A recent study has discovered lithocholic acid (LCA), a metabolite present in the serum of calorically restricted mice, which can mimic the metabolic effects of caloric restriction.

Researchers utilized mass spectrometry to identify over a thousand metabolites in serum, finding that nearly seven hundred were altered by caloric restriction, with LCA emerging as the key metabolite that activates AMP-activated protein kinase (AMPK) at physiological concentrations.

In model organisms like C. elegans and D. melanogaster, treatment with LCA resulted in increased lifespan and improved healthspan markers, with AMPK activity being crucial for these benefits.

Unlike caloric restriction, which often leads to muscle loss, LCA treatment did not cause such loss and even promoted muscle regeneration following damage, indicating its potential for therapeutic applications without the negative effects associated with caloric restriction.

When tested on aged mice, LCA treatment improved physical performance metrics, including running distance and grip strength, while also positively affecting molecular markers such as NAD+ levels and glucose tolerance.

In mice, the lifespan extension effects of LCA were modest, particularly when treatment commenced at one year of age, suggesting that adjustments in dosage or timing may enhance its efficacy.

Mice subjected to four months of caloric restriction had their serum used to treat cell lines, leading to AMPK activation, which indicates that components in the serum can replicate the effects of caloric restriction.

Increased levels of LCA were found in the feces of calorically restricted mice, and similar findings in humans hint at a potential connection between fasting and LCA levels, suggesting broader implications for dietary interventions.

The study also emphasizes the role of gut microbes in LCA metabolism, with specific bacterial species such as Lactobacillus and Clostridium linked to LCA production during caloric restriction.

Caloric restriction has been shown to enhance healthspan and extend lifespan across various model organisms, indicating potential health benefits for humans as well.