Scientists have identified a gene that makes roundworms live longer when they eat less, a finding they hope could lead to drugs that promote human longevity, but without the pain of strict dieting.
Roundworms are excellent subjects for longevity research because they usually only live three weeks, making any increment in lifespan quickly apparent. Although people and worms took divergent evolutionary paths some 600 million years ago, they retain many genetic mechanisms in common, including the insulin-signaling control of metabolism and, quite possibly, the ancient survival mechanism of living longer to ride out famines.
This mechanism has been retained by mice, which live a third longer if fed a healthy but very low-calorie diet. Most people find it impossible to stay on such a diet, so researchers would like to stimulate the life-extension mechanism with a drug instead. But first they need to identify the genetic pathway through which the mechanism is set off so that possible drugs can be tested first in mice and then, perhaps, in people.
Disrupting a gene that mediates the insulin-signaling pathway in roundworms is one way of making them live longer. But researchers have been unsure whether this is the pathway involved in achieving the low-calorie/longer-life effect.
In what may prove to be a major clarification of the issue, researchers at the Salk Institute for Biological Studies reported in today’s issue of the journal Nature the existence of a life-extending genetic pathway, which they believe is the one naturally set off by dietary restriction.
The Salk Institute team, led by Siler Panowski and Andrew Dillin, said the new pathway is mediated by a gene already known from its role in building the worm’s gut while the worm is an embryo. This new pathway works independently of the insulin-signaling pathway, they said, although it shares several genetic elements, and is dedicated just to the famine response.
“This may be the primordial gene that regulates nutrients and helps the animal live a long time through dietary restriction,” Dr. Dillin said. “We think it likely to play a role in the human condition.”
The gene has exact counterparts in mammals, three of them, in fact, because the gene tripled at some point in mammalian evolution. The three genes in mice and in people are known as FoxA 1, 2 and 3. The Fox genes are a large family of master regulator genes that control other genes.
The Salk Institute has applied for a patent based on use of the FoxA genes, Dr. Dillin said.
Klaus H. Kaestner, a researcher at the University of Pennsylvania who has long studied the FoxA genes, said the finding was “very significant and will open new avenues for investigation.”
For his own work, Dr. Kaestner has already engineered strains of mice in which the FoxA-1 and FoxA-2 genes can be switched off. He said he had shipped some of the mice to the Salk Institute team, which will test whether the FoxA genes mediate the diet-related longevity response in mice. If mice on restricted diets do not live longer when their FoxA gene is switched off, that would indicate the genes play an essential role in extending the life of the mice.
Leonard Guarente, a longevity researcher at the Massachusetts Institute of Technology, said the newfound role of the worm gene was not the only mechanism involved in life extension and that “the way in which it will fit into the whole story is not clear yet.”
After many decades of being regarded among scientists as a backwater, research on longevity has been enjoying renewed interest.
The stakes are high: a drug that mimicked the effects of caloric restriction in people could lead to significant increases in lifespan. But much work remains to be done in roundworms and mice to define the genetic pathway and its possible side effects in people, like reduced fertility.
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