By Heidi Ledford of Nature magazine

A widely touted--but controversial--molecular fountain of youth has come under fire yet again, with the publication of new data challenging the link between proteins called sirtuins and longer lifespan.

In a paper published today in Nature, researchers report that overexpressing a sirtuin gene in two model organisms--the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster--does not boost longevity as had been previously reported. Instead, the authors argue that the longer lifespan originally seen was the result of unrelated mutations lurking in the background of the experimental strains.

Some see the results as clearing the air, and freeing the field to focus on other effects of sirtuins, such as regulating metabolism and responding to environmental stress. "The field has been overfocused on overhyped claims of longevity," says Johan Auwerx, a researcher at the Federal Institute of Technology in Lausanne, Switzerland, who has worked with the proteins but was not involved with the new study. "I don't think that's the main function of the sirtuins."

But Leonard Guarente, a sirtuin researcher at the Massachusetts Institute of Technology in Cambridge, who published the original C. elegans work in 2001, argues that the longevity link is real and that the new paper is just "a bump in the road". "Our data are rock solid," he says. "I stand by them, and they have been replicated in other labs."

Background noise

When asked how he decided to investigate the C. elegans longevity results, study author David Gems, a geneticist who studies ageing at University College London sighs, "With reluctance." Initially, he says, he ignored the rumours circulating at conferences that there were problems with a C. elegans strain that overexpressed a sirtuin gene called sir-2.1. Researchers were finding that when they mated the strain with normal nematodes--a practice commonly done to ensure that there are no additional mutations affecting the phenotype--the reported longevity boost disappeared.

"No, I don't want to work on this," Gems says he told a postdoc interested in following up the rumours. "Somebody else can clean up this mess." But no one did, he says, and meanwhile, the sirtuin story was beginning to dominate the agenda at meetings on ageing. Gems likens the experience to discovering a landmine. "If you just walk by, a lot of other people will get blown up," he says. "And that's what happened. A lot of other people have wasted a lot of time."

Gems and a collaborator, geneticist Linda Partridge, also at University College London, have previously teamed up to challenge ageing claims based on genetic studies, and have advocated higher standards for genetic analysis for the field. They also enlisted the help of several other laboratories to confirm their findings.

Ultimately, Gems and his collaborators concluded that the longer lifespan seen in nematodes expressing abnormally high levels of sir-2.1 was due to an unrelated mutation at a second location in the genome. When that second mutation, in a sensory neuron gene previously linked to longevity, was bred out, they found no evidence that sir-2.1 boosted lifespan.

Meanwhile, Patridge's lab checked similar claims in fruitflies that expressed high levels of the Drosophila gene Sir2. They found that the longevity boost in this case came from DNA that had been inserted into the genome as part of the construct used to overexpress Sir2--not to the gene itself.

Disputed findings

The laboratories that originally found the link between sirtuins and lifespan in these animals contest the results. In a related article also published today in Nature, Guarente also finds that an unrelated mutation enhances longevity in C. elegans. But his lab still finds an effect, albeit diminished, of sir-2.1 alone on lifespan. In 2001, his team reported a boost of 15% to 50%; now they have downgraded that result to 10%-14%.

And Stephen Helfand, a molecular geneticist at Brown University in Providence, Rhode Island, who performed the original fruitfly work, says that the publication of Gems' paper surprises him. "Our published studies directly and completely address the genetic background concern," he says, pointing to a 2009 publication in the journal Aging in which his team used a different method to overeexpress Sir2. In that work, the Sir2 gene was overexpressed when the flies were fed a chemical trigger, and Helfand's team compared genetically identical flies with and without the compound. "This approach completely removes concerns about any potential genetic background," he says.

In 2008, London-based pharmaceutical giant GlaxoSmithKline paid $720 million to buy Sirtris, a biotechnology company based in Cambridge, Massachusetts, that was developing drugs to stimulate sirtuins. GlaxoSmithKline declined to grant interviews about the new study, but issued a statement emphasizing Sirtris's focus on boosting health and fighting age-related diseases rather than lengthening lifespan. "These two publications in lower-order species do not have any direct impact on the understanding of the role of sirtuins in human health and disease nor in our drug discovery efforts targeting these enzymes," the statement reads.

But even as the links to longevity come under fire, the benefits of sirtuins on metabolism remain intact, argues David Lombard, who studies the mammalian sirtuins at the University of Michigan in Ann Arbor, and was a graduate student in Guarente's lab. "All of the sirtuins have undeniable beneficial effect with respect to 'healthspan'," he says. "This has been shown in many different labs and in many different contexts."

And Gems agrees that the sirtuins should not be abandoned altogether. "They are very interesting proteins in their own right, and have very interesting metabolic effects," he says. "They may be good drug targets."

But the clamour around sirtuins and longevity--and the ensuing controversy--may have hurt the field, says Auwerx. He has been interested in setting up a biotechnology company based on his work with sirtuins, but he says that investors are wary. "There were too many claims around longevity," he says. "The field needs to calm down."

This article is reproduced with permission from the magazine Nature. The article was first published on September 21.