Highlights

  • Through the analysis of metabolite concentrations affected by calorie restriction, scientists identified lithocholic acid (LCA), which activates a pathway that works against aging.
  • When administered to aged mice fed a standard diet, lithocholic acid mimicked calorie restriction by alleviating insulin resistance and improving physical function.

Calorie restriction (CR), where daily caloric intake is reduced by about 30%, is perhaps the best way aging researchers know of to extend lifespan in various model organisms like mice and monkeys. Maybe even more meaningful, human studies suggest that CR improves aging-associated conditions like frailty, obesity, and insulin resistance. However, figuring out how CR works has remained unclear. This is important, because uncovering how CR works at the molecular level could aid in developing treatments—known as CR mimetics—that mimic CR’s aging intervention effects.

Now, published in Nature, Lin and colleagues from Xiamen University in China show that a bile acid called lithocholic acid (LCA) recapitulates some of CR’s healthspan-extending effects in aged mice. Along those lines, LCA was among about 700 metabolites that showed significantly altered levels in the blood after undergoing CR, where CR increased LCA. Also, LCA stood out as a possible CR mimetic since it activates a protein believed to facilitate CR’s effects—known as AMPK—in mouse and human cells. Confirming that LCA recapitulates CR’s effects, Lin and colleagues found that the bile acid alleviated insulin resistance, increased nicotinamide adenine dinucleotide (NAD+) levels in muscles, and improved grip strength in aged mice. These findings tie LCA to the aging intervention effects of CR and support the notion that it may one day be used as a CR mimetic.

“We provided multiple lines of evidence to show that LCA acts as a [CR mimetic], recapitulating the effects of CR, including AMPK activation and rejuvenating and anti-ageing effects,” say Lin and colleagues in their publication.

Fleshing Out Lithocholic Acid’s Effects Against Aging

Lin and colleagues hypothesized that one or more metabolites contained in blood confers the aging intervention effects of CR. To examine whether this may be the case, the China-based researchers initiated CR in aged mice for four months and then tested what metabolites showed altered blood concentrations. Lin and colleagues measured metabolites with altered blood concentrations since CR may confer effects against aging by increasing or reducing certain metabolites.

Moreover, CR mimetics like the compounds metformin and resveratrol are believed to confer effects against aging by activating the protein AMPK—a cellular protein that helps maintain energy balance. For this reason, Lin and colleagues sought to test what metabolites with CR-induced blood level alterations also activate AMPK to potentially confer effects against aging.

Interestingly, the researchers found about 700 blood metabolites with significantly altered levels. Furthermore, after whittling down candidate metabolites, they uncovered that LCA, which increased with CR, was the only one that activated AMPK in mouse and human cells at concentrations found in the body. These findings made LCA stand out as a metabolite that could work against aging, possibly as a CR mimetic, since along with activating AMPK, it showed elevated blood concentrations after CR.

(Qu et al., 2024 | Nature) CR increases blood LCA about fivefold. Blood LCA concentrations (LCA concentration [µM]) increase incrementally with a CR diet for the first seven days or so and peak at about a fivefold elevation after undergoing CR for two weeks.

Testing Whether Lithocholic Acid Extends Healthspan in Model Organisms

To validate LCA’s potential aging intervention properties, Lin and colleagues measured whether this bile acid prolongs lifespan. Interestingly, LCA significantly extended lifespan in roundworms and flies, however, when tested in mice, LCA induced a non-significant trend for lifespan extension. For mice treated with LCA, lifespan was extended between about 5% and 10% in mice, which did not reach statistical significance.

LCA treatment trended toward increasing lifespan by about 5% to 10%; however, the extension was not statistically significant for most groups.
(Qu et al., 2024 | Nature) LCA treatment trended toward increasing lifespan by about 5% to 10%; however, the extension was not statistically significant for most groups. For one of three groups of mice tested (Cohort 2), LCA treatment increased the average male lifespan by about 5% and female by about 10%. For this cohort, the female lifespan extension was significant, yet neither male nor female groups in the other cohorts showed significant lifespan extension.

Although LCA did not extend mouse lifespan significantly, Lin and colleagues sought to determine if the bile acid enhanced health parameters associated with aging. Indeed, the researchers found that LCA treatment alleviated insulin resistance, increased NAD+ levels in muscle, and improved grip strength in aged mice. These results lend support to the notion that LCA may work against aging by extending healthspan in mice.

CR Increases Gut Bacteria that Biosynthesize LCA

Intriguingly, LCA is produced in the body when certain gut bacteria synthesize this bile acid from molecular precursors released from the liver. In that sense, Lin and colleagues convey the idea that CR may somehow initiate changes to the gut bacterial composition—the microbiome—to thereby increase the biosynthesis of LCA. Thus, not only could LCA someday be used as a CR mimetic but increasing the abundance of LCA-synthesizing gut bacteria—specifically, Lactobacillus, Clostridium, and Eubacterium—could confer effects against aging.

As for why LCA did not significantly extend lifespan in mice, the mice received a certain dosage of LCA beginning at one year of age. Thus, it remains possible that altering the LCA dosage and/or beginning treatment at a different age could push the lifespan extension from LCA toward significance.