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A recent study published in Nature sheds light on the remarkable role of lithocholic acid (LCA) in promoting health and lifespan, effectively mimicking the benefits of calorie restriction (CR). The research, which involved detailed metabolomics analysis, reveals how LCA, a metabolite induced by CR, can activate essential biological pathways that enhance longevity and protect against age-related diseases.
Calorie Restriction and Aging
Calorie restriction (CR) has long been recognized as a powerful non-pharmacological intervention that extends lifespan and improves overall health. Through its effects on metabolic pathways, CR induces changes in cholesterol, free fatty acids, organic acids, and vitamins, all of which contribute to its beneficial outcomes. Studies in multiple species—from yeast and flies to mice and primates—have consistently shown that CR promotes health and combats age-related conditions such as insulin resistance, central obesity, dyslipidemia, and muscle deterioration.
At the cellular level, CR activates AMPK (AMP-activated protein kinase), a key enzyme that helps maintain energy balance within cells. AMPK regulates critical pathways that delay aging, such as the FOXO proteins and TORC1, and contributes to the production of NAD+, which activates beneficial cellular processes. CR mimetics, such as metformin and resveratrol, are known to mimic these effects, but understanding the exact molecular mechanisms behind CR’s success is crucial for developing targeted therapies.
Study Investigating Metabolites in CR
The new study aimed to investigate how specific serum metabolites, altered by CR, contribute to the metabolic changes that promote health and longevity. Researchers analyzed metabolites from serum samples of CR-treated and non-treated mice, as well as flies and nematodes, to identify key molecules associated with CR’s anti-aging effects.
The study uncovered significant changes in the metabolite profiles of CR-treated mice, including reduced levels of phenylalanine, long-chain fatty acids, and tyrosine, alongside increased levels of short-chain fatty acids, bile acids, and acyl-carnitines. Of these metabolites, LCA stood out as a potent activator of AMPK, the central regulator of cellular energy.
Lithocholic Acid’s Role in Health and Longevity
LCA was shown to activate AMPK in various cell types, including mouse embryonic fibroblasts (MEFs), hepatocytes, human kidney cells, and myocytes. This activation was accompanied by reduced mTORC1 activity and increased levels of acetyl coenzyme A carboxylases, crucial markers of metabolic efficiency. Interestingly, LCA treatment did not cause significant energy shifts in the cells or tissues, suggesting that LCA’s benefits arise from its specific modulation of AMPK rather than global energy changes.
In addition to its molecular effects, LCA treatment in aged mice demonstrated significant improvements in muscle performance, muscle regeneration, and glucose metabolism. Mice receiving LCA showed increased oxidative muscle fibers, enhanced running distances and grip strength, and alleviated glucose intolerance. These findings mirror the benefits typically associated with CR, providing compelling evidence that LCA can act as a CR mimetic.
LCA as a Potential Anti-Aging Therapy
The findings from this study highlight LCA as a critical metabolite in the CR-induced metabolic pathway. Its ability to activate AMPK and improve various aspects of health, including muscle function and insulin sensitivity, underscores its potential as a therapeutic agent for promoting longevity and mitigating age-related decline.
As LCA mirrors the effects of CR, it may offer a promising avenue for developing anti-aging therapies that can extend healthspan without the need for drastic dietary changes. Further research into LCA and other CR-induced metabolites could lead to novel treatments aimed at enhancing human health and lifespan.
Conclusion
Lithocholic acid is the latest discovery in the growing list of CR mimetics, with the potential to significantly enhance health and delay aging. This study paves the way for exploring how specific metabolites, such as LCA, can promote longevity and improve quality of life through targeted metabolic pathways, offering new hope for age-related diseases and lifespan extension.
Journal Reference: Qu, Q., Chen, Y., Wang, Y., et al. (2024) Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature 1-9. doi:10.1038/s41586-024-08329-5
