two recently published studies just highlighted the role of lithocholic acid, an intestinal molecule produced by bacteria, in slowing aging in certain animal models.
Intestinal Flora Credit: Dr William Ju, University of Toronto
A new potential proof of the importance of the gut microbiota in our health: researchers from China and the United States have identified a molecule that could play a role in slowing aging in certain animals subjected to a restrictive diet. Their results, which build on years of research on the effects of low-calorie diets, have been published in two articles in the journal Nature.
Read Also: Study Confirms Longevity and Health Benefits of Calorie Restriction
Restrictive Diets, Lithocholic Acid, and Overall Health
For years, studies have shown that a low-calorie diet can improve health. In some animals, such as fruit flies and nematodes (microscopic worms), this type of diet even extends life expectancy. However, testing these effects on humans remains complex due to their relatively long lifespan. To overcome this challenge, scientists are turning to alternative approaches, including studying molecules produced in the gut.
In this new study, the team focused their efforts on lithocholic acid (LCA), a secondary bile acid produced by intestinal bacteria, according to a press release. Though once considered toxic, recent research has revealed that at low doses, LCA may offer significant health benefits. Giving mice, small doses of LCA led to an increase in the production of a protein called AMPK. This protein is known to play a role in energy regulation and has also been shown to slow muscle atrophy which aligns with previous findings that already linked LCA to enhanced grip strength, running capacity, and muscle regeneration in aged mice, mirroring some effects of calorie restriction (CR).
To reach these conclusions, researchers monitored the levels of various metabolites in the intestines of mice on a restrictive diet. Among hundreds of identified compounds, LCA emerged as a key player in AMPK activation. Interestingly, the beneficial effects of LCA were completely dependent on AMPK activation, as blocking AMPK nullified these outcomes. Although no evidence was found linking LCA to increased lifespan in mice, the improvements in healthspan are noteworthy.
Comparison of Lithocholic Acid (LCA) and Calorie Restriction (CR): Effects on Health and Aging
Aspect | Lithocholic Acid (LCA) | Calorie Restriction (CR) |
---|---|---|
Source | Produced by gut bacteria as a secondary bile acid | Reduction in calorie intake without malnutrition |
Activation Pathway | Activates AMPK through gut-derived metabolites | Activates AMPK and other metabolic pathways |
Health Benefits | Improved muscle regeneration, metabolic efficiency, and stress resistance | Improved metabolic health, reduced oxidative stress, and longevity |
Species Studied | Mice, nematodes, fruit flies | Broad range, including humans and model organisms |
Effects on Lifespan | No significant increase in lifespan observed | Extended lifespan in many model organisms |
Effects on Healthspan | Enhanced grip strength, running capacity, and reduced age-related decline | Improved physical and cellular health |
Safety Profile | Low doses are non-toxic | Requires strict dietary adherence, which can be challenging |
Ease of Use | Could be a supplement in the future | Requires long-term commitment to dietary changes |
Potential Applications | Anti-aging therapies, muscle health, metabolic disorder treatments | Broad, including aging, obesity, and metabolic syndrome |
Still, more research is needed
In a second study, researchers explored how LCA activated AMPK. They discovered that this process depended on certain members of the sirtuin enzyme family, which play a crucial role in essential biological processes, such as cellular metabolism, stress response, and aging. The study also highlighted that LCA’s effects extend across species, with nematodes and fruit flies also benefiting from AMPK activation, showing increased stress resistance and lifespan improvements. This cross-species conservation underscores LCA’s fundamental role in cellular energy regulation.
Read Also: Caloric Restriction Enhances Muscle Efficiency and Reduces Age-Related Inflammation, Study Finds
What makes LCA particularly compelling is its safety profile. The concentrations required to activate AMPK and deliver health benefits are well below levels associated with toxicity. This positions LCA as a promising candidate for further exploration as a caloric restriction mimetic (CRM), which could replicate the health benefits of CR without requiring dietary modifications.
Although LCA has not shown a direct effect on the lifespan of mice, its potential health benefits warrant further investigation. By improving metabolic efficiency, enhancing mitochondrial function, and reducing oxidative stress, LCA could hold potential for addressing age-related frailty and metabolic disorders. Researchers hope to determine whether these effects are applicable to humans or if other promising metabolites could be identified. In the meantime, this study reaffirms the importance of the gut microbiota in understanding health and aging processes.
FAQ: Lithocholic Acid (LCA), Calorie Restriction, and Aging
What is lithocholic acid (LCA)?
LCA is a secondary bile acid produced by gut bacteria. It has shown potential to improve health by activating proteins involved in metabolism and cellular health.
How does LCA relate to aging?
LCA activates AMPK, a protein that helps regulate energy and cellular metabolism, reducing muscle atrophy and improving metabolic efficiency, which are factors in aging.
Does LCA extend lifespan?
In mice, LCA did not significantly extend lifespan but improved healthspan by enhancing physical performance and reducing age-related decline.
What is calorie restriction (CR)?
CR is a dietary intervention involving reduced calorie intake without malnutrition. It has been shown to improve health and extend lifespan in many organisms.
How does CR benefit health?
CR triggers metabolic changes that improve cellular function, reduce oxidative stress, and activate pathways like AMPK, which are linked to longevity and better health.
Is calorie restriction the same as fasting?
Not exactly. CR reduces overall calorie intake consistently, while fasting involves periodic abstention from food, such as intermittent fasting. Both can trigger similar biological responses.
How does LCA mimic calorie restriction?
LCA replicates some effects of CR by activating AMPK and improving energy regulation, offering health benefits without requiring dietary changes.
Read Also: Caloric Restriction Can Help Fight Unpleasant Effects of Aging
What are the differences between CR and LCA?
CR affects the entire metabolic system, while LCA specifically targets certain pathways, like AMPK activation. LCA offers benefits without the need for strict dietary changes.
Is LCA safe?
Studies show LCA is safe at low concentrations required for health benefits, but more research is needed before human use is approved.
How does LCA affect muscle health?
LCA has been shown to enhance muscle regeneration and improve physical performance, particularly in aged mice.
What organisms have benefited from LCA in studies?
LCA has shown benefits in mice, nematodes, and fruit flies, including improved healthspan and stress resistance.
What role does AMPK play in aging?
AMPK is a protein that regulates energy and metabolism. Activating AMPK improves mitochondrial function, reduces oxidative stress, and mitigates age-related decline.
Does LCA work in humans?
LCA’s effects in humans are not yet proven. Current research is limited to animals, and further studies are needed.
What are sirtuins, and how do they relate to LCA?
Sirtuins are enzymes that regulate cellular health and longevity. LCA activates AMPK through pathways involving sirtuins.
Could LCA replace fasting or calorie restriction?
While LCA mimics some benefits of CR and fasting, it cannot fully replicate their broader systemic effects. More research is required to determine its role in dietary interventions.
What are potential future applications of LCA?
LCA could be developed into treatments for age-related conditions like frailty, metabolic disorders, and muscle atrophy.
Can LCA be taken as a supplement?
LCA is not yet available as a supplement. It is still under study, and its use in humans requires further research and regulatory approval.
How does calorie restriction compare to intermittent fasting?
CR involves consistently eating fewer calories, while intermittent fasting alternates between eating and fasting periods. Both activate similar pathways, like AMPK, but work differently.
Why is the gut microbiota important in aging research?
Gut bacteria produce metabolites like LCA that influence metabolic health and aging. Understanding these interactions could lead to new therapies.
References
Qu, Q., Chen, Y., Wang, Y. et al. Lithocholic acid phenocopies anti-ageing effects of calorie restriction. Nature (2024). https://doi.org/10.1038/s41586-024-08329-5
Qu, Q., Chen, Y., Wang, Y. et al. Lithocholic acid binds TULP3 to activate sirtuins and AMPK to slow down ageing. Nature (2024). https://doi.org/10.1038/s41586-024-08348-2
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