Study Casts Doubts on a Key Aging Gene

For years, researchers who study aging have chased a dream: a way to mimic the life-extending effects of calorie restriction without the drastic diet. Ten years ago, a group claimed that artificially boosting the activity of a certain gene offered a way to do this. Now, a new paper throws cold water on that claim, adding to doubts that the feted gene influences life span at all.

Scientists who study aging have long known of one reliable way to increase life span in a host of animals: starve yourself. Animals who eat about 30% to 50% less calories than normal live roughly 30% longer, or even more. But how does calorie restriction extend life? About a decade ago, a research team suggested that in worms, the answer was a gene called SIR2. The thinking was that slashing calories boosted the gene's production of its protein and that this in turn prolonged life span. Indeed, this group increased the expression of SIR2 by artificial means (without stopping worms from eating) and extended their life span. It wasn't a big leap to start wondering whether scientists could design a pill to bolster production of the SIR2 protein, allowing people to live a lot longer and healthier than we do now—without going hungry. And in fact, companies are already testing drugs that stimulate production of one of SIR2's relatives—the family of proteins are called sirtuins—in people to treat age-related diseases such as type 2 diabetes.

But in the past year, a handful of studies have questioned whether SIR2 and genes encoding the other sirtuins really do help explain why calorie restriction slows aging.

The new study, published online today in Nature, amplifies the doubts, suggesting that SIR2 doesn't do much at all to extend life span in worms and in flies. David Gems, a biogerontologist at University College London and the study's senior author, says he began reconsidering SIR2 when he was working with genetically modified worms designed to produce extra SIR2 protein. But then someone in Gems's lab mated the worms several times with a normal strain, "and the longevity went away," Gems says, even though the offspring still carried the altered SIR2 gene.

It's difficult to produce large groups of genetically identical worms and flies, so it can be hard for scientists to tell whether a genetically modified strain acts differently than control worms or flies because of its altered DNA—or because the two sets of animals have other genetic variations. Normally, researchers get around this by mating their genetically modified strain several times with a control strain—a strategy called "outcrossing." Outcrossing smoothes out any differences between the genetically modified strain and the control group by making the pair more genetically uniform.

Following up on his lab's initial observation that SIR2's life span effect could disappear in outcrossed worms, Gems teamed up with Matt Kaeberlein at the University of Washington, Seattle, and Linda Partridge of University College London, both of whom have previously questioned the role of sirtuins in aging. Along with other colleagues, they took both worms and flies genetically engineered to make extra SIR2. The worms were outcrossed up to six times, more than other groups had generally done in the past. The resulting animals lived normal life spans—even though they were still producing extra SIR2 protein. In parallel, Partridge's group found that overexpression of SIR2 in flies did not increase their life span, either.

"In terms of aging and dietary restriction," Gems says, SIR2 and related genes are probably "completely irrelevant. ... We tried so hard to see any effects at all in many different settings, and we haven't seen any."

Not so fast, say SIR2 backers. Leonard Guarente of the Massachusetts Institute of Technology in Cambridge, who a decade ago found an SIR2-life span connection, does admit that his original worm paper had an error: In the same issue of Nature as Gems's study, he publishes a short article noting that unbeknownst to him, the worms had a second genetic mutation, in a gene called Dyf. That mutation, it turned out, also helped the worms live longer. When they had only extra SIR2, they lived between 10% and 15% longer than normal, Guarente finds, not the 30% originally reported. "We did have one thing wrong in our study," he says. "We endeavored to set the record straight, and we have."

But that doesn't mean that SIR2 is irrelevant to life span, he argues, especially given extensive work in the field that has repeatedly linked SIR2 to longer life and to calorie restriction. "To say at this late date that sirtuins do not regulate aging, with thousands of sirtuin papers published, is like saying the Earth is flat," Guarente says. Of Gems's study, he notes, "You can always get an experiment not to work."

One reason for varied results is that aging is tough to study in worms and flies, says Scott Pletcher, a geneticist at the University of Michigan, Ann Arbor. "If we're measuring 10%, 20% differences in life span, that can depend on whether the temperature is warmer, whether there's enough food. You really have to control for all those things. It's a challenge." For now, Pletcher is on the fence about what exactly sirtuins do. "Some voice has been given [by the Gems paper] to what's been floating around in the community for some time," Pletcher says, which is "that there's some uncertainty around those early results."