect in humans.

The new research from the Salk Institute for Biological Studies in La Jolla, California, have identified a critical gene in nematode worms that specifically links eating fewer calories to living longer and why persistent hunger leads to a longer life.

Identifying this “longevity pathway” opens the door to the development of drugs that mimic the effects of calorie restriction and might allow people to reap health benefits without adhering to an austere regime that only the toughest ascetics can endure.

In a paper published in the magazine Nature, Prof Andrew Dillin and colleagues show that pha-4, a gene that plays an essential part in embryonic development of the worm, has a newly discovered function in adults – increased activity of the gene is associated with longevity in the “sweet spot” of food consumption between the extremes of harm caused by starvation and overeating.

Professor Dillin says: “After 72 years of not knowing how calorie restriction works, we finally have genetic evidence to unravel the underlying molecular program required for increased longevity in response to calorie restriction,” said Prof Dillin.

“This is the first gene that is absolutely essential and specific for the increased longevity response to dietary restriction.”

Initially, researchers thought that the effect of calorie restriction on ageing was to do with signalling pathways related to the hormone insulin but experiments by graduate student Siler Panowski in Prof DillinÂ’s lab suggested reality was more complex and another gene called SMK-1 was more involved in the effects of starvation, to their surprise.

The work suggests that insulin signalling and calorie restriction are independent pathways, but SMK-1 plays a role in both, said Panowski. The team studied 15 genes that could be involved with SMK-1 and found that the loss of only one, a gene called pha-4, negated the lifespan-enhancing effect of calorie-restriction in the worms.

Dramatically, when researchers undertook the opposite experiment— making more pha-4 in worms — longevity was enhanced, suggesting that this could offer a target for life extension drugs.

Detailed work showed that the gene can boost levels of proteins called SODs (superoxide dismutase) which mop up free radicals, harmful chemicals linked with ageing.

The researchers think that this may be a defence mechanism that helps the creatures tolerate starvation. The pha-4 gene is similar to those in people called Foxa transcription factors, which also have important roles during development and act later in life to regulate glucagons – hormones made by the pancreas to burn fat – and glucose levels, particularly in response to fasting. Humans possess three genes that are “highly similar” to the worm pha-4, all belonging to the Foxa family.

All three play an important role in development and then later on in the regulation of glucagon, a hormone made by the pancreas that unlike insulin increases the concentration of blood sugar and maintains the bodyÂ’s energy balance, especially during fasting.

When food is in short supply, these genes may alter glucagon levels or cause other changes in hormones that are ultimately able to regulate the ageing process.

The team is now going to study these human genes to see if they react the same way as those in nematodes do when the worms are denied their favourite treat, bacteria.

Prof Dillin said that they would also test a range of drugs to see if they can find some that boost the activity of the human equivalent of the worm gene and, in theory, could boost longevity.

So far, only one other gene, called sir-2, has been implicated in the life- and health-prolonging response of the boy to calorie restriction. Increased use of the gene extends longevity of yeast, worms, and flies.

However, the link is not so clean cut because the loss of sir-2 disrupts the calorie restriction response only in some strains of yeast and has no effect on other organisms, such as worms.