Lithocholic acid replicates antiaging effects of food restriction in mice, other animals
- 18 DEC 2024
- 11:05 AM ET
- BYMITCH LESLIE
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It’s a dismaying thought during a holiday season full of cookies and big meals, but severely restricting calories consumed is one of the best supported strategies for a healthier, longer life. Slicing food consumption stretches the lives of animals in lab experiments, and similar deprivation seems to improve health in people, although almost no one can sustain such a calorie-depleted diet for long. Now, researchers in China studying animals on lean rations have identified a molecule made by gut bacteria that delivers some of the same benefits. When given on its own, the molecule makes flies and worms live longer and refurbishes age-weakened muscles in mice, all without leaving the animals hungry.
Although the molecule’s effects in people remain unclear, the discovery is “a really important step forward,” says gerontologist Richard Miller of the University of Michigan, who wasn’t connected to the research. The work, reported in two studiestoday in Nature, “is very thorough.”
Research over the past 90 years has shown that calorie restriction—which to scientists typically means a diet with between 10% and 50% fewer calories than normal—can extend longevity in organisms as diverse as yeast, nematodes, and mice. One experiment also found an effect in monkeys. Trials to test whether calorie restriction increases human life span would take too long, but participants in the 2-year CALERIE trial, which ran from 2007 to 2010 and aimed to cut calorie intake by 25%, enjoyed a slew of improvements, including lower levels of low-density lipoprotein cholesterol, increased sensitivity to insulin, and a 10% reduction in weight. However, the trial also illustrates what makes calorie restriction so challenging: Participants on average cut their caloric intake by only half the experiment’s goal.
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So, scientists have been hunting for molecules that trigger health-promoting, longevity-stretching effects without privation. To identify new candidates, molecular biologist and biochemist Sheng-Cai Lin of Xiamen University and colleagues took a systematic approach, analyzing the levels of more than 1200 metabolic molecules in blood samples from calorically restricted mice and from counterparts with no dietary limits. They discovered that just over 200 molecules became more abundant when food was in short supply. To winnow this list, Lin and colleagues added the molecules to cultured cells to determine which ones stimulate AMPK, a protein that activates a variety of biochemical pathways when energy is scarce, such as during caloric restriction. Eventually the researchers homed in on one, lithocholic acid, which is made by normal bacterial residents of the intestine.
Giving mice that weren’t calorically restricted drinking water laced with lithocholic acid seemed to make the rodents’ metabolism healthier, increasing sensitivity to insulin, improving the response to sugar, and hiking the number and performance of mitochondria, cells’ energy-generating organelles. When the scientists put the rodents through a series of physical tests, the mice ran farther and for longer and showed better grip strength than peers that were lapping regular water. These findings were “the most striking data” from the study, Lin says, because they suggest lithocholic acid can reverse age-related deterioration.
But is the molecule also a fountain of youth? Fruit flies dosed with lithocholic acid survived about 7% to 10% longer, the researchers discovered, and it extended nematodes’ life span by more than 20%. But the benefits for mice were less clear, producing a slight but statistically insignificant boost to longevity.
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Still, Lin says the molecule mimics many of the positive effects of calorie restriction. But he cautions that people shouldn’t start downing lithocholic acid just yet. “It’s promising, but we have to do more tests.”
A second study from the same team, also out today in Nature, dissects how the molecule switches on AMPK, adding credence to the discovery of its antiaging effects. “The molecule is doing two things that are cool,” says molecular physiologist Dudley Lamming of the University of Wisconsin’s School of Public Health, who wasn’t connected to the study. “It is capable of activating AMPK, and it is capable of extending life span.”
However, physiologist John Speakman of the University of Aberdeen says lithocholic acid’s failure to extend longevity in mice is a blow. “If it doesn’t work in mammals, then it likely has little relevance for human aging and life span extension,” he says. But Miller says it’s too early to disqualify the molecule because the authors only tested it in middle-age mice from one strain. Researchers need to evaluate it in a broader range of mice and start dosing the animals at earlier ages before they can judge its impact on mammal life span, he says.
Lin and his colleagues have already begun to study lithocholic acid’s effects in monkeys, but they don’t have final results. In the meantime, he says, there’s still no shortcut to getting the benefits of eating less.
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