For hundreds of years people have longed for the elixir of eternal life, something that can stop the ageing process and perhaps even restore tired and wrinkled bodies to their smooth, unlined and athletic former selves. While nothing discovered so far could be described as a wonder cure against the ravages of time, some substances are thought to at least slow down the visible passage of the years.
Thanks to the suggestion more than 50 years ago that ageing results from molecular damage caused by reactive forms of oxygen, termed superoxides or free radicals, antioxidants have been thought to have anti-ageing properties The faith people have in them is obvious from a visit to any pharmacy, which is likely to have shelves stacked with skin creams with the words "contains antioxidants" written on the container.
Researchers studying nematode worms however believe they have now shown that antioxidants have a minor role or are completely ineffective in preventing ageing. In tests, nematode worm strains that were more resistant to oxidative stress did not have increased lifespans. Also, forms of the worms less resistant to superoxides lived just as long as other nematodes. Dr David Gems, who led the research at the Institute of Healthy Ageing at University College London, says the argument over the role of oxidative stress in ageing could now be over.
"Our study is not the single swing of the axe that's brought down the tree, but it's a bad cut," he says. "I think the theory is finished because it's clear the consensus has been reached among a lot of people in the field of the biology of ageing." Oxidative stress refers to the presence of unstable forms of oxygen that have unpaired electrons - the negatively charged particles that orbit the nuclei of atoms - and are highly reactive.
They are naturally generated as by-products of metabolism and the body breaks them down to prevent them causing damage to cells at the molecular level. The reason that oxidative stress has been implicated in ageing is that, Dr Gems says, a range of studies have shown an apparent link between the two. Dr Gems believes people have in the past drawn the wrong conclusion from studies. "If you put organisms under stressful conditions where oxidation is increased, you see increased ageing. But that doesn't prove that ageing is normally caused by oxidation. It's just you can mimic it by putting animals under oxidative stress," he says.
Similarly, while long-lived mutants of various types of animals have been shown to have high levels of antioxidants, and to be resistant to oxidative stress, that does not necessarily imply that the resistance to oxidative stress is causing the increase in lifespan, he says. As many a schoolchild has been told during a mathematics lesson, "correlation does not imply causation" - a relationship between two variables does not mean one is causing the changes in the other. It seems this warning has often been forgotten when it comes to ageing.
"You see oxidation during ageing damage, but it's not clear that oxidation is the primary cause of ageing. That's been a source of confusion," he says. The researchers created strains of the nematode worm Caenorhabditis elegans that were either more sensitive or less sensitive to superoxides. The nematodes, which are each just 1mm long, are useful for tests as they have short lifespans of two to three weeks and their genetics are well understood.
To produce the specific types for analysis, the worms were exposed to chemical mutagens or radiation, and lines that showed mutations in two types of gene were selected for further study. The scientists were interested in mutations in five genes that code for superoxide dismutase enzymes, which convert superoxides to hydrogen peroxide. They also tested nematodes with mutations in three genes that code for catalase enzymes, which in turn break down the hydrogen peroxide. The different types were put under oxidative stress and their lifespans measured.
"For each strain, we might take 100 worms and measure the average lifespan. For some strains, we did it at least 10 times. We were very thorough," says Dr Gems. "Sometimes the results were very clear. Other times we had to do it again and again to be sure." Dr Gems says "in a few cases there were some small effects", but overall the expected result, namely more sensitive strains having shorter lifespans when exposed to oxidative stress and less sensitive strains living longer, was not apparent.
"This represents the most rigorous testing of the theory to date as it studied ageing in a whole organism," he says. The results tie in with research carried out several years ago by the group, in which feeding synthetic forms of antioxidants to nematodes failed to increase the creatures' lifespans. The cosmetics industry has cautioned against reading too much into the latest research, with officials saying results from nematodes may not apply to people.
Dr Gems himself says people should not relate his study to the use of sunblocks, which he says do have protective qualities and can help to prevent the ageing of skin. "In the UAE, sun damage to the skin is an important issue. Regarding creams with sunblock, if ever there was a treatment against ageing, that is it, although it's only ageing of the skin," he says. He also cautions that his experiments looked specifically at the relationship between oxidative stress and ageing and not the role that foods containing high levels of antioxidants may have in protecting against conditions such as cancer.
However, he believes his results should finally push aside a major theme in ageing research and encourage scientists to focus attention on areas more likely to yield breakthroughs. "It takes something out of the way that has drawn a lot of attention. I hope this will redirect attention to the processes that are really important," he says. What those important processes are is not clear, but it seems there could be a multitude of ways in which molecules can be damaged during the ageing process.
There are thought to be wider detoxification systems that are similar to antioxidants but which protect against a much wider range of harmful substances. "These detoxification systems are designed to get rid of a million forms of toxin, of which a few dozen are related to oxygen," Dr Gems says. "These enzymes are controlled by a regulation system that switches them on and off. Maybe we should study the regulators of these broad-spectrum detoxification systems."
Also of interest is a system of "molecular chaperones" that protect against damage to proteins and seem to be important in combating ageing. "There seems to be a whole range of cell systems protecting against ageing," he says. firstname.lastname@example.org