Lithocholic acid improves health and life span, simulating calorie restriction

Find out how lithocholic acid, a key calorie-restricting metabolite, unlocks the secret to better health, stronger muscles and longer life.

Education: Lithocholic acid phenocopies the antiaging effects of calorie restriction. Image credit: Shutterstock AI / Shutterstock.com

Calorie restriction (CR) is a dietary intervention that promotes various metabolic changes. CR-induced lithocholic acid (LCA) production has been associated with improved life expectancy and many other health-related benefits.

It just passed Nature study used metabolomics to investigate how CR induces metabolic changes that promote physical benefits.

How does CR affect aging?

CR is a non-pharmacological diet that causes several metabolic changes, such as changing cholesterol, free fatty acids, short organic acids, and vitamin levels. Numerous studies have linked CR to improved health and fitness in many organisms, including yeast, mice, flies, nematodes, and monkeys.

Changes in serum metabolite levels can reduce age-related conditions, including homeostasis of cellular proteins, oxidative damage and inflammation. Randomized clinical trials have shown that CR also improves frailty and age-related diseases, such as insulin resistance, central obesity, dyslipidemia and muscle wasting.

CR activates adenosine monophosphate (AMP)-activated protein kinase (AMPK), an enzyme that helps cells maintain energy balance. AMPK regulates several signaling pathways that delay aging, such as forkhead box protein O (FOXO), and rapamycin complex 1 (TORC1). AMPK also produces nicotinamide adenine dinucleotide (NAD+) which activates transcription factor EB (TFEB), activates sirtuins, and inhibits cyclic adenosine monophosphate response element binding protein (CREB)-regulated co- transcriptional activators.

AMPK is associated with many anti-aging cellular processes, such as proteostasis, mitochondrial biogenesis, autophagy, mitohormesis, inflammation, and neurodegeneration. Therefore, AMPK is a key mediator of the health benefits associated with CR.

Metformin and resveratrol are two CR mimetics (CRM) that activate AMPK and contribute to the extended lifespan of many organisms. Therefore, it is important to understand how changes in CR-mediated metabolism in the body help AMPK work to promote health and longevity.

About education

Recent studies have hypothesized that serum metabolites that change as a result of CR may be responsible for its beneficial effects at cellular and physiological levels. To test this hypothesis, the levels of metabolites were analyzed in serum cells, cells, flies and nematodes.

Study findings

Serum analysis revealed that four months of CR treatment in mice (CR serum) induced AMPK in mouse embryonic fibroblasts (MEFs), primary hepatocytes, human embryonic stem cells 293T (HEK293T) and myocytes. in the main. This activity was determined by estimating the levels of phosphorylation of AMPKα (pAMPKα) and substrate acetyl coenzyme A carboxylases (pACC).

Administration of CR serum to mice with an ad libitum diet led to activation of AMPK in liver and muscle. Experimental studies have also shown the presence of heat-stable and low-molecular-weight metabolites in CR serum that can activate AMPK.

Metabolomics and mass spectrometry-based analyzes were performed on serum samples from CR-treated and non-CR-treated mice. A total of 1,215 metabolites were detected, 695 of which were found to be altered in CR serum. Furthermore, compared to the control serum, the CR serum showed decreased phenylalanine, long-chain fatty acids, and tyrosine levels and increased chemical fatty acids, bile acids and acyl-carnitine.

Initial screening tests identified six metabolites that could activate AMPK, which LCA activated AMPK at 1 μM in HEK293T cells, MEF, hepatocytes primary, and primary myocytes. Without AMPK activation, mTORC1 was inhibited, and pACC was increased. MEFs treated with LCA showed reduced phosphoAMPKα2(S345) levels, as well as translocation of TFEB to the nucleus.

After four months of CR treatment, 1.1 μM of LCA was estimated in the serum, which remained stable in mice before and after feeding. For comparison, 0.3 μM LCA was measured in mice fed ad libitum. Experimental studies showed that the CR-induced increase in LCA was independent of muricholate.

LCA treatment did not cause any change in the intensity levels in all the tissue types studied, or in the liver and muscles of the CR-treated mice. LCA treatment did not activate AMPK through TGR5 in MEFs or cause an increase in calcium concentrations that would induce CaMKK2-mediated AMPK activation. Therefore, LCA appears to be a specific metabolite in CR serum that activates AMPK in physiological conditions.

Administration of LCA in male and female mice for one month revealed improved muscle performance, as shown by an increase in muscle oxidative stress and a reduction in glycolytic fibers. This treatment also improved muscle regeneration after damage in aged mice. In mice treated with LCA, a significant increase in plasma glucagon-like peptide 1 (GLP-1) levels was observed.

Aged mice treated with LCA showed improvements in running distance, time and grip strength. This treatment also reduces age-related glucose intolerance and insulin resistance.

Decisions

LCA was identified as a metabolite formed by CR that can activate AMPK and improve the lifespan of many organisms, including hermaphroditic nematodes, flies and mice. Thus, the anti-aging effects of LCA were demonstrated.