Research Identifies New Pathway Affecting Lifespan

By Eric Sauter

A team led by a scientist from the Florida campus of The Scripps Research Institute has identified a new role for a biological pathway that not only signals the body's metabolic response to nutritional changes, but also affects lifespan.

The study, published in the May 12, 2011 issue of the journal Nature, was conducted on Caenorhabditis elegans (nematodes or roundworms), which are a widely accepted model for human aging research.

"We been able not only to identify some of these molecules for the first time in the worm, but also to show they act as a signal of nutrient availability and ultimately influence the worm's lifespan," said Gill. Gill, an assistant professor in the Scripps Research Department of Metabolism and Aging, conducted the research while at The Buck Institute for Research on Aging in Novato, California. "What makes this important is that the same molecules are present in both humans and C. elegans, so these molecules may play similar roles in both organisms."

Dietary restriction is a well-known means of extending lifespan and postponing age-related disease in many species, including yeast, worms, flies, and rodents. However, until this study, little was known about the molecular signals involved.

The molecules identified in the new study are N-acylethanolamines (NAEs), a group of signaling molecules derived from lipids that help indicate nutrient availability in the environment and maintain an animal's internal energy balance. In the study, Gill and his colleagues showed that NAE abundance in the worm is reduced during periods of dietary restriction, and that NAE deficiency in the presence of abundant food is sufficient to extend the animal's lifespan.

"It is well known that if you put C. elegans on a restricted diet, you can extend its lifespan by 40 to 50 percent," Gill said. "However, we were amazed to see that if you add back just one of these NAE molecules, eicosapentaenoyl ethanolamide, it completely abrogates the lifespan extension."

Importantly, this particular NAE is similar to endocannabinoids in mammals, which regulate many different physiological processes including nutrient intake and energy balance, as well as inflammation and neuronal function. "The identification of other components of a novel endocannabinoid system in the worm now brings a new model system to the many researchers studying NAE and endocannabinoid physiology," said Gill.

Intriguingly, the study also established a link among fat, NAE levels, and longevity. Other studies in rodents have shown that the availability of fatty acids can influence NAE levels. However, Gill and his colleagues found that in a genetically altered strain of C. elegans the inability to produce certain polyunsaturated fatty acids was not only associated with a reduction in levels of specific NAEs but also with lifespan extension. He added that the study's findings could shape future drug development efforts to influence aging and age-related disease.

The first author of the study, "N-Acylethanolamine Signaling Mediates the Effect of Diet on Lifespan in C. elegans," is Mark Lucanic, a postdoctoral fellow at the Buck Institute for Research on Aging. Other authors include Jason M. Held, Maithili C Vantipalli, Jill B. Graham, Bradford W. Gibson, and Gordon J. Lithgow of the Buck Institute for Research on Aging; and Ida M. Klang of the Buck Institute for Research on Aging and the Karolinska Institute. For more information, see http://www.nature.com/nature/journal/v473/n7346/abs/nature10007.html.

The study was supported by the Larry L. Hillblom Foundation and the National Institutes of Health.

Send comments to: mikaono[at]scripps.edu

"We been able not only to identify some of these molecules for the first time in the worm, but also to show they act as a signal of nutrient availability and ultimately influence the worm's lifespan," says Matthew Gill, a new assistant professor at Scripps Florida who conducted research while at The Buck Institute for Research on Aging. (Photo by James McEntee.)