Fat tissue (artificially coloured) is reduced by stringent, long-term calorie cutting. A newly identified molecule mimics this diet’s anti-ageing effects. Credit: Steve Gschmeissner/Science Photo Library
For decades, researchers have been trying to unravel why a severe and prolonged reduction in calorie intake extends life for many animals. Now, a team has found a molecule that could provide caloric restriction in a pill ― at least for flies and worms.
The molecule, called lithocholic acid, is made by bacteria in the gut and aids the digestion of fats. In two papers1,2 published on 18 December in Nature, researchers show that lithocholic acid can extend lifespan in nematodes (Caenorhabditis elegans) and fruit flies (Drosophila melanogaster), and make old mice spry again.
There is no evidence yet that taking lithocholic acid would have the same effect in humans. At high doses, it could be toxic.
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The study of ageing and longevity is littered with claims that certain compounds extend lifespan — claims that did not survive closer scrutiny. But the papers are remarkably thorough, says Nicholas Schork, lead investigator of the US National Institute on Aging’s Longevity Consortium and a genomicist at the Translational Genomics Research Institute in Phoenix, Arizona. “I found them very compelling,” says Schork, who was not involved in the works. “They went way beyond what many other groups have done to make claims about potential health benefits.”
Standing up to scrutiny
Previous work has shown that calorie restriction can lengthen lifespan in a variety of animals, including nematodes, flies, mice and some primates. A protein called AMPK is known to be switched on by caloric restriction and plays a crucial part in its beneficial effects.
But constant hunger is not the only price of calorie restriction, which can involve slashing caloric intake by more than half; studies have also linked it to loss of lean muscle mass, difficulty in regulating body temperature and possibly increased risk of infection, says Andrea Di Francesco, who studies the biology of ageing at Calico Life Sciences, a biotechnology company in South San Francisco, California.
Needle in a haystack
Biochemist Sheng-Cai Lin at Xiamen University in China, and his collaborators, decided to sift through the myriad metabolic changes caused by calorie restriction in mice to search for compounds that can turn on AMPK1. It was a daunting task: most of the compounds made during metabolic reactions change in abundance during starvation or calorie restriction, says Lin. “We took a brute-force approach.”
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The team painstakingly analysed more than 200 compounds whose levels increased after caloric restriction, testing each to determine whether it could activate AMPK. Of the six that could, one did so at levels similar to those found in mice after caloric restriction. That one was lithocholic acid, a chemical found in the digestive fluid called bile.
The team then fed lithocholic acid to nematodes, fruit flies and mice. The fruit flies and nematodes lived significantly longer than those that had not consumed added lithocholic acid.