Tuesday, December 30, 2008

A new twist on the free-radical craze

Trying to quash free radicals with vitamins turned out to be more counter-productive than anything else so I think the whole theory is flawed. This application of it should therefore fail

In a back room of New Scientist's offices in London, I sit down at a table with the Russian biochemist Mikhail Shchepinov. In front of us are two teaspoons and a brown glass bottle. Shchepinov opens the bottle, pours out a teaspoon of clear liquid and drinks it down. He smiles. It's my turn. I put a spoonful of the liquid in my mouth and swallow. It tastes slightly sweet, which is a surprise. I was expecting it to be exactly like water since that, in fact, is what it is - heavy water to be precise, chemical formula D2O. The D stands for deuterium, an isotope of hydrogen with an atomic mass of 2 instead of 1. Deuterium is what puts the heavy in heavy water. An ice cube made out of it would sink in normal water.

My sip of heavy water is the culmination of a long journey trying to get to the bottom of a remarkable claim that Shchepinov first made around 18 months ago. He believes he has discovered an elixir of youth, a way to drink (or more likely eat) your way to a longer life. You may think that makes Shchepinov sound like a snake-oil salesman. I thought so too, but the more I found out about his idea, the more it began to make sense.

The story began two years ago, while Shchepinov was working at a biotechology company in Oxford, UK, and using his spare time to read up on the latest ideas about what causes us to age. The most widely accepted idea is the free-radical theory. This holds that our slide into decrepitude is the result of irreversible damage to the biomolecules that make up our bodies. The main agents of this destruction are oxygen free radicals, aggressive chemical compounds that are an unavoidable by-product of metabolism.

The reason oxygen radicals are so dangerous is that they have a voracious appetite for electrons, which they rip out of anything they can lay their hands on - water, proteins, fats, DNA - leaving a trail of destruction in their wake. This damage gradually builds up over a lifetime and eventually leads the body's basic biochemical processes to fail.

One of the worst types of damage is something called protein carbonylation, in which an oxygen radical attacks vulnerable carbon-hydrogen bonds in a protein (see diagram). This has been linked to many of the worst diseases of old age, including Parkinson's, Alzheimer's, cancer, chronic renal failure and diabetes (The EMBO Journal, vol 24, p 1311). Other important targets of free-radical attack are DNA and the fatty acids in cell membranes. The human body produces legions of antioxidants, including vitamins and enzymes, that quench free radicals before they can do any harm. But over a lifetime these defence systems eventually fall victim to oxidative attack too, leading to an inevitable decline. Many anti-ageing medications are based on supplementing the body's own defences with antioxidant compounds such as vitamin C and beta-carotene, though there is scant evidence that this does any good (New Scientist, 5 August 2006, p 40).

Shchepinov realised there was another way to defeat free radicals. While he was familiarising himself with research on ageing, his day job involved a well-established - if slightly obscure - bit of chemistry called the isotope effect. On Christmas day 2006, it dawned on him that putting the two together could lead to a new way of postponing the ravages of time. The basic concept of the isotope effect is that the presence of heavy isotopes in a molecule can slow down its chemical reactions. This is because heavy isotopes form stronger covalent bonds than their lighter counterparts; for example, a carbon-deuterium bond is stronger than a carbon-hydrogen bond. While the effect applies to all heavy isotopes, including carbon-13, nitrogen-15 and oxygen-18 (see chart), it is most marked with deuterium as it is proportionally so much heavier than hydrogen. Deuterated bonds can be up to 80 times stronger than those containing hydrogen.

All of this is conventional chemistry: the isotope effect was discovered back in the 1930s and its mechanism explained in the 1940s. The effect has a long pedigree as a research tool in basic chemistry for probing the mechanisms of complex reactions.

Shchepinov, however, is the first researcher to link the effect with ageing. It dawned on him that if ageing is caused by free radicals trashing covalent bonds, and if those same bonds can be strengthened using the isotope effect, why not use it to make vulnerable biomolecules more resistant to attack? All you would have to do is judiciously place deuterium or carbon-13 in the bonds that are most vulnerable to attack, and chemistry should take care of the rest.

In early 2007 Shchepinov wrote up his idea and submitted it to a journal called Rejuvenation Research. Unbeknown to him, the journal's editor is controversial gerontologist Aubrey de Grey of the Methuselah Foundation in Lorton, Virginia, who is well known for supporting ideas other gerontologists consider outlandish. De Grey sent the paper out for review and eventually accepted it (Rejuvenation Research, vol 10, p 47).

In the paper, Shchepinov points out that there is masses of existing science backing up his ideas. Dozens of experiments have proved that proteins, fatty acids and DNA can be helped to resist oxidative damage using the isotope effect. Shchepinov's paper brought the idea to a wider audience, including successful biotechnology entrepreneurs Charles Cantor and Robert Molinari. Impressed, they teamed up with Shchepinov to set up a company called Retrotope, with de Grey as a scientific advisor.

It was around this time that I first got in touch with Shchepinov. I'd never heard of the isotope effect, and de Grey's involvement made me cautious. But there was something in the idea that intrigued me, and I kept on coming back to it. There were obvious objections to the idea. For one, how do you get the isotopes to exactly the sites where you want them? After all, the human body contains trillions upon trillions of chemical bonds, but relatively few are vulnerable to free-radical damage. And what about safety - swallowing mouthfuls of heavy isotopes surely can't be good for you, can it? That, of course, is how I ended up sharing a teaspoon of heavy water with Shchepinov.

Neither, it turns out, is a big problem. Some heavy isotopes are radioactive so are obviously ruled out on safety grounds - hydrogen-3 (tritium) and carbon-14, for example. Others, notably deuterium and carbon-13, are just as stable as hydrogen and carbon-12. Both occur in small amounts in nature and are a natural component of some biomolecules in our bodies (see "Heavy babies"). Deuterium and carbon-13 also appear to be essentially non-toxic. Baby mice weaned on a highly enriched carbon-13 diet are completely normal, even when 60 per cent of the carbon atoms in their body are carbon-13. Deuterium also has a clean bill of health as long as you don't go overboard. Decades of experiments in which animals were fed heavy water suggest that up to a fifth of the water in your body can be replaced with heavy water with no ill effects.

Similar experiments have been done on humans, albeit with lower levels of deuterium. One recent experiment kept humans on a low-level heavy-water diet for 10 weeks, during which their heavy-water levels were raised to around 2.5 per cent of body water, with no adverse effects (Biochimica et Biophysica Acta, vol 1760, p 730). The researchers also found that some deuterium became incorporated into proteins.

Heavy water, however, isn't completely safe. In mammals, toxic effects start to kick in around the 20 per cent mark, and at 35 per cent it is lethal. This is largely down to the isotope effect itself: any protein in your body has the potential to take up deuterium atoms from heavy water, and eventually this radically alters your entire biochemistry. You'd have to drink a vast amount to suffer any ill effects - my 5 millilitres did me no harm whatsoever - but even so, Retrotope is not advocating heavy water as an elixir of youth.

Instead, it wants to package up heavy isotopes in what Shchepinov calls "iFood". This method has huge advantages, not least because it allows the heavy isotopes to be targeted to the most vulnerable carbon-hydrogen bonds. Of the 20 amino acids used by humans, 10 cannot be made by the body and must be present in the diet. That means if you supplement your diet with essential amino acids that have already had their vulnerable bonds strengthened, your body's proteins will have these reinforced amino acids incorporated into them. Some of the building blocks of fats and DNA can also only be acquired via your diet, which means they too can be targeted using the iFood approach.

What's more, this approach ought to be completely safe, says Shchepinov. Deuterium atoms bound to carbon in amino acids are "non-exchangeable" and so don't leak into body water. Another possibility is to produce meat, eggs or milk enriched with deuterium or carbon-13 by feeding deuterated water or isotope-enriched amino acids to farm animals. For now, though, iFood remains on the drawing board as nobody manufactures the right compounds. To solve that problem, Retrotope has signed up the Institute of Bio-organic Chemistry in Moscow, Russia and Minsk State University in Belarus to make customised amino acids and fatty acids. "There are a lot of good isotope chemists in Russia," says Cantor.

Another hurdle Retrotope will have to overcome is cost. At current prices, a litre of heavy water will set you back $300. "Isotopes are expensive," says Shchepinov. "But there's no need for them to be. Methods are there to extract them, but nobody wants them." Unless demand rises, there is no incentive to produce them in bulk, and this keeps the price high.

These obstacles haven't stopped Retrotope launching a research programme to test Shchepinov's big idea. A team at the Institute for the Biology of Ageing in Moscow recently fed various amounts of heavy water to fruit flies to see if it had any effect on longevity. Though large amounts were deadly, smaller quantities increased lifespans by up to 30 per cent. It's a promising start, but it's too early to say whether the human lifespan can also be extended in this way, or how much deuterium-enriched food you would have to eat to get a beneficial effect. "This is preliminary and needs to be reproduced under a variety of conditions," says Shchepinov. "It's possible that the flies don't like the diet, and what we're seeing is the effects of caloric restriction [the only proven strategy for extending lifespan in experimental animals]. We need to do a lot more experiments. But still..."

Retrotope has signed up some heavyweight gerontologists to join de Grey as scientific advisors, including Jan Vijg of the Albert Einstein College Of Medicine in New York and Cynthia Kenyon of the University of California, San Francisco. Kenyon recently started work on Retrotope's second round of experiments, giving a deuterium-enriched diet to nematode worms. "It's a beautiful idea," says Vijg. "It gives us a serious chance of retarding ageing." He cautions, however, that Shchepinov's ideas hinge on free radicals being at the root of ageing. While this is still the leading theory in the field, many researchers argue that free-radical damage alone cannot account for all the biological changes that happen as we get old (Nature, vol 451, p 644).


Baby born deaf and blind after mother took Botox-like drug

How do they know that the Botox did it? They don't. It's just speculation. And since the stuff is widely used but no other similar cases have been reported, this is just a do-gooder scare

An anti-wrinkle treatment virtually identical to the booming Botox has been linked to serious birth defects. An Australian baby was born deaf and blind in November 2005 after the mother was given facial cosmetic injections of the drug Dysport in the first week of pregnancy. Documents from the Federal Health and Ageing Department, released under Freedom of Information, have revealed the "serious and unexpected pregnancy outcome".

Dysport and Botox are both botulinum type A toxin drugs rapidly growing in popularity as muscle-relaxant cosmetic treatments. The birth defect link was among 46 different adverse reactions to botulinum type A toxin reported to the Therapeutic Goods Administration since July 1, 1994. The most common are temporary facial paralysis, visual disturbances, fatigue, dizziness, difficulty swallowing, hallucinations and anxiety. The European Medicines Agency has recorded more than 600 negative effects from the use of drugs made from botulinum type A toxin, including 28 deaths. And in the US, the Food and Drug Administration has warned of side-effects including death, but stopped short of a ban.

A 2006 report on the Australian birth defect case, written by the medical services manager for Dysport manufacturer Ipsen, admits a "possible" link with the drug's use. "A female subject was injected with Dysport at about one week of gestation. The infant was born deaf and blind," the report states. Another report, however, claimed there was no such link.

A Health and Ageing Department spokeswoman said she was unaware if there were any further findings. "It absolutely would have been investigated, but it does not appear it warranted further action," she said.

Both Botox and Dysport are schedule three drugs that can only be used on prescription. Consumer information for both recommends against treatment when pregnant. An Ipsen spokesman said Dysport, unlike Botox, was more commonly used for purposes other than smoothing treatments, such as by neurologists for movement disorders. "When the drug is administered according to specifications, it's one of the safest drugs out there," he said.

A spokeswoman for Australian Botox distributor Allergan said its safety had been established over 40 years. "More than 2000 clinical studies and review articles have been published on the effectiveness and safety of Botox," she said. Cosmetic Physicians of Australia spokeswoman Dr Mary Dingley said she administered up to 10 treatments a day using either Botox or Dysport without serious reactions. She said most adverse reactions she experienced were trauma around the injection site, while in other cases the problems related to the drug affecting nearby muscles


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