Proteins link diet to longevityP

By NICHOLAS WADE

Scientists have elucidated a key element of how diet restriction might boost life span. A single pair of proteins, whose activity is linked to diminished food intake, is responsible for significantly increasing the lifespan of worms, a study published in this week's Nature reports.

"[This study] is going to open a field that's probably going to be important for mammalian life," said gerontologist Nir Barzilai of the Albert Einstein College of Medicine in New York, who was not involved in the study. He cautioned that since the study was done in worms, its relevance to mammalian aging isn't yet clear. "It's not totally translatable, but it is exciting," he said.

Scientists have been studying the phenomenon of increased longevity with diet restriction for about 70 years, and have replicated the effect in many species, from mice and fish to yeast and primates. But until about two years ago, when Andrew Dillin of the Salk Institute for Biological Studies in La Jolla and his team showed that a transcription factor called PHA-4 (or FOXA in humans) was involved, little of the genetic mechanism behind the lifespan benefit had been revealed. The present study, also from Dillin's lab, elucidates upstream elements of the conserved pathway responsible for making diet restricted animals live longer. "It's sort of like a ladder," Dillin told The Scientist. "The bottom rung was FOXA, and now we've added on a few more rungs to the ladder."

Most likely, caloric restriction causes longevity through some combination of genetic and environmental factors, with a reduced flow of nutrients into the body triggering genetic switches that lead to longer life, according to Barzilai. "Those are the switches [Dillin] is working on," Barzilai told The Scientist. "What Dillin is doing here is connecting the interaction between genes and the environment" in Caenorhabditis elegans.

Dillin and his colleagues knew that eliminating a gene involved in protein degradation -- wwp-1 -- from the C. elegans genome resulted in adult worms that were more vulnerable to environmental stresses. This led them to suspect that the gene and the enzyme for which it coded -- WWP-1 -- might play a role in longevity. They showed that mutating WWP-1 in diet-restricted C. elegans could reduce the longer lifespans seen in diet restricted worms with normally functioning WWP-1. Preliminary studies suggested that another enzyme -- UBC-18 -- works in tandem with WWP-1 to produce this effect. "It was very surprising that this enzyme pair was so incredibly specific for the response to diet restriction," said Dillin.

In humans, Dillin said, this enzyme pathway is conserved, so it may be possible to find compounds that alter the activity of these enzymes, essentially tricking the human body into thinking it is calorie-restricted under normal dietary conditions. That in turn could produce the longevity gains seen in calorie restricted individuals without the need for dieting. "WWP-1 and UBC-18 are both enzymes, so they give us good pharmacological targets to make small molecules to go after them," said Dillin.

"You want to have some drug that will imitate caloric restriction, without us eating less," Barzai said, calling Dillin's findings "a natural step" towards this goal.

Dillin and his colleagues elicited this exact effect in normally-fed C. elegans when they over expressed WWP-1 and found that the worms lived 25% longer than normal.

Dillin's lab is now searching for a receptor upstream of WWP-1 and UBC-18 that likely orchestrates the whole longevity/dietary-restriction pathway. His team is also searching for small molecules that target the two enzymes. "We may have some hints, but we don't have any homeruns yet," he said.

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