Sunday, May 10, 2009

Article in New scientist

A controversial aricle called "Would eating heavy atoms lengthen our lives?" was published in New Scientist (27 November 2008 by Graham Lawton).
It is a good introduction to the potential of using the isotope effect to extend lifespan; however, the author is putting too much emphasis on using D2O or heavy water as a dietary supplement.
The main idea of fortifying the organic compounds with heavier isotopes, proposed by Dr. Michael Shchepinov, does not involve complete 12C->13C and H->D substitution in lipids, proteins and nucleic acids. Dr. Shchepinov's original idea was to stabilize only specific bonds that are commonly attacked by free radicals.


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.
Enriched eggs

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).

All of which makes other mainstream researchers very sceptical. "Shchepinov's idea is interesting, but we're discovering that it only makes sense to think about ageing in terms of multiple underlying causes," says Tom Kirkwood of the University of Newcastle, UK. "The history in the field is cluttered with hypotheses which are only partially supported by the data. Therefore, it is very unlikely that his suggested mechanism will prove to be more than a small part of the much bigger picture."

Others are more positive. "I've heard some pretty crazy ideas about how we might live longer, but I'm intrigued by this one," says Judith Campisi of the Buck Institute for Age Research in Novato, California and the Lawrence Berkeley National Laboratory, who has no formal links to Retrotope. "It's very original and novel."

While Retrotope is concentrating its efforts on ageing, Shchepinov says there are other applications of the isotope effect he'd like to explore. One is shielding long-term space travellers from the effects of cosmic rays and other ionising radiation, which cause damage much like ageing.

Oxidative attack on carbon-hydrogen bonds is a problem in many other areas, from drug discovery to cancer, cosmetics chemistry and electronics. If the ageing research doesn't work out, Retrotope will try something else. "We need to sort out what works and what doesn't, and what works well enough to be commercially exploited," says Cantor. "But this is going to work somewhere, because the basic science is sound."

Sound basic science, of course, doesn't mean that Shchepinov really has cracked a problem that's been troubling humanity for millennia. Realistically, it's much more likely his insight will lead to a more prosaic application, such as stopping coloured plastics from fading in sunlight. But until he's proved wrong, I'll keep on hoping that I shared my sip of heavy water with a scientist who will be remembered long after I'm forgotten.
Heavy babies

The idea of using chemical isotopes to combat ageing may be new, but nature may already be onto that strategy as a way of protecting us against free-radical attack, thought to be a key cause of ageing. Babies and mice are born with much more of the isotope carbon-13 in their bodies than their mothers, and women appear to become unusually depleted in carbon-13 around the time they give birth. Both findings suggest that there is active transfer of carbon-13 from mother to fetus.One possible reason for this, suggests Mikhail Shchepinov, chief scientific officer of the biotechnology company Retrotope, which is investigating the use of isotopes to slow ageing, is that the growing fetus selectively builds carbon-13 into its proteins, DNA and other biomolecules to take advantage of the way that heavy isotopes make these molecules more resistant to free-radical attack.It would make good evolutionary sense, as many of the proteins and DNA molecules formed early on have to last a lifetime. "Every single atom in the DNA of the brain of a 100-year-old man is the same atom as when he was 15 years old," says Shchepinov (BioEssays, vol 29, p 1247).


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