iFood, Heavy Water and Ageing

[Guest guest]

Would eating heavy atoms lengthen our lives?

* 27 November 2008 by Graham Lawton

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 Cantor and 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 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).

http://aging-management.com/ - Optimising Health for Longevity