New insights into how cells cope with stress could help combat neurological dise

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New insights into how cells cope with stress could help combat

neurological diseases and reduce the ravages of aging.

http://blog.wired.com/wiredscience/2009/02/cellstress.html

Scientists have known for years that moderate stressors, such as a

calorie-restricted diet, increase lifespan in a variety of organisms.

Now new research is illuminating how this works at the molecular

level. A particular protein is key in regulating at least one aspect

of the stress response and may be a good model for anti-aging drugs.

" What we have here is an essential protective pathway that now looks

like a very effective therapeutic target, " said biologist

Morimoto of Northwestern University.

Most research on this protein, called sirtuin1 (SIRT1), has

concentrated on its ability to regulate and protect mitochondria —

cellular power generators that are corroded over time by reactive

oxygen molecules. But SIRT1 also protects DNA in the cell nucleus.

Morimoto's findings, published Thursday in Science, give a precise

mechanical explanation for the effects.

Cells have evolved a particular response to stay alive in adverse

conditions. When a cell starts getting too hot, too hungry or too

oxygen-deprived, certain proteins migrate into the nucleus. There,

they latch onto sections of DNA and cause heat-shock proteins to be

produced. Heat-shock proteins — so named because they were first

discovered in cells experiencing high temperatures — cruise around

the cell, fixing damaged or improperly folded proteins.

" Proteins are very delicate, " Morimoto said. " Any change in the

environment causes them to misfold. "

Repairing proteins keeps cells, and the body, in top shape. Animals

exposed to only minor stresses — such as a calorie-restricted diet —

reap the benefits and live longer.

" A little stress is good, " said lead author Sandy Westerheide, also

of Northwestern. " You don't want to overdo it, though. "

Normally the repair process falls off quickly, because heat-shock

proteins inhibit the proteins that grab onto the cell's DNA and

summon them in the first place. But Morimoto and his colleagues found

that jacking up levels of SIRT1 keeps the protein-repair process

going for hours and hours.

SIRT1 helps recruit at least one of the summoner proteins to its

proper place on the cell's DNA. And the compound has direct survival

benefits. The researchers subjected normal cells and those with high

SIRT1 levels to temperatures of 115 degrees Fahrenheit. Compared to

the control group, only one-third as many high-SIRT1 cells died.

" The results support the idea that low levels of stressors influence

lifespan and provide additional potential molecular targets that can

be further manipulated experimentally or therapeutically, " write

biologists Saunders and Verdin in an accompanying review

paper in Science.

Westerheide said the team is indeed screening molecules for promising

medical potential. Now that they know more about how the stress

pathway works, finding or designing a drug to boost SIRT1 levels is

more feasible.

Another option is finding something that makes SIRT1 more efficient

inside the cell. In the study, Westerheide and her colleagues used

the compound resveratrol, which occurs naturally in red wine, to this

effect. Other researchers have linked resveratrol to extended

lifespan in yeast, worms, fruit flies, fish and mice. The compound

occurs naturally in red wine, but probably not in high enough

concentrations to have an appreciable effect on human health.

Researchers are working to synthesize more potent compounds that have

the same effect as resveratrol.

A drug modeled on the SIRT1 pathway could also help treat currently

incurable neurological diseases such as Alzheimer's, Parkinson's and

Lou Gehrig's disease, Morimoto said.

" These are all protein-misfolding diseases, diseases of aging, " he

said. " For neurodegeneration, there's nothing that can be done right

now. "

The study will also give more confidence to people who are trying to

extend their lives by severely restricting their food intake. Such

extreme dieting, popularized by the late Roy Walford, has grown into

a movement.

" I'm not going to get on the diet-restriction bandwagon, " Morimoto

said. " But a little less consumption would be good for us. If you

fast for 12 hours, that's enough to send the right signals to your

system. "

Citation: " Stress-Inducible Regulation of Heat Shock Factor 1 by the

Deacetylase SIRT1. " By Sandy D. Westerheide, Julius Anckar, Stanley

M. s Jr., Lea Sistonen, I. Morimoto. Science Vol. 323,

20 February 2009.