From: http://www.independent.co.uk/news/UK/Science/2000-09/secret010900.shtml

Worms hold the secret of eternal youth

By Steve Connor, Science Editor

1 September 2000

A microscopic worm that lives in the soil may have just yielded the secrets of immortality, or at least tantalising clues that might make it possible one day to pop a pill and live for more than 120 years.

The nematode worm, Caenorhabditis elegans, normally dies of old age after about 20 days but, in research published today, scientists have doubled the creature's lifespan with the help of drugs.

For the first time, medical researchers have been able to demonstrate that it is possible to delay the ageing process and postpone a natural death by using a pharmaceutical product. The big unknown is whether this could turn out to be the elixir of life for humans.

An Anglo-American team of scientists used two drugs that mimic the body's natural way of reducing the damage caused by highly reactive by-products of normal metabolism – so-called oxygen free radicals.

Scientists call such damage "oxidative stress" and the purpose of the drugs – synthetic catalytic scavengers – is to mop up free radicals as quickly as they are formed, so they have no time to attack the healthy tissues and DNA of the body.

Simon Melov, of the Buck Institute for Age Research in California, said the research raised the question of whether human ageing would soon become "curable", much like a lung infection or a broken leg. "These results are the first real indication we have had that ageing is a condition that can be treated through appropriate drug therapy," Dr Melov said. "Further studies on higher organisms in the near future will allow us to answer whether or not we have to reconsider ageing as an inevitability."

Gordon Lithgow, another member of the team and a senior lecturer at the University of Manchester, said the findings indicate that ageing is a "solvable biological problem. The hope is that in the future we may be better able to rationally design drugs that prevent or postpone age-related diseases," Dr Lithgow said.

A nematode worm may seem a lowly beast to study, but it has become the focus of a huge international research effort into ageing and how to prevent it. The effort reflects the anxiety many of us have over the prospect of growing old. The search for the elixir of life is as old as Ancient Egypt and as modern as Wall Street, which has invested heavily in biotechnology companies chasing anti-ageing treatments.

The latest research, published in the journal Science, has demonstrated that anti-oxidative stress is a key factor in the ageing process. Anything that can prevent the damage of oxidative stress could become as sought-after as the anti-impotence drug Viagra.

The drugs used in the experiment were, in effect, synthetic versions of two natural enzymes, superoxide dismutase and catalase, which take the damaging oxygen free radicals and convert them to water and ordinary, harmless oxygen.

Worms grown in the presence of the drugs lived for between 30 per cent and 120 per cent longer than the average lifespan of those grown in their absence.

"We were amazed by what we were seeing down the microscope as these experiments progressed. As the untreated worms began to die, the drug-treated worms were swimming around, full of life," Dr Lithgow said. "Every time we repeated the experiment, it worked and we realised we were on to something pretty significant." He added: "It will take a lot more work to find out exactly what is going on here."

Genetic studies on worms, flies and mice have all shown that genes play an important role in determining the speed at which living organisms age. Some gene studies have, in fact, supported the idea that ageing is largely the result of a build-up of damage due to oxidative stress.

Fruits flies normally live 45 days but those carrying mutations that boost their production of antioxidants can live about 75 days – some have lived for as long as 95 days. Research last year showed that mice carrying a genetic mutation can live on average 30 per cent longer than ordinary mice. Scientists found that they were also resistant to a poison that works by generating oxygen radicals.

"It's a ridiculously simple idea that ageing is due to oxidative stress but all the data is pointing to it," Dr Lithgow said.

Attempts to establish whether these drugs work in humans could come sooner than many expect. Already there are plans to conduct clinical trials using them on patients suffering from radiation burns, which are known to generate the free radicals that cause oxidative stress.

"These drugs have in fact been developed to attack the diseases that are due to oxidative stress. There are diseases associated with old age, such as Parkinson's and Alzheimer's, where oxidative stress is thought to be a contributory factor," Dr Lithgow said. "These diseases might be age-related because they have an oxidative-stress component. It looks like oxidative stress is the main player in ageing."

Another line of inquiry has revealed that restricting the number of calories eaten in a lifetime could also play a role in extending life. Scientists have called this "under-nutrition, without malnutrition", and "caloric restriction" has already become a vogue for health-conscious Americans wanting to live long, and stay slim. However, the idea has not yet been shown to apply to humans. Clearly, people in the world who do not get enough to eat do not as a rule live longer than those who overeat.

Nevertheless, caloric restriction has provided yet further evidence that the underlying process at work in ageing is oxidative stress. Mice and rats fed about half as much as ordinary laboratory rodents can live up to one-third longer than their well-fed cousins. They are lighter and smaller but they perform better in tests of stamina and endurance and have a reduced rate of developing cancer.

Some scientists have proposed that caloric restriction merely reduces the rate of metabolism, allowing the animal to survive the lean times so they can reproduce at a later date when life gets better.

By slowing metabolism, however, the animals produce fewer toxic by-products, notably free radicals, thereby reducing oxidative stress and increasing the chances of living longer. Thus, the life-enhancing benefits of caloric restriction have provided further evidence that ageing is largely the result of a build-up of toxic by-products.

"There's no such thing as an ageing mechanism as such. There are things that go on in our bodies that cause ageing as a side-effect," Dr Lithgow said.

One day, with the help of the nematode worm, scientists should find a way of preventing or even reversing the damage to our tissues that we call ageing. "I envisage drugs used against specific conditions rather than a general life-expanding drug," he said.

The ultimate goal is to improve the quality of life in old age rather than merely allow sick people to life longer, Dr Lithgow said. "If we can improve healthspan, rather than just lifespan, it will be amazing. If for instance you can eliminate Alzheimer's disease from the picture, it will be wonderful."

An anti-ageing pill aimed at improving healthspan rather than increasing lifespan could end up being the true elixirof life.