A protein regulating stress response could be a good model for anti-aging drugs, it has been found.
"What we have here is an essential protective pathway that now looks like a very effective therapeutic target," said biologist Richard 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 Laura Saunders and Eric 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, writes Michael Wall on Wired.
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."
He also felt that 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," Morimoto stressed.