Researchers who re-tested findings of previous studies suggesting the so-called “longevity gene” prolonged lifespan through the production of sirtuin proteins, say the effect is most likely not due to that gene but to other confounding genetic factors in the modified organisms used in the experiments. They also show that dietary restriction alone probably increases lifespan, independently of sirtuins. The researchers, led by Dr David Gems at the Institute of Healthy Ageing at University College London (UCL), UK, write about their findings in a paper published this week in the journal Nature.
Previous studies suggested sirtuins significantly increased lifespan in organisms used as biological models for studying aging in humans. They showed than when the genes of yeast, the nematode worm and the fruit fly were engineered to over-produce sirtuin, this increased their lifespan, by as much as 50% in the case of nematodes.
Further work looking at the effects of dietary restriction on longevity, also suggested this effect was due to activation of sirtuins.
The studies received a lot of publicity, and the sirtuin-producing gene became known as the “longevity gene”.
Some anti-aging creams also claim to target sirtuins by including a plant-based drug called resveratrol, thought to be a sirtuin activator: traces of resveratrol can be found in red wine. But later studies have cast doubt on whether resveratrol stimulates sirtuin production.
In their Nature study, which was funded by the Wellcome Trust and the European Union, Gems and his team at UCL, joined by colleagues from the University of Washington, Seattle, in the US, and Semmelweis University in Budapest, Hungary, provide almost conclusive evidence that the effects on animal longevity demonstrated in the earlier studies were not due to sirtuin.
They started by looking at two different strains of nematode worm, each from a different prior study. The worms had been genetically modified so their sirtuin genes were over-active.
Not surprisingly, they found that the genetically modified worms lived longer than the “wild” type control worms that had not been genetically modified.
However, when they did the test again, this time making sure that the only difference between control and manipulated worms was the latter’s ability to overproduce sirtuin, they found the longevity effect disappeared. This suggested some other genetic factor had caused the previous effect. In one of the two original strains, they identified a likely mutation in a gene that is involved in the development of nerve cells.
The researchers then turned to another set of experiments, this time using a transgenic model of the fruit fly Drosophila melanogaster that had been the subect of the earlier studies that had suggested longevity was due to overproduction of sirtuins.
Again, the researchers found that genetic factors other than sirtuins were behind the longevity effect. They suggest it was the DNA that had been inserted in the fly’s genome as part of the construct used to overproduce sirtuin that had caused the effect. They became even more convinced when they produced a new strain of fruit fly that produced even higher levels of sirtuins and found it did not have a longer lifespan.
And, despite repeated attempts, both in the UK and the US labs, the researchers were not able to show that resveratrol activates sirtuin.
In a third set of experiments, Gems and colleagues re-examined the suggestion that dietary restriction causes longevity by activating sirtuins. For these they modified fruit flies so they lacked the sirtuin gene and found that dietary restriction still led to longer lifespan. They concluded dietary restriction did not work through sirtuins.
Gems told the press they found the results “very surprising”.
“We have re-examined the key experiments linking sirtuin with longevity in animals and none seem to stand up to close scrutiny. Sirtuins, far from being a key to longevity appear to have nothing to do with extending life.”
But he said they see this as good news, because it is just as important to revise old ideas as to present new ones.
“This work should help to redirect scientific efforts toward those processes that really do control aging,” he added.
The study has had a mixed reception. Some researchers say it has helped to clear the air, there has been a lot of hype about sirtuins, while others claim the sirtuin case is still robust.
Johan Auwerx, a researcher at the Federal Institute of Technology in Lausanne, Switzerland, has worked with sirtuins but did not take part in the Gems study. He told Nature News the Gems study will help to free 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,” said Auwerx, “I don’t think that’s the main function of the sirtuins.”
But another sirtuin researcher, Leonard Guarente, based at the Massachusetts Institute of Technology in Cambridge, who published the original research on the nematode worm, argues that the longevity link exists, and describes Gems’ paper as a mere “bump in the road”.
“Our data are rock solid,” he told Nature News, “I stand by them, and they have been replicated in other labs.”
Gems himself was originally reluctant to work on this, but he eventually decided to investigate the rumours that were circulating and questioning some of the original findings.
Auwerx said the previous hype may have done some damage to the field. He was interested in starting a biotech company to use his work on sirtuins, but investors were getting nervous. He said there were too many claims around longevity, and “the field needs to calm down”.
Gems told Nature News we should still be interested in sirtuins. They were interesting proteins in their own right, and have some very interesting metabolic effects: they could still be useful drug targets, he added.
Written by Catharine Paddock PhD