This Molecule Mimics the Antiaging Effects of Dieting—Without the Hunger

After several glorious days of large meals and Christmas cookies, I’m ready to eat healthier and slash some calories. It’s not to drop holiday pounds: Cutting calories is one of the most promising ways to stave off aging in multiple species. In some animals, it could prolong life.

But there’s a caveat: Clinical studies assessing health benefits of caloric restriction in humans are mixed. One reason? Dieting is hard. Dramatically reducing calories for years is nearly impossible for most people.

What if we could mimic the effects of dieting in a pill—reaping benefits without hunger pangs?

In two studies published in Nature, a team from China did just that. After screening over 1,000 molecules from the blood of mice, either on a diet or eating normally, they found a molecule that mimics the effects of caloric restriction.

Called lithocholic acid, or LCA, it’s made naturally by bacteria in our guts and is a component of bile, a yellow-green liquid that digests fats. Feeding LCA to worms and flies—both commonly used to study aging in the lab—extended their lifespans. Elderly mice given water spiked with the molecule also regained muscle strength and athleticism, running far longer when given the choice, and showed improved blood sugar management and overall metabolism.

To be clear, there isn’t any evidence that LCA has similar effects in humans. And in large doses, it could be toxic. But the authors “make a compelling case” that LCA “triggers many of the age-defying and potentially lifespan-extending health benefits of low-calorie diets,” wrote David Sinclair, a prominent longevity researcher at Harvard University, who was not involved in the study.

Long Diet, Long Life

Researchers have known for nearly a century that cutting calories by up to 50 percent, without sacrificing nutrients, can prolong lifespan in worms, flies, and some kinds of mice. Researchers saw similar results in one monkey study (but not another), with health benefits lasting into old age.

Saying no to the caloric equivalent of a muffin a day also seems to slow the pace of aging in humans. In the two-year clinical study CALERIE, one of the largest caloric restriction trials to date, young to middle-aged participants who shaved just a smidge off their usual diet were rewarded with myriad health improvements, such as lower levels of blood-vessel-clogging cholesterol and higher sensitivity to insulin.

But not everyone stuck to their diet. The original goal was to cut calories by 25 percent. Most managed just half of that. This is partly why caloric restriction is so hard to study in people. Forget longevity, when hungry, it’s oh so easy to reach for that enticing chocolate bar.

Cravings aren’t the only downside. Eating less also causes muscles to waste away, increases the risk of infections, and makes it hard to regulate body temperature—all of which may sound sadly familiar to people living with an elderly grandparent and are antithetical to anti-aging.

There’s a straightforward solution that potentially bypasses the negatives of cutting calories. If we can find out how caloric restriction battles aging, it’s then possible to mimic the process with a pill, potentially without the side effects of dieting, hunger and all.

An Unexpected Source

Our bodies react to food in extremely complicated ways. A slew of proteins springs into action to aid digestion, while others rally to absorb nutrients and trigger downstream effects—for example, building muscle or amping up the immune system.

Digging through the maze of metabolism is a headache, but the authors had one lead: A protein dubbed AMPK. Like a conductor, AMPK sparks to life and organizes multiple processes in cells after caloric restriction.

They decided to hunt for molecules in serum—the liquid part of the blood after clotting—that stimulate AMPK production in mice undergoing a diet and those that ate to their heart’s content. After sorting through over 1,200 metabolic molecules, they found roughly 200 that increased in dieting mice. Each molecule was then tested on cells to see if it activated AMPK.

“We took a brute-force approach,” study author Sheng-Cai Lin told Nature.

One molecule stood out: LCA, a component of bile. A liquid that helps digest fat and absorb vitamins, bile is synthesized in the liver and stored in the gallbladder. When released into the digestive tract, harmless gut bacteria transform it into LCA and other similar chemicals.

Called “bile acids,” these chemicals were previously shown to extend the lifespans of worms, yeast, and fruit flies. LCA is naturally produced by the body. So, what happens if we give a little extra?

Have Your Cake and Eat It Too

The team laced drinking water with a small dose of LCA and gave it to old mice for a month. These mice could eat anytime they wanted—no dieting required.

Compared to mice sipping normal water, those sipping on LCA had improved metabolism, insulin sensitivity, and control of blood sugar levels. They also ran further and for longer and could grab onto a bar with more strength, their muscles healing better from the tear-and-wear of physical workouts. Even their cells’ energy factories, or mitochondria, hummed along more efficiently and grew in numbers.

Surprisingly, LCA also boosted levels of GLP-1—the hormone that Ozempic and other blockbuster drugs are based on—without triggering any muscle loss. All these effects were based on AMPK. Mice without the protein didn’t reap any health benefits from LCA.

What about longevity? Feeding LCA to worms and fruit flies significantly extended their lifespan by up to 20 percent. Mice, in contrast, only had a very slight boost that wasn’t statistically significant—meaning the trend could be due to chance. However, just the health benefits are a good starting point to potentially stave off common age-related problems, wrote the team.

Another article from the same team dug deep into the weeds of how LCA works inside cells. Its main target came as another surprise—a protein previously known for its anti-aging effects in yeast, worms, and flies when given resveratrol, a chemical found in red wine. Evidence for resveratrol’s effect on extending longevity is mixed. But together, the new findings suggest the protein target could be a “hub” coordinating how diets impact healthy longevity.

“These data essentially prove that LCA works through the same activation mechanism as resveratrol…—a remarkable finding,” wrote Sinclair.

Lots of questions remain. Many people have had their gallbladders—organs that store bile—removed. So far, there isn’t any evidence the procedure increases the chance of age-related diseases. LCA at high doses is also toxic to the liver and, when combined with DNA-damaging chemicals, could boost the risk of cancer.

Diet is only part of the picture when it comes to longevity. A recent study in genetically diverse mice undergoing caloric restriction suggests that genes may play a larger role. LCA may need to be tested in a larger genetic variety of mice and at different ages, potentially with longer duration.

The team is beginning to give monkeys LCA while monitoring their health. If the results hold up, “these findings could be remembered as a milestone linking caloric intake to age-related diseases,” wrote Sinclair.