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Wednesday, Oct. 11, 2006

NATURAL SELECTIONS

MOLE-RAT CONUNDRUM

Bizarre rodents confound a venerable theory of aging


We've all heard the claims. Drink enough green tea and you'll live to be 100. Eat tofu every day to protect against cancer. Recently, there's even been research suggesting that eating curry helps to boost brain power.

News photo
Naked Mole-Rats may look rather like maggots crossed with walruses, but their truly astonishing longevity despite suffering severe oxidative damage is posing science with a whole new raft of questions. PHOTO COURTESY OF fridayanimal.com

One thing many of these claims have in common is that the food being lauded contains antioxidants.

These are compounds that prevent damage to our cells by preventing oxidation reactions. Due to their presence in fresh fruit and vegetables, and perhaps in green tea and tofu, too, antioxidants almost certainly keep us fit and healthy.

They do so because we are constantly exposed to low levels of nasty little chemicals called free radicals.

Although they sound like a student protest group in 1960s San Francisco, free radicals are any chemicals that have an unpaired electron -- making them unstable and desperate to oxidize something in order to gain another electron.

When a free radical does this -- and in the process damages an enzyme or part of our cell structure -- it may produce more free radicals which themselves need to rush about and quench their electron-thirst by oxidation. Antioxidants soak up the damage that free radicals cause.

Incidentally, there is little or no evidence to suggest that popping an "antioxidant pill," such as those that are widely available at health-food shops, has the same effect. Despite what the manufacturers of such pills might claim, once the pills are swallowed, they don't work to prevent oxidative damage -- you're far better off eating lots of fresh fruit and vegetables.

Even so, that will not stop millions of dollars being invested in research into artificial antioxidant treatments. If someone can find a way to reliably reduce oxidative damage -- and thereby diminish the effects of aging and prolong lifespan -- well, you don't need to be a marketing executive to see how such a product might make some money.

As usual though, it's not going to be easy. New research presented this week at an American Physiological Society conference in Virginia Beach, Virginia, might end up changing our understanding of what's termed the oxidative stress theory of aging. Ironically enough, the findings come from work on a bizarre, wrinkled, ugly-looking creature: the naked mole-rat (Heterocephalus glaber).

This small, 8- to 10-cm-long, 30- to 35-gram rodent lives in colonies of 20 to 300 individuals in systems of underground tunnels excavated with its huge front teeth beneath the tropical East African savannahs of Kenya, Ethiopia and Somalia. Naked mole-rats are fascinating creatures in many ways -- such as each colony only having one breeding female, like a queen ant -- but of particular interest regarding oxidative stress and aging is that they can live to a relatively ancient 28 years old.

Compared to a mouse, for example -- which is roughly the same size but lives only 3 years -- the naked mole-rat has much higher levels of oxidative damage, and its oxidative repair mechanisms are not as good. All the theory would have predicted the opposite. So what's going on?

Rochelle Buffenstein, of The City College of New York, who led the study, says that the naked mole-rat's extraordinary lifespan stems from its ability to defend against acute bouts of oxidative stress. That is, the kind of oxidation that happens because of an unusual occurrence rather than the kind that happens as a result of normal aerobic respiration.

She knows this because her team treated a lab culture of naked mole-rat cells with a strong oxidizing agent -- hydrogen peroxide, the stuff you bleach your hair with. This would cause some serious damage to normal cells, but naked mole-rat cells are tough. They were able to soak up the damage, repair it quickly, and carry on growing. When the test was done on mouse cells in a culture, they were badly damaged and became unviable.

"Mole-rats must have something happening at the biochemical level to allow them to do this," said Blazej Andziak, of Cornell University in New York state.

The team wanted to see if oxidative stress could explain the difference between mice and naked mole-rats, so they compared the ratio of reduced glutathione, an antioxidant, to oxidized glutathione.

We have a pool of reduced glutathione in our cells to help fight oxidative stress, and as we use it up, the pool of oxidized glutathione increases. This ratio of reduced-to-oxidized glutathione is thus an indicator of oxidative stress: the higher the ratio, the less oxidative stress has occurred. The researchers expected that naked mole-rats would have a higher ratio because they had soaked up more oxidizing compounds.

But they found that the opposite was true. Naked mole-rats had less reduced glutathione and thus a lower ratio, indicating that they experienced much more oxidative stress and suffered greater oxidative damage. But nevertheless, they still lived so much longer.

OK, Buffenstein and Andziak thought, so the naked mole-rat suffers greater oxidative stress, but its physiology somehow prevents damage from occurring. So they looked directly at oxidative damage.

What they found was that compared to mice, the lipids, DNA and proteins in the naked mole-rats showed much higher levels of damage. The liver, heart tissue and kidneys were all significantly more damaged in naked mole-rats than mice. They might be ugly, but naked mole-rats sure are tough.

"All of the classical measures of oxidative stress are higher in the mole-rat," Andziak said. "Given that naked mole-rats live an order of magnitude longer than predicted based on their body size, our findings strongly suggest that mechanisms other than attenuated oxidative stress may explain the impressive longevity of this species."

The next step, clearly, is to determine how the naked mole-rats manage to live with the damage caused by oxidative stress -- and not just live with it, but live to be nine times older than the comparably sized mouse.

I'd accept looking like a wrinkled old naked mole-rat if I could live twice as long as normal -- let alone nine times as long as normal. But understanding how naked mole-rats do it is likely to be a long way off yet.

"This animal may one day provide the clues to how we can significantly extend life," said Buffenstein.

Until then, we'll just have to keep eating our fruit and veg and guzzling that green tea.

The second volume of Natural Selections columns translated into Japanese has just been published by Shinchosha at 1,500 yen. The title is "Hito wa ima mo shinka shiteru (The Evolving Human: How new biology explains your journey through life)."


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