Living

For decades, researchers have been trying to answer a question: why strict and long-term calorie restriction can extend the lifespan of many animals. Now, a team has found a molecule that can have the effect of calorie restriction in the form of a pill - at least in fruit flies and worms. 

This molecule is called lithocholic acid, which is produced by bacteria in the gut and helps break down fat. In two papers [1, 2] published in Nature on December 18, 2024, researchers demonstrated that lithocholic acid can extend the lifespan of nematodes (Caenorhabditis elegans) and fruit flies (Drosophila melanogaster), and can rejuvenate old mice. Currently, there is no evidence that taking lithocholic acid has the same effect on humans.

 High doses of lithocholic acid may be toxic. Strict and long-term calorie restriction can reduce adipose tissue (artificially colored).

A newly discovered molecule can mimic the anti-aging effects of this diet.

 In the research on aging and longevity, claims that certain compounds can extend lifespan are always "rife", but these claims do not hold up to scrutiny.

However, these two papers are very comprehensive, said Nicholas Schork, the principal investigator of the Longevity Consortium at the US National Institute on Aging and a genomics scientist at the US Translational Genomics Research Institute. "I find these two papers very convincing," said Schork, who was not involved in the study. "They have done much more work than other teams that have proposed potential health benefits."

 Before being testedPrevious studies have shown that calorie restriction can extend the lifespan of a large number of animals, including nematodes, fruit flies, mice, and some primates.

 Calorie restriction can "activate" a protein called AMPK, which plays a key role in these benefits.

However, long-term starvation is not the only cost of calorie restriction. Sometimes, these restrictions require reducing calorie intake by more than half - research has found that this is associated with a decrease in muscle mass, difficulty in regulating body temperature, and a possible increased risk of infection, said Andrea Di Francesco, who studies the biology of aging at the California biotech company Calico Life Sciences.

 Looking for a needle in a haystackLin Shengcai, a biochemist at Xiamen University in China, and his collaborators decided to screen various metabolic changes in mice caused by calorie restriction to find compounds that can activate AMPK [1]. This task was no small feat: most of the compounds generated during metabolic reactions change significantly during starvation or calorie restriction, Lin Shengcai said.

"We adopted a brute force method." The team painstakingly analyzed more than 200 compounds whose levels increased after calorie restriction and tested them one by one to see if they would activate AMPK. Among the six compounds with activation effects, one was similar to the level found in mice after calorie restriction.

This compound is lithocholic acid, which exists in the digestive fluid called bile.

The team then fed lithocholic acid to nematodes, fruit flies, and mice.

 The lifespan of fruit flies and nematodes was significantly longer than that of their counterparts without additional lithocholic acid intake.

 The effect on the lifespan of mice was not statistically significant, but the team found that mice fed lithocholic acid were more youthful in various indicators such as grip strength and muscle composition.

This result is exciting enough, Schork said. "Lithocholic acid, like dietary restriction, can indeed bring health benefits." Lin Shengcai and his team then studied how lithocholic acid activates AMPK and identified another protein, TULP3, as the receptor for lithocholic acid [2].

What centenarians have to saySchork said that the next step is to test this reaction in mice with various genetic backgrounds. A study published in October found that genetic background has a greater impact on lifespan than calorie restriction [3]. Previous studies have indicated that lithocholic acid and other compounds in bile may be important in calorie restriction, Di Francesco said. In particular, he mentioned a study [4] that found high levels of lithocholic acid in Japanese centenarians.

Even so, Lin Shengcai said, we still don't know the impact of lithocholic acid on human life expectancy and healthy lifespan.

 The team is conducting research on non-human primates to further understand the best time and dose for administering lithocholic acid. "We have a responsibility to remind people not to take lithocholic acid without more experiments," Lin Shengcai said. "When it comes to immortality, some people tend to lose their senses."