Tuesday, December 8, 2009

"light" water and its proposed impact in aging

Very interesting experiment results on gamma-irradiated irradiated mice:

Aviakosm Ekolog Med. 2009 Mar-Apr;43(2):29-32.
[The "light" water effect on lenticular opacity development in mice after repeated low dose gamma-irradiation]

[Article in Russian]

Abrosimova AN, Rakov DV, Siniak IuE.

Action of "light" water with reduced quantities of heavy stable hydrogen and 18O ions on incidence and progress of lenticular opacity was studied in gamma-irradiated mice (60Co, 1.0 Gy). The animals were subjected to electroophthalmoscopy regularly till end of life time. The observation showed that chronic intake of "light" water safeguarded the irradiated mice against lenticular opacity. The experimental data indicate that "light" water strengthens the general body resistance as well as slows down aging of mammals.

Tuesday, September 22, 2009

Isotope-Reinforced Polyunsaturated Fatty Acids Protect Yeast Cells from Oxidative Stress

Dr. Catherine Clarke, a prominent lab head from UCLA, presented her findings on using the isotope-fortified PUFAs in yeast:

K. Hirano, V. V. Shmanai, B. N. Marbois, R. Molinari, S. Morvaridi, M. Shchepinov, C. F. Clarke
Department of Chemistry and Biochemistry University of California, Los Angeles 607 Charles E Young Dr E Los Angeles CA 90095-1569

Polyunsaturated fatty acids (PUFAs) are exquisitely sensitive to autoxidation damage. The autoxidation products include peroxyl and alky radicals, and small molecule aldehydes that form cross-links to other membrane components, or diffuse to other cellular sites and damage proteins and nucleic acids. Cells protect themselves from these autoxidation products by maintaining an arsenal of enzymes designed to keep reactive oxygen species in check, as well as a defensive system of small molecule antioxidants that terminate radical chain reactions. The enhanced vulnerability of PUFAs to such autoxidation stems from the labile nature of the bis-allylic hydrogen atoms. The facile abstraction of bis-allylic hydrogens from PUFAs is the hallmark chemistry responsible for initiation and propagation of autoxidation reactions. PUFAs synthesized to contain Deuterium atoms uniquely at the bis-allylic sites (termed isotope-reinforced PUFAs) would be expected to be more resistant to autoxidation reactions due to the isotope effect. This hypothesis was tested by making use of the coenzyme Q-deficient Saccharomyces cerevisiae model. The yeast coq mutants have defects in biosynthesis of coenzyme Q (CoQ, or ubiquinone). CoQ plays a well-known role in respiratory energy metabolism and also functions as a lipid soluble chain terminating antioxidant. Although yeast cannot synthesize PUFAs, they are able to incorporate exogenously supplied PUFAs into their membrane lipids. Yeast coq mutants incubated in the presence of linolenic acid (C18:3) exhibit profound loss of viability as ascertained by greater than 99% loss of colony formation at 4 hours. In contrast, the coq mutants treated with either the monounsaturated oleic acid (C18:1), or the isotope-reinforced linolenic acid (bis-allylic D4-C18:3) retain 80-90% viability, a value similar to wild-type or CoQ-replete yeast. These results indicate that isotope reinforced PUFAs are stabilized as compared to standard PUFAs, and the coq mutant yeast cells containing the D4-linolenic acid are protected against the toxic effects of lipid autoxidation products.

Presenting author: Clarke, Catherine
Keywords: Isotope Effect, Lipid Autoxidation, Coenzyme Q, Ubiquinone, Fatty Acid

Wednesday, June 24, 2009

Response to Zhang: another trick of heavy isotopes

Deuterium cannot be kept for long enough at
exchangeable DNA sites to achieve this desired effect in
vivo because it will readily (within a few minutes) be
replaced by hydrogen atoms from normal water, the major
component of live cells, owing to fluctuational openings
of DNA base pairs (DNA ‘breathing’). Otherwise,
normal water would have to be almost completely replaced
by heavy water, which is not possible owing to the
known lethal toxicity of heavy water for mammals at
concentrations >35%. This was the reason that high
KIE was only observed in the condensed phase or in waterfree
solutions whereas even traces of natural water basically
abolished this effect.
For this reason, to achieve the goal of reducing the
amount of unfavorable tautomers it was suggested that
deuterium be placed at non-exchangeable sites of DNA
purines and pyrimidines. In this case, other heavy
isotopes can also be used for KIE (Figure).

caution should be exercised in choosing sites for isotopic
replacement because certain studies estimated an unusually
highamount of unfavorable tautomers in tRNAwhen
the natural 14N isotope was completely replaced with its
heavier 15Nsubstitute.Note that thishighamount of
unfavorable tautomers exceeds the amount of mutationcausing
tautomer of a highly mutagenic analog of cytosine. It is noteworthy that isotopic changes in non-exchangeable
DNA sites might reduce the level of age-related
mutations, including epigenomic modifications, by other
mechanisms too.

Vadim V. Demidov
Trends in Biotechnology
Volume 26, Issue 3, March 2008

Wednesday, June 17, 2009

Another trick of heavy isotopes

Hong-Yu Zhang speculate that non-radioactive heavy
isotopes might resist diseases and ageing by another
Forty years ago, Lo¨wdin proposed a DNA mutation
model that was built on inter-base double proton (or hydrogen)
transfer (DPT).

As illustrated in Figure, following the DPT the four bases (A, G, C, T) are turned into
tautomeric forms (A*, G*, C*, T*), which will no longer
bind to the normal Watson–Crick partners but to others,
especially C, T, A and G, respectively, resulting in new base
pairs: A*–C, G*–T, C*–A and T*–G. As a result, nucleotide
mutation occurs, which results in a time-dependent loss of
genetic information and thus leads to various diseases and
ageing. Since the first description of the model it has
attracted much interest and has been supported by
increasing theory and experimental evidence.
According to the principle of KIE, the inter-base DPT
can be efficiently slowed down by substituting the transferred
protons with heavy isotopes. For instance, a high
KIE (7.4) for deuteration has been observed in photoinduced
inter-base DPT of model DNA base pairs.
Therefore, we propose that by replacing the transferred
hydrogen atoms (labeled in red in Figure) in the base
pairs with deuterium atoms, the DPT rate will be considerably
reduced, which should reduce the possibility
for DNA mutation and thus slow the progression of
some diseases, as well as the ageing process. Consequently,
we suggest that another way for heavy
isotope substitution in biomolecules to benefit our health
exists – that is, through decreasing the DPT-based DNA
mutation rate.

Another trick of heavy isotopes
Hong-Yu Zhang
Trends in Biotechnology
Volume 26, Issue 3, March 2008, Pages 118-120

Wednesday, June 10, 2009

Deuteronation and aging.

Deuterium has one proton and one neutron in its atomic nucleus, but hydrogen has only proton. The natural abundance of deuterium is 1 per approximately 6600 hydrogen atoms. Therefore deuterated water (both HOD + D(2)O [heavy water]) abundance is 1 per approximately 3300 water molecules. One dissociation product of deuterated and heavy water is deuteron (proton + neutron, D(+), H(2)OD(+)/D(3)O(+)). Because heavy water has a lower ionization constant than water, the D(+)/H(+) ratio is approximately 1/15,000 in biological fluids. O-D bond length is shorter than O-H, and D-O-D angle is lesser than H-O-H. Once a deuteron exchanges with proton on the water-exposed surface of a macromolecule, it can lead to a conformational change and the reverse exchange will be less likely. Deuteron bonds are stronger than proton bonds. Therefore an increase of deuteronated macromolecules can be expected in due course of time. In order to test this hypothesis, we conducted a pilot study and measured the D/H ratio in the tails of three Sprague-Dawley rats at different ages (4 weeks, 5 weeks, and >1-year old) by elemental analysis coupled with isotope ratio mass spectrometry (EA-IRMS) technique. To prevent the effect of daily water consumption, the homogenized tails were lyophilized before analysis. The results, as mean of several measurements, of 4 weeks, 5 weeks, and >1-year-old rats were per thousand-94 +/- 9.56, per thousand-101.71 +/- 6.89, per thousand-83.68 +/- 3.46 delta((2)H) relative to VSMOW, respectively. Although there is a slight increase in >1-year-old rat, the difference among the animals was not significant. We propose that, before reaching to a final conclusion about the accumulation of deuterium with aging, the measurements should be done not in whole tissue samples but in purified macromolecules from a larger set of animals.

Ann N Y Acad Sci. 2007 Apr;1100:400-3.
Olgun A, Oztürk K, Bayir S, Akman S, Erbil MK.

Wednesday, June 3, 2009

New anti-ageing strategy on course: Kinetik Isotope Effect vs. ROS

Oxford-based researcher Mikhail Shchepinov noticed that ROS oxidize cellular substrates by a mechanism typically involving hydrogen abstraction in a rate-limiting step. Through his university background in chemical kinetics, Shchepinov also knew about the effect of an isotope substitution on a rate of chemical transformation. The strength of a covalent bond is subtly influenced by the atomic masses at either end of the bond: heavier isotopes form stronger bonds than light isotopes of the same elements, and so reactions involving the breaking of those bonds proceed more slowly. For example, hydrogen comes in two stable isotopes, the common ‘light’ hydrogen isotope (H) and its twice-heavier sibling, deuterium (D). The C–D bond is significantly stronger than the C–H bond, and therefore a cleavage of the former bond will occur several times more slowly than the corresponding cleavage of the latter bond. The common ‘light’ carbon atom 12C of the C–H bond can also be substituted for a heavier, stable 13C isotope, but the bond-cleavage-rate decrease will be smaller than that involving substitution of H for D because 13C is only 8% heavier than 12C. This is called the kinetic isotope effect (KIE).

Shchepinov's idea is to use the KIE to make proteins, nucleic acids and lipids more resistant to ROS damage. It is summarized as follows: replace all ‘light’ atoms at the ROS-targeted sites of biomolecules with their heavier isotopes, which should evidently be both non-radioactive (stable) so as not to damage the cell and non-exchangeable with the intracellular environment to avoid their loss via exchange with normal ‘light’ isotopes. Besides non-radioactive D and 13C, stable 15N and 18O ‘heavy’ isotopes can also be used to take the place of common ‘light’ nitrogen and oxygen constituents of biomolecules. Note that such isotopic ‘make-up’ will not change the chemical nature of the compounds: the bonding structure of isotopical ‘twins’ will be identical, and their chemistry will basically be similar. However, the heavier sibling will be less reactive. Also note that even if the ‘heavy’ isotope is not a part of the bond that is cleaved by ROS, a small decrease in the oxidation rate, known as a secondary KIE, can nevertheless usually be observed.

Vadim V. Demidov (2007) Heavy isotopes to avert ageing?
Trends in Biotechnology, Volume 25, Issue 9, September 2007, Pages 371-375

Current defense strategies from reactive oxygen species (ROS)

The traditional strategy of combating free radicals is based on counteracting ROS with antioxidants, free-radical scavengers or readily oxidizable substances acting as free-radical captors. Common antioxidants include vitamins (vitamin C, vitamin E), carotenoids (β-carotene, lycopene) and microelements (zinc and selenium; the latter can also enhance the body's own repair pathways). To prevent ageing and age-related diseases, these compounds are usually taken as dietary supplements, which are widely used in industrialized countries.

It is thought that such nutraceuticals protect human cells and tissues from the damaging effects of oxidation. Many nutraceutical and health-food companies are now involved in the production and distribution of antioxidant-containing dietary supplements. However, despite widespread public optimism about the likely beneficial anti-ageing effects of antioxidants, so far there is no solid proof that use of antioxidants can stop or reverse the ageing process. Although some researchers claim that antioxidant supplements do show positive results in the battle against ageing, others have not identified any statistically significant benefit from the use of antioxidants. Some studies indicate that dietary antioxidants might only be effective in men because their bodies are somewhat lower in the contents of certain antioxidants, for example, β-carotene, than women's bodies.

However, the amounts in which these antioxidants should be consumed to be truly beneficial without being harmful has to be carefully considered, especially for elderly or other vulnerable populations. Indeed, by modulating cellular redox status, an optimal ROS level could be very important in homeostasis of aerobic life. In this regard, a recent study has come to a shocking conclusion: treatment with β-carotene, vitamin A and vitamin E might actually increase mortality! This study also concluded that the potential roles of vitamin C and selenium in longevity in humans need further investigation.

The contradictory results obtained with antioxidants as anti-ageing agents make it clear that alternative approaches are needed. A fresh look at the old problem has just been taken from the chemical kinetics viewpoint.

Vadim V. Demidov (2007) Heavy isotopes to avert ageing?
Trends in Biotechnology, Volume 25, Issue 9, September 2007, Pages 371-375

Monday, May 25, 2009

Reactive Oxygen Species, Isotope Effect, Essential Nutrients, and Enhanced LongevityReactive Oxygen Species, Isotope Effect, Essential Nutrients, and

A method is proposed that has the potential to lessen detrimental damages caused by reactive
oxygen species (ROS) to proteins, nucleic acids, lipids, and other components in living
cells. Typically, ROS oxidize substrates by a mechanism involving hydrogen abstraction in a
rate-limiting step. The sites within these (bio)molecules susceptible to oxidation by ROS can
thus be “protected” using heavier isotopes such as 2H (D, deuterium) and 13C (carbon-13). Ingestion
of isotopically reinforced building blocks such as amino acids, lipids and components
of nucleic acids and their subsequent incorporation into macromolecules would make these
more stable to ROS courtesy of an isotope effect. The implications may include enhanced
longevity and increased resistance to cancer and age-related diseases.
DOI: 10.1089/rej.2006.0506

Read more here: http://www.liebertonline.com/

Tuesday, May 19, 2009

single low dose of heavy ion irradiation can affect the stability of the genome

To investigate the long-term biological effect of extreme low dose ionising radiation, we irradiated normal human fibroblasts (HFLIII) with carbon ions (290 MeV u(-1), 70 keV microm(-1)) and gamma-rays at 1 mGy (total dose) once at a low dose rate (1 mGy 6-8 h(-1)), and observed the cell growth kinetics up to 5 months by continuous culturing. The growth of carbon-irradiated cells started to slow down considerably sooner than that of non-irradiated cells before reaching senescence. In contrast, cells irradiated with gamma-rays under similar conditions did not show significant deviation from the non-irradiated cells. A DNA double strand break (DSB) marker, gamma-H2AX foci, and a DSB repair marker, phosphorylated DNA-PKcs foci, increased in number when non-irradiated cells reached several passages before senescence. A single low dose/low dose rate carbon ion exposure further raised the numbers of these markers. Furthermore, the numbers of foci for these two markers were significantly reduced after the cells became fully senescent. Our results indicate that high linear energy transfer (LET) radiation (carbon ions) causes different effects than low LET radiation (gamma-rays) even at very low doses and that a single low dose of heavy ion irradiation can affect the stability of the genome many generations after irradiation.

Br J Cancer. 2007 Jun 4;96(11):1707-10. Epub 2007 May 8.
Single extreme low dose/low dose rate irradiation causes alteration in lifespan and genome instability in primary human cells.
Okada M, Okabe A, Uchihori Y, Kitamura H, Sekine E, Ebisawa S, Suzuki M, Okayasu R.

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.

From: http://www.newscientist.com/article/mg20026841.800-would-eating-heavy-atoms-lengthen-our-lives.html?full=true

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).