Lithocholic Acid Phenocopies Anti-Ageing Effects of Caloric Restriction

Academic Background

Caloric restriction (CR) is a dietary intervention used to promote health and longevity by reducing food intake. Although CR has been shown to extend the lifespan of various organisms, the specific metabolic mechanisms behind its effects remain unclear. In particular, it is still unknown which metabolites undergo changes during CR and directly contribute to its physiological benefits. To address this question, researchers conducted metabolomics analyses to identify metabolites that significantly change during CR and further validated their functions.

Source of the Paper

This study was conducted by a team of researchers from the School of Life Sciences at Xiamen University, including Qi Qu, Yan Chen, Yu Wang, and others. The findings were published in Nature in 2024. The research team used metabolomics to identify lithocholic acid (LCA) as one of the metabolites significantly upregulated during CR and further validated its role in mimicking the anti-ageing effects of CR.

Research Process and Results

1. Metabolomics Analysis and Identification of LCA

The study began with metabolomics analysis of serum from mice subjected to 4 months of CR. Using techniques such as high-performance liquid chromatography-mass spectrometry (HPLC-MS), gas chromatography-mass spectrometry (GC-MS), and capillary electrophoresis-mass spectrometry (CE-MS), the researchers detected 1,215 metabolites. Among these, 695 metabolites showed significant changes in CR serum, with LCA being one of the most significantly upregulated metabolites.

2. Functional Validation of LCA

The researchers further validated the function of LCA, finding that it activates AMP-activated protein kinase (AMPK), enhances muscle regeneration, and improves grip strength and running capacity in mice. Additionally, LCA extended lifespan and healthspan in Caenorhabditis elegans and Drosophila melanogaster. Notably, since nematodes and fruit flies cannot synthesize LCA, these results indicate that these organisms can transmit LCA’s signaling effects once it is administered.

3. Mechanism of AMPK Activation

The study found that knockout of AMPK abolished LCA-induced phenotypes in all three animal models, indicating that LCA’s anti-ageing effects depend on AMPK activation. Further research revealed that LCA activates AMPK, inhibits the mTORC1 signaling pathway, and promotes mitochondrial biogenesis, thereby improving muscle function and delaying ageing.

4. Physiological Effects of LCA

In aged mice, LCA administration significantly increased the proportion of oxidative muscle fibers, reduced muscle atrophy, and accelerated muscle regeneration after injury. Additionally, LCA increased NAD+ levels in muscle, enhanced mitochondrial function, and improved age-related glucose intolerance and insulin resistance.

5. Lifespan Extension by LCA

In nematodes and fruit flies, LCA significantly extended mean lifespan and improved healthspan. In aged mice, LCA administration also showed a trend toward lifespan extension, although this effect was not statistically significant.

Conclusions and Significance

This study is the first to reveal that LCA, as a metabolite upregulated during CR, can mimic the anti-ageing effects of CR by activating AMPK. This discovery not only provides new insights into the molecular mechanisms of CR but also offers a potential target for developing anti-ageing drugs. As a natural metabolite, LCA can improve healthspan without causing malnutrition, making it a promising candidate for therapeutic applications.

Research Highlights

1. Discovery of LCA: LCA was identified as a metabolite significantly upregulated during CR, and its anti-ageing effects were validated.
2. Dependence on AMPK: LCA’s anti-ageing effects depend on AMPK activation, highlighting the central role of AMPK in CR.
3. Validation Across Species: LCA extended lifespan and healthspan in mice, nematodes, and fruit flies, demonstrating its broad biological significance.
4. Potential Therapeutic Value: As a natural metabolite, LCA has the potential to be developed into an anti-ageing drug that improves healthspan without causing malnutrition.

Additional Valuable Information

The study also found that LCA administration did not lead to muscle loss, contrasting with the muscle atrophy commonly observed during CR. Furthermore, LCA increased LCA synthesis by modulating the gut microbiota, further revealing the important role of gut microbes in the effects of CR.

Through this research, the team not only uncovered the molecular mechanisms of CR but also provided a theoretical foundation for developing novel anti-ageing drugs.