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Cellular Compounds May Extend Lifespan

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05/15/2014 09:40 am ET | Updated May 15, 2014

Every day, our cells manufacture small amounts of a molecule that, in higher doses, might be the key to leading a longer, healthier life. A team of researchers has found that this molecule boosts the lifespan of worms by more than 50%, raising the possibility that it will increase human longevity.

“I think the data are really convincing,” says molecular geneticist William Mair of the Harvard School of Public Health in Boston. “They have a very strong lifespan effect using this [compound].”

The route to a long life doesn’t lead through the kitchen. Researchers have known for decades that when animals eat dramatically less—undergoing what’s known as calorie restriction or dietary restriction—they live longer and delay or avoid age-related problems like cardiovascular disease and diabetes. But if you’re planning to try this at home, there are a few catches. For one thing, scientists haven’t confirmed the benefits of calorie restriction for primates, including humans. Although eating less does help monkeys age gracefully, it’s unclear whether calorie restriction increases their lifespan. And surviving on far fewer calories is no picnic. “The problem is that requirement is so stringent that almost nobody can make it,” says Jing Huang of the University of California, Los Angeles.

As a result, researchers have been testing alternative ways to slow aging and lengthen life, such as the grape extract resveratrol and the immune-suppressing drug rapamycin. Although both have shown promise in experimental animals—rapamycin increases the longevity of middle-aged mice—they’ve also shown drawbacks. Rapamycin, for example, meddles with sugar metabolism and may lead to diabetes. Huang and her colleagues deduced that because aging depends on metabolism, compounds produced in cells by metabolic reactions—known as metabolites—might also boost lifespan.

The researchers tested their idea on nematodes, millimeter-long worms commonly used in longevity studies. They hit the jackpot with the first molecule they tried, α-ketoglutarate (α-KG), an intermediate in a metabolic cycle that helps a cell extract energy from food. When the researchers added the compound to the worms’ culture dishes, the animals survived up to 70% longer than normal, the team reports online today in Nature. The animals carried about 50% more α-KG in their cells than did control worms. Like calorie restriction, the extra α-KG postponed the worms’ physical deterioration.

To figure out how α-KG works, Huang and colleagues used a technique they developed that identifies the proteins in human cells that α-KG interacts with. The results showed that the compound attaches to ATP synthase, an enzyme that makes ATP, the cell’s main energy-carrying molecule. ATP synthase resides in the energy-producing structures called mitochondria. By studying the mitochondria from cow heart cells, the researchers found that α-KG blocks ATP synthase, thus turning down the cell’s metabolism.

When the researchers further traced the cellular effects of α-KG, they discovered that it indirectly inhibits a protein called TOR that gauges nutrient supplies and, scientists suspect, helps determine how fast we grow old. Alpha-KG “may be an internal fountain of youth, if you will, that may be regulated to counteract aging,” Huang says. Calorie restriction causes side effects in animals such as reduced reproduction, but the researchers didn’t see those downsides in the worms that ate α-KG.

Mitochondrial biochemist Michael Ristow of the Swiss Federal Institute of Technology in Zurich says that the molecular mechanism for this effect took him by surprise. He notes that other studies have shown that calorie restriction boosts ATP synthesis by making mitochondria more efficient, so you’d predict that α-KG would do the same. “That’s what makes it interesting,” he says. “It’s unexpected.”

Dietary supplements that contain α-KG and allegedly build muscle are already on the market. The study drops a barbell on their use, however, by suggesting that α-KG inhibits TOR, thus thwarting muscle growth. “If people are taking this as a muscle builder, you would think it doesn’t cause the desired effect,” Mair says.

There’s no guarantee that α-KG will have the same effects on aging in people as it has in worms. And before researchers can even address that issue, they’ll have to figure out if the compound also extends the lives of laboratory organisms such as flies and mice. Nonetheless, Mair says, researchers have long hoped to identify small molecules that slow human aging, and the study “is the next step toward that goal.”

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