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Biochemistry

A bile acid may mimic caloric restriction

The molecule, known to be toxic at higher doses, may activate sirtuin signaling

by Laurel Oldach
December 18, 2024

Over the years, researchers have amassed strong evidence that caloric restriction can extend lab animals’ lives. Unfortunately, extending those benefits to humans has proved difficult, in part because the restrictive diets required are difficult for most people to maintain.

In the hunt for more palatable ways to achieve the same lifespan-extending effects of caloric restriction, researchers are trying to identify the molecular mechanisms behind them. In a paper in Nature, researchers at the Chinese Academy of Sciences and Xiamen University report that they have identified one such caloric restriction mimetic—a bile acid called lithocholic acid, or LCA (2024, DOI: 10.1038/s41586-024-08329-5).

Structure of the bile acid lithocholic acid.
Like most bile acids, lithocholic acid is derived from cholesterol.

Humans and other organisms make bile acids to help solubilize fats for digestion. But once they’re secreted into the gut, these molecules become subject to secondary metabolism. Enzymes from bacteria chemically tweak host bile acids for their own ends, producing a kaleidoscope of modifications and conjugations that researchers are just beginning to understand.

Lithocholic acid is one such secondary metabolite, made by gut bacteria from a bile acid produced by the host. But the idea that LCA could provide health benefits surprises some gastroenterologists, who are more used to thinking of LCA as an unusual example of an endobiotic molecule—a metabolite—that is also a toxin.

According to Paul Dawson, who studies bile acid metabolism at Emory University, bile acids are “the Jedi knights of small molecule endobiotics. They have great power for good or evil.”

Bile acids are 'the Jedi knights of small molecule endobiotics. They have great power for good or evil.'
Paul Dawson, gastroenterologist, Emory University

Researchers have typically considered LCA to belong to the dark side because high doses can cause liver damage, Dawson says. In fact, some gastroenterologists use it to induce liver damage in animal models so they can research protective treatments. But increasingly, at low concentrations, people are finding biological effects of LCA that are unrelated to its endotoxic activity, he says.

Past studies have shown that mice on a lower-calorie diet show higher activity of a protein called AMPK in their muscles and less sign of muscular atrophy. In cultured cells, serum from fasting mice can activate AMPK.

In the new study, the authors identified hundreds of metabolites that change significantly in mouse serum during caloric restriction. By subjecting serum to dialysis, heat inactivation, and lipid extraction and then testing for AMPK activation, the researchers made a candidate list of roughly 340 polar metabolites that could be involved. By treating cultured cells with most of these compounds, the team identified LCA as one driver of AMPK activation.

Mice that received low levels of LCA and a cyclodextrin vehicle in their drinking water also showed higher AMPK activity, and the treatment appeared to prolong some markers of healthy aging like grip strength and an ability to run longer distances. The authors say these changes indicate that elevated LCA may be behind some of the health benefits that calorie-restricted mice enjoy.

But, the study’s authors found that while the compound extends the life of fruit flies and nematode worms, it does not make a statistically significant difference in mouse lifespan. That finding suggests that there are other missing components, Dawson says.

In a companion paper exploring how LCA activates AMPK (Nature 2024, DOI: 10.1038/s41586-024-08348-2), the same authors report that the molecule’s activity depends on signaling from sirtuins, an enzyme family thatresearchers have long linked to aging but have had difficulty pinning down. The authors identify a protein that binds to LCA and activates sirtuins, launching a signaling pathway that also kick-starts AMPK when glucose is in short supply. In a commentary for Nature, Harvard Medical School biologist David Sinclair, who studies aging, writes that “these findings could be remembered as a milestone linking caloric intake to age-related diseases.”

Vijay Yadav, a longevity and metabolism researcher at Rutgers University, says in an email that LCA “could very well be one component that may mediate effects of [caloric restriction] in some tissues” but he strongly doubts that it acts alone. In addition, he is concerned that the study did not examine LCA-treated mice for potential liver damage.

In an email to C&EN noting that LCA seems to act through the same pathway as the well-known drug metformin, corresponding author Sheng-Cai Lin says that “since we observed all the pro-health effects of LCA, we were not concerned about any damage to the liver.” But according to Yadav, mice, humans, and other primates each have their own pathways for detoxifying LCA, meaning that the molecule’s toxicity profile differs between species—so care will need to be taken with follow-up studies.

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